Sooner or later, every man in Australia runs into problems with impotency cialis australia like other bodily functions, must be in order.

Ch50-x3197 611.619

Evidence-Based RegenerativeInjection Therapy (Prolotherapy)in Sports Medicine K. Dean Reeves, MD; Bradley D. Fullerton, MD, FAAPMR;and Gaston Topol, MD use of prolotherapy, which is also called regenerative injection ther-apy (RIT), is expected to greatly accelerate in the next decade. This . The treatment of sports injuries to the point of restoration of full chapter will cover the pathology of injury; the current treatment meth- sports performance is an obvious goal in sports medicine.
ods and their limitations; and the rationale, basic science, and clinical However, healing is the preferred goal because returning studies of prolotherapy/RIT. In the latter section, it will also introduce connective tissue to normal strength allows for a durable return two areas of particularly pertinent research approaches in sports med- to full sports performance.
icine: the treatment of connective-tissue–based, career-threatening injuries and the use of high-resolution ultrasound to document healing.
Regenerative injection therapy (prolotherapy) is the injection of growth factors or growth factor production stimulants topromote the regeneration of normal cells and tissue.
PATHOLOGY OF INJURY Inflammation is not required, and scarring is not the result.
. Open-label clinical trials have been uniformly positive in During sports participations, tendons are subjected to unpredict- outcome, but double-blind clinical trials have been hampered by able mechanical loads as they transmit forces to bone. Ligaments a needling control that does not appear to be a placebo. Recent are likewise unpredictably stressed as they attempt to hold bony studies are making use of a noninjection control.
structures together at a fixed length. These mechanical loads, . Making use of consecutive patient data from athletes with when excessive, lead to unhealthy changes in tendon or ligament career-threatening injuries (i.e., chronic groin strain in soccer or structures. Numerous terms have been used to describe these rugby players) that are not responsive to other treatments is a unhealthy changes. Tendinitis implies inflammation, and tendino- recommended study approach to assess regenerative sis implies degeneration. Because inflammation and degeneration injection therapy's ability to reverse otherwise permanent can only be confirmed via biopsy, the generic term tendinopathy is conditions. This is an avenue for the critical assessment of proposed as perhaps the best descriptive term.1 regenerative injection therapy's potential.
Mechanical testing of tendon specimens has provided a stress- . Serial high-resolution ultrasound images are limited somewhat strain curve, and this curve demonstrates that collagen fibers by uniformity of technique, but they offer a way to follow healing uncrimp by 2% stretch of a tendon and microscopically rupture from regenerative injections.
beginning at 4% to 8% stretch. Beyond 8% stretch, macroscopictears are noted, and, beyond 12%, complete rupture is likely.1Repetitive submaximal loading can cause microscopic injuriesthat, through the failure of individual collagen fibers, reduce theeffective cross-sectional area of the tendon or ligament and thus make it more susceptible to failure.2 The treatment of sports injuries to the point of restoration of full sportsperformance is an obvious goal in sports medicine. Healing, how-ever, is the preferred goal because returning connective tissue to CURRENT TREATMENT METHODS AND THEIR normal strength allows for a durable return to full sports performance.
Given the advancements in the knowledge of the degenerative nature of chronic sprain or strain and the ability of high-definition Although the structure, composition, and mechanical properties of ultrasound to demonstrate the objective healing of soft tissue, the the tendon can change favorably in response to altered mechanical Chapter 50 . Evidence-based regenerative injection therapy (prolotherapy) in sports medicine loading conditions, that response is not consistently favorable, CURRENT DEFINITION AND POPULAR even in animal models. For example, although the strength ofthe insertion site may increase after long-term training,3 the max- NON—CONNECTIVE TISSUE USES OF imum stress of failure of the tendon may still decrease.4 Although appropriate training or exercise produces positive effects on tendons, long-term repetitive loading often produces Since 1995, the definition of prolotherapy has changed.22 The inflammatory mediators such as prostaglandin E2 and degradative prior definition of prolotherapy concentrated on the injection enzymes such as matrix metalloproteinase 1 and 3, even when of inflammatory solutions to induce growth. However, as our loads are within the strength limits of the tendon.5 Other factors understanding of the direct use of growth factors and multi- such as vascular supply, age, and genetics can also contribute ple ways to stimulate them has expanded, the definition of to tendinopathy, which helps explain how it can occur in seden- prolotherapy is best described simply as RIT, or, more specifically, as ‘‘the injection of growth factors or growth factor production It has been observed that rest is limited in its efficacy for bring- stimulants to promote regeneration of normal cells and tissue.''23 ing about healing in tendons in part because tendon metabolic The most widespread form of RIT is the injection of erythrocyte activity is only 13% of muscle; this leads to an extended healing growth factor (erythropoietin) to cause red cell proliferation in period that is not practical for the athlete.7 Eccentric exercise patients with chronic anemia and, more recently, in preparation appears to offer benefit in tendinopathy, and it has been used for an acute loss of blood such as occurs during surgical since the 1980s.8 Mechanical loading with certain magnitudes and frequencies may enhance tendon repair and remodeling via At this point, the question has become more complicated: fibroblast stimulation.9 Although virtually all physicians are ordering the injection of The major goal of clinicians when treating acute musculoske- growth factors for non—soft-tissue applications, what is the evi- letal injuries is to return athletes to their preinjury level of function, dence for injection of growth factor or growth factor production ideally in the shortest time possible and without compromising stimulators in sports medicine conditions such as degeneration in tissue-level healing.10 Inflammation can lead to the degradation tendons, ligaments, or cartilage? of intact collagen and to viable cell death, thus potentially increas-ing the functional deficit and recovery period. Nonsteroidalanti-inflammatory drugs (NSAIDs) are the most frequently used Growth stimulation through single pharmacologic substances for the treatment of tendinopathy.11 growth-factor injection It was logical years ago to assume, without rigorous clinical Wang and colleagues describe the ‘‘application of growth factors study or sufficient basic science backing, that inflammation that stimulate cell proliferation and extracellular matrix synthesis in might be harmful during healing, and thus treatment with anti- tendinopathy,''25 and they cited Molley and colleagues regarding inflammatory medications or the injection of such should be this description. 26 helpful. However, it has been shown in animal studies that To confirm its practical usefulness, growth-factor injection merely limiting neutrophil and leukocyte numbers after injury should cause a microscopic or macroscopic change in structure, does not necessarily improve tendon function or strength.12 a measurable mechanical improvement in the local structure, A key issue is that many cellular and subcellular events that and an improved functionality of the animal or human. All occur during the inflammatory response lead to the production three of these have not been studied systematically for any and release of a plethora of growth factors that trigger the healing single growth factor. However, primary publication findings do phase.13 During the late 1990s, basic science evidence began show the following: accumulating about the negative effects of NSAIDs on fibroblastgrowth.14 In 2001, Elder and colleagues published a sentinel arti-cle showing that a COX-2 inhibitor impaired the repair of the Microscopic or macroscopic change in structure from medial collateral ligament in rats after induced injury.15 NSAIDs single growth-factor injection likely vary in their degree of inhibition of fibroblast growth, as 1. Improved collagen structure from the injection of insulin-like Riley and colleagues showed with human patella and flexor growth factor (IGF-1) in injured or degenerated animal tendon cells.16 There is currently no randomized, controlled trial evidence of the tissue-level effects of cyclooxygenase inhibitors on 2. Increase in the amount of tendon callus in transected rat acute musculoskeletal injuries.10 Further questions regarding the Achilles tendon via the injection of bone morphogenetic pro- use of these agents have been raised given the links between teins 13 and 1428 NSAIDs and adverse cardiovascular events.10 It is fair to state 3. Increase in cell proliferation and gene expression of procolla- that care needs to be taken before presumptively interfering gen types I and III when bone morphogenetic protein 12 is with the natural processes of the healing cascade. It is now added to human patellar tendon fibroblast cultures29 accepted that, when fracture healing or spine fusion is desired,NSAIDs should be avoided.17 Current recommendations are tobegin limiting the use of certain NSAIDs in soft-tissue injuries,18 Measurable mechanical improvement in the and, as nonselective NSAIDs are further investigated, these recom- local structure due to a single growth-factor mendations may expand. Cohen and colleagues' recent publica- tion showing that both traditional and COX-specific NSAIDs 1. Improved tensile strength in transected tendons via the injec- significantly inhibited tendon-to-bone healing in a study of tion of cartilage-derived morphogenetic protein 230 rotator cuff repair in rats is particularly sobering.19 Given the ques- 2. Increase in failure load of transected and repaired Achilles tionable effects of oral anti-inflammatory drugs on soft tissue, it is tendon by a single injection of transforming growth factor b31 understandable that the anti-inflammatory effects on criticalgrowth factors are particularly profound if an anti-inflammatorysolution is injected. Thus, the intratendinous injection of Improved pain or function of the animal or human corticosteroids leads to negative rather than positive mechani- via single growth-factor injection cal effects, such as reduced tensile strength and a loss of 1. Improved walking pattern after the injection of IGF-1 in simu- viscoelasticity in tendons.20,21 lated Achilles-equivalent injury in rat tendon32 Current definition and popular non—connective tissue uses of prolotherapy/RIT( Summary of single growth-factor injection Improved pain or function of the animal or human Single growth factor use has been studied at the animal level, but from the injection of multiple growth factors via no single growth factor has been studied enough to demonstrate thrombin-activated platelet aggregates all key elements of macroscopic or macroscopic change in struc- 1. In patients with refractory tennis elbow symptoms, autolo- ture, improved mechanics, or improved pain or function in either gous blood injections eliminated pain even during strenu- animals or humans.
ous activity in 22 out of 28 subjects (LOE: D).38 Providing multiple simultaneous growthfactors by injection: Emphasis on Summary of multiple growth-factor injection using thrombin-activated platelet aggregates The provision of multiple growth factors more closely simulates The most important complexity thus far discovered about growth natural healing and is attainable via thrombin-activated platelet factors is that they work in coordination and cooperation with each concentrate. Microscopic evidence of proliferation, measurable other. For example, IGF-1 primarily stimulates fibroblast migration mechanical improvement in animals, and improved function in a and proliferation and increased collagen production; transforming human application (tennis elbow) have been described in recent growth factor b regulates cell migration and the binding tendencies studies but require repetition to confirm the results.
of collagen; vascular endothelial growth factor is heavily related toangiogenesis; platelet-derived growth factor stimulates IGF-1 pro-duction and has a role in tissue remodeling; and basic fibroblast Providing multiple simultaneous growth growth factor stimulates angiogenesis and regulates cell migration factors by stimulating their production: and proliferation. In addition, increasing the breaking energy of a Emphasis on noninflammatory dextrose healing tendon is a verifiable effect of several growth factors (IGF- Diabetic research into the effects of elevated glucose levels on 1, transforming growth factor b and platelet-derived growth human fibroblasts and other cells has provided much of the in factor).26 Tsubone and colleagues demonstrated that all major vitro basic science for such an alternative.
growth factors are expressed within 10 days after tendon A normal human cell contains only 0.1% dextrose. Normal injury but by different cell types and in different locations (i.e., human cells, when exposed to an extracellular d-glucose (dex- some in tendon cells [platelet-derived growth factor, vascular trose) concentration of as little as 0.5%, begin to produce endothelial growth factor] and some in inflammatory cells only platelet-derived growth factor,39 transforming grown factor b,40,41 [epidermal growth factor, IGF, basic fibroblast growth factor]).33 epidermal growth factor,42 basic fibroblast growth factor,43 IGF,44 Intervention with a growth-factor injection will ideally be done and connective tissue growth factor.41 Note that these growth fac- with an awareness of this healing timeline when each factor is tors are pertinent to the growth of tendon, ligament, and cartilage but not to bone.45 Dextrose from 0.5% to 10% continues to be Injecting multiple growth factors simultaneously may be done noninflammatory in nature. This is evidenced by the peripheral with combinations of artificially produced (recombinant) growth vein tolerance of hypertonic dextrose up to 10%. Ten percent dex- factors. For example, Thomopoulos and colleagues demonstrated trose has been studied sparingly because the standard concentra- that platelet-derived growth factor BB and basic fibroblast growth tion in clinical use for many years has been 12.5%, and it has factor in combination led to more proliferation effect than either generally been accepted (but not proven) that 12.5% dextrose is factor demonstrated individually.34 Another method of injecting the minimum concentration that will stimulate the inflammatory multiple growth factors simultaneously is by injecting thrombin- cascade for a more vigorous growth effect. However, it is impor- activated platelet concentrates (platelet-rich plasma), which con- tant to demonstrate that something as simple and ubiquitous in the tain the chief growth factors for connective tissue. Platelet-rich body as dextrose, when concentrated, can create a stimulation of plasma, when activated by thrombin, can also serve to stimulate growth by noninflammatory means. In short, we truly have a pro- further growth-factor production by cells that are exposed to the totype for noninflammatory, inexpensive growth stimulation. What solution.35 The results from the injection of thrombin-activated we know about noninflammatory, dextrose growth is summarized platelet concentrates are as follows.
by the following: Microscopic or macroscopic changes in structure Microscopic or macroscopic changes in structure due to from the injection of multiple growth factors through noninflammatory dextrose exposure thrombin-activated platelet aggregates 1. Cell proliferation and collagen synthesis increase has been 1. Human tendon fibroblasts exposed to activated platelet con- demonstrated in human renal cortical fibroblasts (0.6% centration react by proliferation.35 Measurable mechanical improvement in the Measurable mechanical improvement in the local structure from the injection of multiple local structure by the injection of noninflammatory growth factors via thrombin-activated platelet 1. In a pilot study, consecutive patients with anterior cruciate lig- 1. After transection repair and the injection of platelet concen- ament laxity as measured by mechanical arthrometer (KT-1000) trate in postsurgical hematoma, the Achilles tendon equivalent were injected with 9 mL of simple 10% dextrose at 0, 2, and in rats improved 30% more in strength and stiffness than did the 4 months. Subsequently, they were injected as needed if they were symptomatic at 6, 8, and 10 months (LOE: C).47 Sixteen 2. The normal patellar tendon of the rabbit, when injected directly patients were included in this trial, and 14 of 16 had moderate to with autologous blood, improved significantly in strength as severe osteoarthritis as demonstrated by osteophyte formation compared with noninjected control tendon; it also maintained and minimal (<3 mm) residual cartilage. Despite this, at 1 year, normal morphology.37 the difference in KT-1000-measured anterior displacement Chapter 50 . Evidence-based regenerative injection therapy (prolotherapy) in sports medicine from side to side improved 54%, and 9 out of 16 patients cascade at all.25 Thus, growth-factor production is either time no longer tested as having laxity using standard KT-1000 limited or does not occur at all in many sports-related injuries.
When the inflammatory cascade is stimulated by injury, celldeath and tissue stretch need to be corrected. However,growth-factor stimulation by brief inflammation does not require Improved pain or function of the animal or human significant damage to the tissue in question, and, thus, positive from the injection of noninflammatory dextrose changes in structure and function can occur without having to 1. In the previously described study involving patients with correct the negative effects of injury. The primary solutions in anterior cruciate ligament laxity and concomitant knee clinical use for inflammatory cascade initiation have been dex- osteoarthritis, patients were followed for 3 years using trose 12.5% to 25% (which becomes inflammatory at those data dropout.
levels), phenol from 0.5% to 1.25%, and sodium morrhuate pain improvement at 1 year was 40%, subjective swelling 0.1% to 1%. Research in the area of inflammation induction improved 52%, and range of motion improved by 14.1 for repair has been hampered by limited research funding as a result of the inexpensive solutions being used; differences in 2. A double-blind, placebo-controlled study was conducted on technique among investigators sometimes leading to incorrect patients with knee osteoarthritis (LOE: A).48 One hundred injection methods, which can be counterproductive (LOE: eleven knees were injected with 9 mL of 10% dextrose at 0, A)50; and the lack of a placebo control because the trauma 2, and 4 months. Knee pain had been present for an average of of needling and microbleeding have led to significant benefit more than 8 years, an average of less than 3 mm of cartilage in a number of cases (LOE: B).51 remained, and 35 out of 111 knees were bone on bone inat least one compartment. Walking pain reduced 35%, subjec-tive swelling reduced by 45%, knee buckling episodes Microscopic or macroscopic changes in structure reduced by 67%, and range-of-motion improvement was 13.2 after injection to briefly activate an inflammatory degrees with three injections of dextrose solution. Control solu- tion injection led to improvements as well, but multivariate 1. After the injection of Sylnasol into the rabbit Achilles equiva- analysis demonstrated that the dextrose solution was superior lent, 40% macroscopic thickening as compared with the oppo- (P = 0.028).
site leg control at 9 months postinjection was seen.52 3. A double-blind, placebo-controlled study of patients with 2. Macroscopic increase in the size of the attachment of rabbit finger osteoarthritis was also conducted (LOE: A).49 Subjects Achilles tendon equivalent to bone was found 9 months after were patients with finger osteoarthritis as determined by stan- the injection of Sylnasol as compared with the opposite control dard radiographic criteria and who had had pain for more than 5 years. In this study, symptomatic finger joints were injected 3. An increase in ligament fibril diameter of rabbit medial with 0.25 to 0.5 mL of 10% dextrose on both sides of each joint at 0, 2, and 4 months; and this resulted in a 42% with sodium morrhuate as compared with saline-injected improvement in grip pain and 8 degrees of improvement in the flexion range of motion. The study demonstrated the supe- 4. An increase in the number of cells in rabbit patellar and Achilles rior results of dextrose as compared with placebo with regard tendons occurs when they are injected with sodium morrhuate to pain (P = 0.027) and flexibility of joints (P = 0.003) at as compared with saline-injected control.54 Measurable mechanical improvement in local Summary of basic science and clinical research structure after injection to briefly activate an on the injection of noninflammatory dextrose inflammatory cascade Dextrose elevation to as little at 0.6% in vitro stimulates human 1. Increases in thickness of 28%, in mass of 47%, and in ligament- cells to produce key growth factors, and it has been demonstrated to-bone-junction strength of 27% were seen in rabbit medial to cause cell proliferation in renal fibroblasts. In addition, it has collateral ligament that was injected with sodium morrhuate been shown in pilot studies to tighten loose anterior cruciate as compared with saline-injected control.53 ligaments and to be safe and probably effective therapeutically 2. Increases in the diameter of rabbit patellar and Achilles tendons by two double-blind studies in patients with osteoarthritis.
were seen when they were injected with sodium morrhuate as More basic science data and the repetition of double-blind compared with saline-injected control.54 studies are recommended. If simple dextrose stimulates the 3. An increase in the strength of the rabbit patellar ligament of production of all key growth factors for ligament, tendon, and 36% was seen when it was injected once with sodium cartilage, it would be an inexpensive method of noninflammatory morrhuate 5% as compared with saline control.55 growth stimulation that may prove to be cost-effective for the 4. Injection of knees with phenol 1.25%, dextrose (glucose) 12.5%, and glycerin 12.5% (P2G)56 resulted in a highly signifi-cant decrease in laxity, as measured by AP drawer testing with Providing multiple simultaneous growth the Genucom knee apparatus.
factors by stimulating their production:Emphasis on the use of brief inflammatory Improved pain or function of the animal or cascade activation human after injection to briefly activate Although the stimulation of growth without inflammation has an inflammatory cascade some advantages, the most cost-effective approach to RIT Many studies have been conducted, but only those with 25 or may involve the use of the natural inflammatory route of more patients, the name of the solution used, the percentage growth factor stimulation. This inflammatory cascade is also of improvement, and the percentage of patients with pain briefly stimulated after a significant injury, but smaller (overuse) resolved or pain measured with a visual analog scale are summar- sports injuries create damage and do not stimulate the healing Current definition and popular non—connective tissue uses of prolotherapy/RIT( 1. Older case series in chronic back pain patients (not clearly injection for both low back and neck pain, and they suggest effi- stated as consecutive patients): cacy.67 However, double-blind studies with P2G or dextrose for a. A subjective average pain improvement of more than 50% back pain have been hampered by design flaws, including treat- with Sylnasol injection was seen among 100 adults with low ments simultaneous to injection,64,65 incomplete injection techni- back pain and sacroiliac laxity (LOE: D).57 que,66 improper patient selection leading to incorrect area b. Complete pain relief was seen in 48% of 42 adults injection,50 a control that is not a placebo,50,64-66 and the inclusion with low back pain who were injected with Sylnasol of patients who are receiving compensation for disability.50 Nevertheless, treatment in each study resulted in considerable c. The resolution of pain was seen in 82% of 267 adult patients and sustainable improvement in pain and function. Similar to acu- with low back pain who were injected with Sylnasol/ponto- puncture and manipulation, true placebo controls for studies in caine or zinc/phenol (LOE: D).59 RIT are difficult to design and expensive for investigators without d. Among 136 adults with low back pain who were injected usual funding sources for research.
with P2G, 45% experienced pain relief of more than 75%(LOE: D).60 Using regenerative injection therapy for e. Of 43 adults with low back pain who were injected with sodium morrhuate, more than 75% pain relief was experi- the treatment of connective-tissue based, ence by 72% of patients (LOE: D).61 career-threatening injuries in sports medicine 2. Older case series in chronic neck or head pain patients (not (example of inflammatory dextrose use) clearly stated as consecutive patients): Conditions that are critically blocking full performance in the ath- a. Eighty-two patients with chronic neck sprain with pain were lete and that are not amenable to surgery or that would require injected with P2G, and good to excellent pain reduction was long periods of sports cessation are suitable for consecutive patient seen in 82% of them (LOE: D).62 study using noninflammatory or inflammatory proliferant solu- b. Three hundred twenty-two patients with posttraumatic tions. An example is a study by Topol and colleagues of 24 con- headache with pain that had lasted an average of 4 years secutive elite athletes (22 rugby and 2 soccer) with career- were injected with Sylnasol, phenol/dextrose/glycerine, or threatening or, potentially, career-ending chronic groin pain pre- zinc sulfate. Good to excellent pain elimination was seen venting full sports participation that was nonresponsive to therapy among 59% of these patients (LOE: D).63 with graded sports reintroduction.23 Patients received monthly 3. Recent double-blind studies with clear methods in low back injection of 12.5% dextrose and 0.5% lidocaine in adductor and abdominal insertions and the symphysis pubis, depending on pal- a. Eighty-one patients with chronic back pain were treated pation tenderness. Injections were given until complete resolution with P2G in lidocaine or with saline. Pain improvement of or lack of improvement for two consecutive treatments occurred.
60% as compared with 23% in control was seen at 6 months A mean of 2.8 treatments were given. A reduction in the visual (P < 0.001) (LOE: A).64 analog pain scale score for pain with sports was from a mean of 6.3 b. Chronic back pain in 81 patients was treated with P2G in to 1.0 (P < 0.0001), and the reduction in the Nirschl pain phase lidocaine or saline with lidocaine. Pain improvement of 53% scale score was from 5.25 to 0.79 (P < 0.0001). Twenty out of 24 as compared with 38.5% in controls was seen at 6 months patients had no pain in the groin at an average follow-up time of (P = 0.056) (LOE: A).65 17 months, and 22 out of 24 patients were no longer restricted with c. Chronic back pain in 74 patients was treated with P2G in regard to sports participation, with a success rate of return to elite lidocaine or 0.5% lidocaine in saline. Incorrect injection sites sports of 92% (LOE: D).
using inflammatory solution led to worse results in the active Further such studies are forthcoming and will likely involve the group (5% improvement in pain) and less than a placebo use of brief inflammatory cascade stimulation; this appears to be result in the control group (15% improvement in pain) not only economical and safe, but it also has been the best studied in both animals and humans.
d. One hundred ten patients with chronic back pain were injected with dextrose 20% in 0.2% lidocaine or 0.2% lido-caine. Incomplete injection method with deep sacroiliac lig- Use of high-resolution ultrasound to document ament not treated for four sessions and inferior sacroiliac changes after proliferant injection and sacrospinous/sacrotuberous ligaments not treated.
Case 1: Complete Achilles tendon rupture A more than 50% reduction in pain was noted among 46% A sectional study was recently published by Lazzara using radio- of glucose patients as compared with 36% of control graphic imaging (magnetic resonance imaging and high-resolution patients. This difference was not significant, but results ultrasound) to document healing (LOE: E).68 The subject was a were durable at 2 years in both groups, thus indicating 26-year-old former European national soccer player who, during a strongly that needling has a therapeutic effect even without soccer tournament, ruptured her Achilles tendon with a 1.1-cm gap; proliferant included in the solution (LOE: A).66 this was treated with casting in plantarflexion and no weight bearingfor 60 days. The player refused surgery against medical advice, andshe opted for proliferant injection. Strict avoidance of weight bear- Summary of basic science and clinical research ing was continued, and RIT was performed approximately every on the injection of inflammatory proliferants 10 days for 8 treatments over 3 months using 15% dextrose RIT using an inflammatory solution has received considerable clin- and 3.75% sodium morrhuate. Palpable filling in of the gap was ical research attention for many years. Animal studies regarding noted by the second treatment visit, and, by 6 weeks (after three microscopic and macroscopic changes are missing for dextrose treatments), high-resolution ultrasound demonstrated newly formed and P2G, but they have been performed with sodium morrhuate.
tendon bridging the gap. Magnetic resonance imaging obtained at Mechanical changes in thickness, mass, and the strength of the the tenth week after treatment onset showed an intact Achilles ligament have been studied only with sodium morrhuate,53 but tendon. The athlete was jogging and aggressively stretching her tightening of knee laxity by an arthrometric measure has been Achilles tendon by 4 months. Clearly this was an instance in which demonstrated in a pilot study using P2G.56 Case reports over surgery was the preferred alternative for treatment, and yet it serves many years demonstrate the safety of inflammatory solution to illustrate the potential for radiographic confirmation of soft-tissue Chapter 50 . Evidence-based regenerative injection therapy (prolotherapy) in sports medicine healing by brief inflammatory cascade stimulation. Radiographicfindings are found in the original source manuscript, but the follow-ing cases have ultrasound images available.
Case 2: A 61-year-old male golfer with extensortendinosisThis patient had 3 years of left lateral elbow pain and 2 years ofextension deficit in his elbow range, and he had received 3 steroidinjections. His chief complaint was difficulty playing golf. On exam-ination, he had a firm end feel to extension at 10 degrees, and there was pain over the common extensor insertion and the radial head.
Magnetic resonance imaging was diagnostic for common extensortendinosis. Figure 50.1 shows a high-resolution ultrasound of theelbow in pronation at three different points in time. The images onthe left and right are identical, but the images on the right are labeledanatomically: A is the radial head; the line labeled B is the bonynarrowing between the lateral epicondyle and the capitulum of the humerus (the rounded portion of the end of the humerus that articu-lates with the radial head); C represents movement up the bonetoward the lateral epicondyle; and E, which is only seen clearly inthe bottom right view, is along the side of the capitulum of thehumerus, which is better seen after proliferant injection. This patientreceived 9 injection sessions beginning on November 29, 2004.
Several treatments were with dextrose 15%, and two included 0.5% Patellar tendinosis changes with regenerative injection sodium morrhuate. Common extensor entheses, annular ligament, radial collateral ligament, and capsular entheses were injected. Theclinical result by August 15, 2005, was an extension range gain to 3 degrees, no pain on palpation, and no functional limitations. The serial ultrasounds demonstrate hypoechoic (dark) areas of tissue sep- Case 3: A cyclist with patellar tendinosis aration or insufficiency and edema (D is the common extensor A 40-year-old male competitive cyclist was first seen in November tendon). By the time of the ultrasound on August 15, the entire 2004 because he could not run or handle rough terrain or sustained region above the bones was more densely populated with organized hills as a result of knee pain. He had history of remote distal realign- connective tissue fibers. It is interesting to note that the capitulum ments (patellofemoral tracking type surgery). Pain was at the inferior (although it is not seen well on the first two ultrasounds) appears to patella and over the tibial tuberosity. He was treated on February 17, move closer to the radial head, and dynamic ultrasound showed that 2005, and April 21, 2005, with an injection of 15% dextrose over the radial head subluxation ceased as treatment progressed. This appears patellar tendon origin on the inferior patella pole and its insertion to correlate with the range-of-motion loss at treatment onset that also over the tibial tuberosity. Complete symptom resolution occurred resolved with treatment. Note also that, although bony growth factors with the last follow-up evaluation on January 23, 2006, at which are not stimulated by injection, the typical effects after treatment with point the patient was training for the racing season. Figure 50.2 proliferant include a periosteal reaction that allows for the better visu- shows a high-resolution ultrasound at the time of the first two ses- alization of contours of bone and an increased echogenicity of the soft sions and at 6-month follow-up on October 19, 2005. On the right tissue as edema resolves and tissue becomes more tightly packed.
side of the figure are the same images but with red outlining thepatellar tendon to depict its thickness. In addition, the yellow circlesurrounds an area of hypoechogenicity. From February 17, 2005,through October 19, 2005, an increase in the echogenicity of thetendon is demonstrated.
Case 4: An 85-year-old male patient with bicipitaltendinosisAlthough this patient was not an athlete in the competitive sense,he was quite active for 85 years of age. This patient had chronic,worsening anterior shoulder pain. The initial examination on May16, 2005, showed that the bicipital tendon and the surroundingregion were painful to palpation. The patient received three treat-ments consisting of the injection of 15% dextrose around the bici-pital region on May 27, June 17, and July 8, 2005, without regardfor whether the injections were precisely extratendinous or intra-tendinous because the injections are always given on bone insuccessive rows. Figure 50.3 shows a longitudinal ultrasoundthrough the bicipital tendon at the time of the first evaluationand at follow-up on August 18, 2005. On the right side are thelabeled images. Deltoid muscle thickness is represented by A inthe figure, and the degree of decrease in the swelling in the deltoid Extensor tendinosis changes with regenerative injection is easily seen by the decrease in thickness by August 18. The long head of the bicipital tendon is outlined in yellow on the right, and, Summary of basic science and clinical work in prolotherapy/regenerative injection therapy( SUMMARY OF BASIC SCIENCE AND CLINICALWORK IN PROLOTHERAPY/REGENERATIVEINJECTION THERAPY Single growth-factor use is not likely to be fruitful as a result of theimportance of cooperation among various growth factors. Multiplegrowth-factor provision by platelet concentrate is promising butlimited in the area treatable by the volume of purified platelet con-centrate. Noninflammatory dextrose appears to provide clinicalbenefit in both joint and ligament applications, and it is quite inex-pensive. Inflammatory proliferant injection should be more potentthan noninflammatory dextrose injection due to the multiplicationeffects of stimulating the inflammatory cascade. However, the occa-sional truly inflammatory process may be flared by such inflamma-tory proliferant solutions. Many studies have been performed toaddress growth stimulation and have covered all of the describedapproaches, and many more are desired. The biggest forces drivingprolotherapy/RIT toward common usage are its low cost, its abilityto actually tighten loose connective tissue, its promising effects on Biceps tendinosis changes with regenerative injection therapy joints, its potential for widespread use in athletics to truly repair overuse injuries and partial tears, and its ability to objectively dem-onstrate radiographic healing with the increasing use of musculos- between May and August, the tendon changes shape to become keletal ultrasound. It is likely that this will be the century for RIT in more linear as edema decreases in the proximal portion. Again, an sports medicine. Although methods for prolotherapy performance echogenicity increase throughout the region is seen. The point are not the intent of this chapter, Boxes 50.1 and 50.2 present marked C is the proximal humerus at the distal onset of the bici- indications, contraindications, pitfalls, and complications for pital groove. Figure 50.4 is a transverse ultrasound image at the the interested reader. A recommended text is by Hackett and col- distal bicipital groove showing the subscapularis entheses as A, the leagues,69 and recent chapters addressing technique are found lesser tubercle at B, the greater tubercle labeled E, and the deltoid in Pain Procedures in Clinical Practice70 and Waldman's Pain thickness labeled F. The area labeled C is a hypoechoic area just outside the biceps tendon, and it is seen to decrease in echogeni-city between May 16 and August 18, 2005. The point marked D isthe biceps tendon itself in transverse view. The decrease in edemaboth in the overlying tissue and in the tendon itself is clearly seenalong with an increase in the density of the bicipital tendon.
Cases 2 through 4 were performed in the same clinic by the same clinician. At each follow-up, the ultrasound examination, the patient Box 50.1: Indications and Contraindications position, the probe pressure, and the machine settings (including for Regenerative Injection Therapy transmit and gain) were reproduced exactly as they had beenduring the prior study. In other words, the amount of sound transmit- ted by the probe was the same at each study; thus, the increase in 1. Pain from chronic sprain or strain impairing athletic performance tissue signal is felt to be related solely to an increase in tissue density.
2. Connective tissue laxity impairing athletic performance (i.e., shoulder capsular laxity, wrist laxity, anterior cruciate ligamentlaxity, repetitive ankle inversion tendency) 3. Pain from career sport or activity impairing rest and quality of life Contraindications1. Potential local infection 2. Allergies (i.e., to local anesthetics if they are used or to shellfish if sodium morrhuate is used); phenol is used digestively and can haveno allergy; corn allergy does not appear to be an issue or very rarely(dextrose is made from corn) 3. Local inflammatory process: noninflammatory proliferants would be suggested, potentially after deinflammation with steroid 4. Injection of a prosthetic joint (on principle as a result of increased morbidity in the event of a rare infection); injection around a prostheticjoint as a result of external joint pain sources may be necessary 5. Patient on anticoagulation with an elevated international normalized ratio (it is preferable to have coumadin held before injection similarto other injection procedures); intraspinal hematomas have neverbeen reported but hemarthrosis and hematomas have been either inthose with an elevated international normalized ratio or in those Biceps tendinosis changes with regenerative injection therapy (transverse view).
Chapter 50 . Evidence-based regenerative injection therapy (prolotherapy) in sports medicine Woo SL, Gomez MA, Amiel D, et al: The effects of exercise on the biomechanicaland biochemical properties of swine digital flexor tendons. J Biomech Eng Box 50.2: Pitfalls and Complications of Regenerative Injection Therapy Soslowsky LJ, Thomopoulos S, Tun S, et al: Overuse activity injures the supraspinatustendon in an animal model: a histologic and biomechanical study. J Shoulder Elbow Needling Risks (Depending on the Portion of the Body Being Treated) Surg 2000;9:79-84.
Kjaer M: Role of extracellular matrix in adaptation of tendon and skeletal muscle to 1. Septic joint: This appears to be similar to steroid injection risk at a mechanical loading. Physiol Rev 2004;84:649-698.
rate of 1 in 10,000 to 1 in 40,000 for intra-articular injections.
Young JS, Kumta SM, Maffulli N: Achilles tendon rupture and tendinopathy: manage- 2. Spinal headache: This is estimated to occur in 1 in 300 low back ment of complications. Foot Ankle Clin 2005;10:371-382.
procedures with lumbosacral junction treatment.
Zernicke RF, Garhammer J, Jobe FW: Human patellar-tendon rupture. J Bone Joint SurgAm 1977;59:179-183.
3. Peripheral nerve contact: As a result of the ubiquitous presence of Stanish WD, Rubinovich RM, Curwin S: Eccentric exercise in chronic tendinitis. Clin small nerve branches and the occasional contact of larger nerve Orthop Relat Res 1986;208:65-68.
branches, nerve irritation will occur rarely with treatment. Burning Kannus P, Jozsa L, Natri A, Jarvinen M: Effects of training, immobilization and remo- pain reactions are typical, lasting from days to several months.
bilization on tendons. Scand J Med Sci Sports 1997;7:67-71.
Warden SJ: Cyclo-oxygenase-2 inhibitors: beneficial or detrimental for athletes with 4. Pneumothorax: This is estimated to occur in about 1 in 20,000 acute musculoskeletal injuries? Sports Med 2005;35(4):271-283.
needle insertions in the thoracic region.
Saltzman CL, Tearse DS: Achilles tendon injuries. J Am Acad Ortho Surg 1998;6:316-325.
Marsolais D, Cote CH, Frenette J: Nonsteroidal anti-inflammatory drug reduces neu-trophil and macrophage accumulation but does not improve tendon regeneration. Lab 1. Stiffness and soreness after treatment: Typically this will last from 1 to 3 days but will occasionally last longer. It is important to have Marsolais D, Frenette J: Inflammation and tendon healing. Med Sci 2005;21(2):181- patient contact the physician if flare lasts for more than 10 days because this can be counterproductive in patients with chronic pain.
Sun R, Gimbel HV, Liu S, et al: Effect of diclofenac sodium and dexamethasone oncultured human Tenon's capsule fibroblasts. Ophthalmic Surg Lasers 1999; 2. Allergy: Any physician performing injection should prepare for such a reaction and check, in particular, for shellfish allergy before Elder CL, Dahners LE, Weinhold PS: A cyclooxygenase-inhibitor impairs ligament administering sodium morrhuate.
healing in the rat. Am J Sports Med 2001;29(6):801-810.
3. Chemical arachnoiditis: This appears to occur with midline injection Riley GP, Cox M, Harrall RL, et al: Inhibition of tendon cell proliferation and matrixglycosaminoglycan synthesis by non-steroidal anti-inflammatory drugs in vitro. J Hand only of stronger proliferants such as phenol and when boluses in the midline exceed 0.5% or the concentration of phenol exceeds Dahners LE, Mullis BH: Effects of nonsteroidal anti-inflammatory drugs on bone 1.25%. However, this is rare and almost always temporary.
formation and soft-tissue healing. J Am Acad Orthop Surg 2004;12(3):139-143.
Nevertheless, paraspinal injections anywhere near the neural Paoloni JA, Orchard JW: The use of therapeutic medications for soft-tissue injuries in foramina should be with a lesser solution or with small doses and sports medicine. Med J Aust 2005;183(7):384-388.
a careful emphasis on concentration limits.
Cohen DB, Kawamura S, Ehteshami J, et al: Indomethacin and celecoxib impairrotator cuff tendon-to-bone healing. Am J Sports Med 2006;34(3):362-369.
Kennedy J, Willis RB: The effects of local steroid injections on tendons: a biomecha-nical and microscopic correlative study. Am J Sports Med 1976;4:11-21.
Nirschl RP: Elbow tendinosis/tennis elbow. Clin Sports Med 1992;11(4):851-870.
Reeves KD: Technique of prolotherapy. In Lennard TA (ed): Physiatric Procedures in Clinical Practice. Philadelphia, Hanley and Belfus, 1995, pp 57-70.
Topol GA, Reeves KD, Hassanein K: Efficacy of dextrose prolotherapy in elite malekicking-sport athletes with chronic groin pain. Arch Phys Med Rehabil 2005; Suboptimal healing may lead to elimination of symptoms and return to full sport. However, suboptimal tissue leaves the athlete Price S, Pepper JR, Jaggar SI: Recombinant human erythropoietin use in a critically ill with a decrease in tensile strength of the damaged tissue or relative Jehovah's witness after cardiac surgery. Anesth Analg 2005;101(2):325-327.
laxity with stretch of fixed length nerve endings. These effects Wang JH, Losifidis MI, Fu FH: Biomechanical basis for tendinopathy. Clin Orthop RelatRes 2006;443:320-322.
increase susceptibility of the athlete to repetitive injury or rupture, Molloy T, Wang Y, Murrell G: The roles of growth factors in tendon and ligament can reflexly inhibit full performance, and create a regional stiff- healing. Sports Med 2003;33:381-394.
ness, even without associated pain. All these are threats to a full Dahlgren LA, van der Meulen MC, Bertram JE, et al: Insulin-like growth factor-1 and enjoyable carrer for the elite athlete and can increase the improves cellular and molecular aspects of healing in a collagenase-induced potential for chronic pain after retirement. Much remains to be model of flexor tendinitis. J Orthop Res 2003;20:910-919.
discovered about stimulating regeneration and blocking degenera- Aspenberg P, Forslund C: Bone morphogenetic proteins and tendon repair. Scand JMed Sci Sports 2000;10:372-375.
tion after acute or chronic sports injuries. However, current agents Fu SC, Wong YP, Chan BP, et al: The roles of bone morphogenetic protein (BMP) 12 in appear capable of restoring connective tissue organization, as seen stimulating the proliferation and matrix production of human patellar tendon fibro- by ultrasonographic confirmation. The choice of agents will blasts. Life Sci 2003;72:2965-2974.
depend on such factors as speed of healing needed, cost efficacy, Forslund C, Aspenberg P: Improved healing of transected rabbit Achilles tendon after and the stage of the season.
a single injection of cartilage-derived morphogenetic protein-2. Am J Sports Med2003;31:555-559.
Education on the basic science of connective tissue injuries and Kashiwagi K, Mochizuki Y, Yasunaga Y, et al: Effects of transforming growth factor-beta training on how to choose and apply the most cost-effective 1 on the early stages of healing of the Achilles tendon in a rat model. Scand J Plast method of regenerative injection therapy will best be achieved Reconstr Surg Hand Surg 2004;38(4):193-197.
in the context of routine physical medicine and rehabilitation Kurtz CA, Loebig TG, Anderson DD, et al: Insulin-like growth factor I accelerates training. Ultrasonographic documentation of lesion reversal may functional recovery from Achilles tendon injury in a rat model. Am J Sports Med ultimately be used to monitor healing efficacy in this age of Tsubone T, Moran SL, Amadio PC, et al: Expression of growth factors in canine flexor tendon after laceration in vivo. Ann Plast Surg 2004;53(4):393-397.
Thomopoulos S, Harwood FL, Silva MJ, et al: Effect of several growth factors on canine flexor tendon fibroblast proliferation and collagen synthesis in vitro. J Hand Surg2005;30(3):441-447.
Anitua E, Andia I, Sanchez M, et al: Autologous preparations rich in growth factors Wang JH: Mechanobiology of tendon. J Biomech 2006;39:1563-1582.
promote proliferation and induce VEGF and HGF production by human tendon cells in Kirkendall DT, Garrett WE: Function and biomechanics of tendons. Scand J Med Sci culture. J Orthop Res 2005;23(2):281-286.
Aspenberg P, Virchenko O: Platelet concentrate injection improves Achilles tendon Altay T, Gunal I, Ozturk H: Local injection treatment for lateral epicondylitis.
repair in rats. Acta Orthop Scand 2004;75(1):93-99.
Clin Orthop 2002;398:127-130.
Taylor MA, Norman TL, Clovis NB, et al: The response of rabbit patellar tendons after Hackett GS. Ligament and Tendon Relaxation Treated by Prolotherapy, 3rd ed.
autologous blood injection. Med Sci Sports Exerc 2002;34(1):70-73.
Springfield, IL, Charles C. Thomas, 1956.
Edwards SG, Calandruccio JH: Autologous blood injections for refractory lateral epi- Liu YK, Tipton CM, Matthes RD, et al: An in-situ study of the influence of a sclerosing condylitis. J Hand Surg 2003;28A(2):272-278.
solution in rabbit medial collateral ligaments and its junction strength. Connect Di Paolo S, Gesualdo L, Ranieri E, et al: High glucose concentration induces the Tissue Res 1983;11:95-102.
overexpression of transforming growth factor-beta through the activation of a platelet- Maynard JA: Morphological and biochemical effects of sodium morrhuate on tendons.
derived growth factor loop in human mesangial cells. Am J Pathol 1996; J Orthop Res 1985;3(2):236-248.
Aneja A, Karas SG, Weinhold PS, et al: Suture plication, thermal shrinkage, and Oh JH, Ha H, Yu MR, et al: Sequential effects of high glucose on mesangial cell sclerosing agents: Effects on rat patellar tendon length and biomechanical strength.
transforming growth factor-beta 1 and fibronectin synthesis. Kidney Int 1998; Am J Sports Med 2005;33(11):1729-1734.
Ongley MJ, Dorman TA, Eek BC, et al: Ligament instability of knees: a new approach to Murphy M, Godson C, Cannon S, et al: Suppression subtractive hybridization identifies treatment. Man Med 1988;3:152-154.
high glucose levels as a stimulus for expression of connective tissue growth factor and Bahme BB: Observations on the treatment of hypermobile joints by injection. J Am other genes in human mesangial cells. J Biol Chem 1999;274(9):5830-5834.
Osteopath Assoc 1945;45:101-109.
Fukuda K, Kawata S, Inui Y, et al: High concentration of glucose increases mitogenic Blaschke JA: Conservative management of intervertebral disc injuries. J Okla State responsiveness to heparin-binding epidermal growth factor-like growth factor in rat Med Assoc 1961;54:494-501.
vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1997;17(10): Myers A: Prolotherapy treatment of low back pain and sciatica. Bull Hosp Joint Dis Ohgi S, Johnson PW: Glucose modulates growth of gingival fibroblasts and periodon- Peterson TH: Injection treatment for back pain. Am J Orthop Surg 1963;246:320-321.
tal ligament cells: correlation with expression of basic fibroblast growth factor.
Schwartz RG, Segedy N: Prolotherapy: a literature review and retrospective study.
J Periodontal Res 1996;31(8):579-588.
J Neurol Orthop Med Surg 1991;12:220-223.
Pugliese G, Pricci F, Locuratolo N, et al: Increased activity of the insulin-like growth Hackett GS, Huang TC: Prolotherapy for headache. Headache 1962;2:20-28.
factor system in mesangial cells cultured in high glucose conditions. Relation to Kayfetz DO, Blumenthal LS, Hacket GS, et al: Whiplash injury and other ligamentous headache: its management with prolotherapy. Headache 1963;3:21-28.
Ongley MJ, Klein RG, Dorman TA, et al: A new approach to the treatment of chronic Woo SL, Hildebrand K, Watanabe N, et al: Tissue engineering of ligament and tendon low back pain. Lancet 1987;2:143-146.
healing. Clin Orthop Relat Res 1999;367S:312-314.
Klein RG, Bjorn CE, DeLong B, et al: A randomized double-blind trial of dextrose- Jones SC, Saunders HJ, Qi W, et al: Intermittent high glucose enhances cell growth glycerine-phenol injections for chronic low back pain. J Spinal Disord 1993;6:23-33.
and collagen synthesis in cultured human tubulointerstitial cells. Diabetologia Yelland MJ, Glasziou PP, Bogduk N, et al: Prolotherapy injections, saline injections, and exercises for chronic low-back pain: a randomized trial. Spine 2004;29(1):9-16.
Reeves KD, Hassanein K: Long term effects of dextrose prolotherapy for anterior Rabago D, Best TM, Beamsley M, Patterson J: A systematic review of prolotherapy for cruciate ligament laxity: a prospective and consecutive patient study. Altern Ther chronic musculoskeletal pain. Clin J Sport Med 2005;15(5):376-380.
Health Med 2003;9(3):58-62.
Lazzara MA: The non-surgical repair of a complete Achilles tendon rupture by pro- Reeves KD, Hassanein K: Randomized prospective double-blind placebo-controlled lotherapy: biological reconstruction. A case report. J Orthop Med 2005;27(3): study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Altern Ther Health Med 2000;6(2):68-80.
Hackett GS, Hemwall GA, Montgomery GA. In Hemwall Gustav A (ed): Ligament and Reeves KD, Hassanein K: Randomized prospective placebo controlled double blind Tendon Relaxation Treated by Prolotherapy, 5th ed. IL, Oak Park, 1992.
study of dextrose prolotherapy for osteoarthritic thumbs and finger (DIP, PIP and Reeves KD: Prolotherapy: basic science, clinical studies, and technique. In Lennard trapeziometacarpal) joints: evidence of clinical efficacy. J Altern Complement Med TA (ed): Pain Procedures in Clinical Practice, 2nd ed. Philadelphia, Hanley and Belfus, 2000, pp 172-190.
Dechow E, Davies RK, Carr AJ, et al: A randomized, double-blind, placebo-controlled Reeves KD: Prolotherapy: injection of growth factors or growth factor production trial of sclerosing injections in patients with chronic low back pain. Rheumatology stimulants to grow normal cells or tissue. In Waldman SD (ed): Pain Management.
Philadelphia, Elsevier, 2006, pp 1106-1127.


Final Accepted Version C-00463-2003.R1 Characterisation of T-type calcium current and its contribution to electrical activity in the rabbit urethra J. E. Bradley, U. A. Anderson, S. M. Woolsey, K. D. Thornbury, N. G. McHale & M. A. Hollywood Smooth Muscle Group, Department of Physiology, The Queen's University of Belfast, 97Lisburn Road, Belfast, BT9 7BL, N. Ireland.

Issue 5, March 2016 OQNHE 3rd INTERNATIONAL OQNHE conference, Benchmark, Test Blueprint and more. Hello friends.Oman Quality Network in Higher Education is proud to announce the publication of the fifth issue of its e-newsletter. This issue provides a glimpse into the activities conducted by the Network through some articles related to the higher