Platelet-rich plasma (PRP) is defined as a platelet-rich concentrate with platelet levels greater than the baseline platelet count in whole blood. This autologous derived substance, also referred to as autologous platelet-derived growth factors, platelet gel, platelet-rich concentrate, autogenous platelet gel, plasma rich in growth factors, or platelet releasate, has been proposed for the treatment of multiple conditions to enhance healing. Theoretically, these growth factors function as a mitogen for fibroblasts, smooth muscle cells, osteoblasts, and vascular endothelial growth factors.2,3 While PRP may work by activating the innate immune response and stimulating tissue anabolism, its precise mechanism of action is still unclear.3 The role that white blood cells may play is particularly unclear, as the immune cells may act as antimicrobial and/or proinflammatory agents. Furthermore, PRP preparations are not standardized and exhibit wide variability in platelet and white blood cell concentrations and the use of thrombin activators. How variations in PRP composition may impact clinical outcomes is also unclear.4 Mishra et al.5 proposed classifying these types in 3 categories: the presence of white blood cells (e.g., leukocyte-rich or - poor), whether the PRP is activated or not, and the concentration of platelets.
Several factors have contributed to the growing popularity of biologic therapies despite the dearth of high-quality clinical trials supporting their use. Musculoskeletal conditions are both severe and prevalent. Conventional treatment, for the most part, is lacking in success. Platelet-rich plasma has the appeal of a simple, minimally invasive treatment with little regulation, which can be easily administered via local injection by clinicians. In addition, the biotechnology companies that manufacture the equipment used to assist in producing these therapies have conducted nationwide marketing directly to clinicians and consumers, touting success with high profile professional athletes.
A collection and preparation system is used to collect a small sample of blood at the patient’s point of care or clinical laboratory. The systems used for preparing autologous platelet-derived growth factors are Federal Drug Administration (FDA) approved under the 510(k) process. While the technology to obtain PRP is FDA-approved, PRP itself is currently not indicated for direct injection. Centrifugation of this blood sample separates the denser red cells from the plasma. The plasma components are divided into a buffy coat and an adjacent layer. The buffy coat contains leucocytes and most of the platelets. The adjacent layer of plasma is less rich in platelets and has few leucocytes.6
There are various techniques used to harvest the buffy coat, the adjacent plasma layer, or both. Some methods concentrate the buffy coat further using a "double spin" technique. This process involves a second centrifugation of the supernatant obtained from the initial centrifugation and produces a more concentrated sample. Depending on the method used, the number of platelets in PRP varies between 1 and 9 times that of whole blood. Techniques that produce higher platelet concentrations (e.g., double spin) typically produce higher leucocyte concentrations. Hence, PRP is often referred to as leucocyte rich (LR-PRP) or leucocyte poor (LP-PRP).7
Some practitioners add exogenous calcium salts to the PRP before administration to ensure platelet activation, while others assume that contact with tendon collagen will suffice.8 PRP composition can also differ by donor age, health status, gender, and even time of day when collected.9
Administration protocols also vary per type of injury. PRP may be injected using a peppering technique, whereby the PRP is injected with several penetrations of the tendon from a single skin penetration10 or may be injected directly into a joint. The frequency of injections varies. For tendon conditions, one to four intratendinous injections are given over two weeks. Joint conditions typically have three injections within a 6-month time frame, usually performed 3-4 weeks apart.11 A local anesthetic is often utilized, and an ultrasound (US) may provide guidance. Local anesthetics may compromise the efficacy of the PRP.12 Patients need to refrain from non-steroidal anti-inflammatory medications for two weeks before harvesting due to the effect on platelet function.13 There are no accepted exercise protocols or return-to-sport guidelines following PRP treatment. PRP usage can be broadly separated into three categories which will be discussed further: primary treatment for tendinopathies/non-tendon inflammation, the surgical augmentation of repairs, and primary treatment for osteoarthritis.
Primary Treatment for Tendinopathies/Non-Tendon Inflammation
The evidence regarding PRP treatment of tendinopathies/non-tendon inflammation includes multiple randomized control trials (RCT) and systematic reviews with meta-analyses (SR/MA). Typical outcomes are pain relief and functional status. The literature is clustered around usage for the following: lateral epicondylitis (LE), carpal tunnel syndrome (CTS), rotator cuff (RC) tears, plantar fasciitis (PF), Achilles tendinopathy (AT), and patellar tendinopathy (PT).
Andia3 conducted a review of over 1500 patients treated with PRP for tendinopathies in 58 studies evenly distributed between lower and upper extremities. Six of these were of Level 1 Evidence Quality, primarily utilizing LR-PRP. Given the heterogeneity in tendinopathies and preparation of PRP, they concluded the data was insufficient to make a recommendation for treatment.
A 2014 systematic review of 19 randomized and quasi-randomized trials of PRP for musculoskeletal soft tissue injuries, involving 1088 participants, noted no difference in clinically meaningful outcomes.14 The quality of these studies was limited by small numbers of participants, non-standardization of treatment preparation, and outcome measures that focused on subjective pain scores rather than more objective measures of tendon tissue healing or improvement in function. Additional limitations were the lack of accounting for other confounding factors, such as differentiation between an overuse injury vs. degenerative tendon rupture and whether or not bursal involvement was present. As previously stated, the role of leukocytes in tendon healing is controversial, but the few randomized trials that differentiated between LR-PRP and LP-PRP suggest that LR-PRP may be more effective in the treatment of tendinopathies.15 The evidence, examined in detail below, is insufficient to determine the benefit of PRP on health outcomes for tendinopathies/non-tendon inflammation.
Lateral epicondylitis (LE), commonly known as “tennis elbow”, affects approximately 1-3% of the population, with men and women equally represented. An overuse injury is characterized by angiofibroblastic hyperplasia.16 Patients typically complain of pain for 6-12 weeks, but in some cases, pain can persist for up to 2 years. Eighty percent recover with no treatment.17 Although self-limiting, this condition still results in disability, lost productivity, and health care utilization costs. Conservative efforts include non-steroidal anti-inflammatory drugs, orthotic devices, physical therapy, glucocorticoid injection, and extracorporeal shock wave therapy.
The Washington State Health Care Authority18 recently published a comprehensive health technology assessment, in which they examined the efficacy and safety of PRP when used in the patient with recalcitrant LE (> 6 months duration). The authors included 5 RCTs that compared PRP with corticosteroid injection (CS)19-23 and 2 RCTs that compared PRP with an anesthetic.10,24 In the short term, neither CS nor local anesthetic differed from PRP regarding pain or function. While in the intermediate term, low quality evidence suggested PRP was superior to CS (P = 0.007) for pain and function, but not local anesthetic (P = 0.08). In the long term, low quality evidence suggested PRP and CS were not different (P = 0.11), but PRP was superior to local anesthetic (P < 0.00001).
Stratification of systematic review/meta-analysis (SR/MA) of 8 randomized controlled trials (RCT) by Mi et al.25 found that treatment with PRP appeared to be more effective than CS at intermediate term (12 weeks) and long term (6 months and one year) intervals, whereas CS demonstrated superiority in the short term (2-8 weeks).
Montalvan et al.26 conducted a RCT, which found that 2 US guided PRP injections in 25 patients were no more efficacious than saline injections at 6 and 12 months on either pain score reduction or functional improvement. Mishra et al.10 conducted a RCT of 112 patients with LE comparing LR-PRP and bupivacaine injections, concluding there were no differences in global pain scores at 12 weeks. Schoffl found no significant difference between PRP vs. saline in functional improvement at three months in a double-blinded (DB) RCT of 50 patients.27
Li et al.28 conducted a systematic review and meta-analysis to compare the effectiveness of PRP vs. corticosteroids for treatment of patients with lateral elbow epicondylitis. Five RCTs were included in the meta-analysis. Authors concluded local corticosteroid injections demonstrated significantly lower DASH scores compared with local PRP treatments during short-term follow-up (4 weeks and 8 weeks post-treatment). Whereas, at long-term follow-up (24 weeks post-treatment), PRP injections significantly improved pain and function more than corticosteroid injections. Study limitations include small sample size, varying follow-up times, and high to unclear risk of bias in included trials.
Simental-Mendia et al.29 performed a systematic review and meta-analysis to compare the effects of PRP injection vs. placebo (saline injection) on pain and joint function in lateral epicondylitis in randomized placebo-controlled trials. Five RCTs comprised of 276 patients were included. Authors reported no difference in improvement regarding joint pain and function between the PRP and placebo injection groups. Study limitations include small sample size, high heterogeneity across trials, possible confounding, lack of technique protocols, and various tools used to report outcomes.
Tang et al.30 conducted a systematic review, pairwise and network meta-analysis of RCTs to compare PRP, autologous blood (AB) and corticosteroid injections for lateral epicondylitis. Twenty RCTs with 1271 patients were included in this study. Pain intensity, strength, and function were outcomes measured with standardized assessment tools. Authors concluded PRP achieved more improvement than the comparators among pain intensity and function long term whereas, corticosteroids achieved the most improvement in the short term follow up.
Linnanmaki et al.31 performed a parallel group, randomized, controlled participant- and assessor-blinded study including adults with clinically diagnosed LE. The participants were recruited from a secondary referral center after not responding to initial nonoperative treatment. One hundred nineteen participants were randomized to receive PRP, saline, or autologous blood. Follow-up visits were at 4, 8, 12, 26, and 52 weeks after the injection. The primary outcome measure was improvement in pain, measured with Visual Analog Scale (VAS) in a 0-10 range, without specification as to whether the pain was activity related or at rest, from baseline to 52 weeks. The secondary outcomes were the Disabilities of the Arm, Shoulder, and Hand (DASH) score. There were no clinically significant differences in the mean VAS pain or DASH scores among the groups at any timepoint. Level of evidence Level II therapeutic study.
One small study looked at PRP as an alternative to operative management. Mayo Clinic32 conducted a nonrandomized trial where 15 patients were treated with a series of 2 LR-PRP injections, and 18 patients were treated with surgery. Outcome measures included time to pain-free status, time to a full range of motion (ROM), the Mayo Elbow Performance Score (MEPS), and the Oxford Elbow Score (OES). Successful outcomes were observed in 80% of patients treated with PRP and 94% of those treated operatively (P = 0.37). A statistically significant improvement was noted in both time to full ROM (42.3 days for PRP vs. 96.1 days for surgery; P < 0.01) and time to pain-free status (56.2 days for PRP vs. 108.0 days for surgery; P < 0.01). No significant difference was found in return-to-activity rates, overall successful outcomes, MEPS scores, or OES scores.
Overall, the current evidence suggests that PRP may yield some long-term benefits that are not apparent before six months, particularly when compared with CS. However, the quality of evidence is limited by sample size too small to be sufficiently powered and lack of correction for multiple comparisons.
Carpal Tunnel Syndrome
Literature reports comparing 5% Dextrose in Water (D5W), CS and PRP injections with non-surgical management of carpal tunnel syndrome (CTS) were systematically reviewed by Lin et al.33 Ten studies with 497 patients comparing five treatments (D5W, PRP, splinting, CS, and normal saline (NS)) were included. The primary outcome was the standardized mean difference (SMD) of the symptom severity and functional status scales of the Boston Carpal Tunnel Syndrome Questionnaire 3 months after injections. The results showed that D5W injection was likely to be the best treatment, followed by PRP injection, in terms of clinical effectiveness in providing symptom relief. For functional improvement, splinting was ranked higher than PRP and D5W injections. Lastly, CS and saline injections were consistently ranked fourth and fifth in terms of therapeutic effects on symptom severity and functional status. D5W and PRP injections are more effective than splinting and corticosteroid or saline injection for relieving the symptoms of CTS. Compared with splinting, D5W and PRP injections do not provide better functional recovery.33
In 2009, the UK National Institute for Health and Clinical Excellence (NICE) stated that current evidence on PRP's safety and efficacy for tendinopathy is inadequate in quantity and quality.34 This was reiterated in recent systematic reviews of the evidence.35
Rotator Cuff Tears
Rotator cuff (RC) tears are a common clinical problem in the geriatric population with rates as high as 80% in those over age 80, and debate exists over how to best provide pain relief and restore shoulder function. Treatment options can be broadly divided into non-surgical and surgical, with most patients initially placed on a trial of conservative therapy. A primary concern with RC repairs in older patients is decreased vascularity and healing potential of the tendons. With more inadequate healing, there is an increased risk of re-rupture, and older age is associated with higher rates of failure following repair. For those with irreparable RC tears, low functional demand, or interest in nonoperative management, there are many non-surgical treatments to consider, including rehabilitation and injections of CS, hyaluronic acid (HA), and PRP.
Several meta-analyses have been published, but none have focused exclusively on level 1 RCTs until Chen’s work.36
Eighteen Level I studies were evaluated. The VAS scores were significantly improved short term (-0.45 [95% CI, - 0.75 to -0.15]; P < 0.01). Sugaya grade IV and V retears in PRP-treated patients were significantly reduced long term (odds ratio [OR], 0.34 [95% CI, 0.20-0.57]; P < 0.01). In PRP-treated patients with multiple tendons torn, there were reduced odds of retears (OR, 0.28 [95% CI, 0.13-0.60]; P < 0.01). Long-term odds of retears were decreased, regardless of leukocyte content (LP-PRP: OR, 0.36 [95% CI, 0.16-0.82]; LR-PRP: OR, 0.32 [95% CI, 0.16-0.65]; all P < 0.05) or usage of gel (non-gel: OR, 0.42 [95% CI, 0.23-0.76]; gel: OR, 0.17 [95% CI, 0.050.51]; all P < 0.01). The conclusion was that long-term retear rates were significantly decreased in patients with rotator cuff-related abnormalities who received PRP. Significant improvements in PRP-treated patients were noted for multiple functional outcomes, but none reached their respective minimal clinically important differences. Overall, the results suggest that PRP may positively affect clinical outcomes, but limited data, study heterogeneity, and poor methodological quality hinder firm conclusions.
In their double-blind RCT of 40 patients (average age 51) with RC tears, Kesikburun et al.37 randomized patients to a single 5-mL injection of either PRP or saline, in addition to a standard 6-week exercise program. At 1-year follow-up, the authors found that PRP was no better than placebo at improving quality of life, pain, disability, and shoulder ROM. In contrast, positive results were reported by Rha et al.38 in their study of 39 patients (average age 45) with tendinosis or partial RC tears. Patients were randomized to either two injections of PRP or dry needling spaced four weeks apart. At the 6-month follow-up, those treated with PRP had superior results regarding pain, function, and ROM.
Singh et al.39 conducted an SR/MA study comparing PRP injections and CS injections for plantar fasciopathy (PF). Studies were assessed using the Cochrane Risk of Bias Tool and the Newcastle Ottawa Scale (NOS). The primary endpoint was pain and function score at 3- and 6-month follow-up. Ten studies with a total of 517 patients were included. Seven studies were randomized. Studies reported outcomes using the VAS and American Orthopedic Foot and Ankle Score (AOFAS). At 3-month follow-up, PRP injections were associated with improved VAS scores (standard mean difference [SMD], -0.66; 95% CI, -1.3 to -0.02; p = 0.04) and AOFAS scores (SMD, 1.87; 95% CI, 0.16-3.58; p = 0.03). However, by the 6-month follow-up, there was no difference in VAS score (SMD, -0.66; 95% CI, -1.65 to 0.3; p = 0.17) or AOFAS scores (SMD, 1.69; 95% CI, -1.06 to 4.45; p = 0.23).
Sarah Johnson-Lynn et al.40 randomized 28 patients with six months or more of magnetic resonance imaging (MRI)-proven PF to PRP or saline. Using the VAS, both treatments resulted in a similar, significant improvement in symptoms at six months. Levels of Evidence: Level II.
A larger, randomized trial41 of 115 patients compared CS to PRP using Foot Function Index pain score (FFI) for chronic plantar fasciitis. In the control group, FFI Pain scores decreased quickly and then remained stable during follow-up. FFI Pain reduction was more modest in the PRP group, but reached a lower point after 12 months than in the control group. After adjusting for baseline differences, the PRP group showed significantly lower pain scores at the 1-year follow-up than the control group (mean difference, 14.4; 95% CI, 3.2-25.6). The number of patients with at least 25% improvement (FFI Pain score) between baseline and 12-month follow-up differed significantly between the groups. Of the 46 patients in the PRP group, 39 (84.4%) improved at least 25%, while only 20 (55.6%) of the 36 in the control group showed such an improvement (P = 0.003). The PRP group showed significantly lower FFI Disability scores than the control group (mean difference, 12.0; 95% CI, 2.3-21.6).
A 2014 study with fifty patients compared PRP to corticosteroids and reported statistically significantly higher visual analog scores in the PRP group at six weeks and six months (p<0.001).42 This study's limitations include that it was not randomized, and there were no placebo group results, no radiological or biological results, a small sample size, and a short follow up period.
A 2015 meta-analysis comparing PRP, shockwave therapy, and corticosteroids for plantar fasciitis treatment showed a trend favoring PRP over corticosteroids at three months but slightly inferior at six months. Shockwave therapy had the highest likelihood of treatment success, but less remarkable for pain reduction at three and six months.43 This data was limited by substantial heterogeneity in therapeutic protocols, definitions, and measurement of outcome variables among the included studies, a small number of trials, the inclusion of non-randomized trials, lack of comparison to the placebo group making the conclusions suggestive of a trend but without sufficient data to drawn reliable conclusions.
A 2017 randomized controlled trial (RCT) comparing twenty-eight patients receiving PRP to corticosteroid injections for plantar fasciitis who did not respond to conservative treatment concluded both treatments were equally effective. The authors report the cost and time for preparation of the PRP were disadvantages of the PRP treatment.44 Another small single-blinded RCT (n= 32) reported similar results and lacked adequate sample size, blinding, and follow-up duration.45
A 2019 prospective, randomized double-blinded control trial compared PRP to corticosteroid injections in sixty patients with chronic plantar fasciitis. Statistically significant improvements were reported in the visual analog score (VAS), and American Orthopedic Foot and Ankle Society (AOFAS) score in both groups. Plantar fascia thickness was reduced in both groups.46 Limitations of the study include small sample size and variability of platelet concentration among different patients. While the authors conclude that PRP is an effective treatment for chronic plantar fasciitis when compared to steroids, the authors acknowledge that lack of standardized preparation, the concentration of platelets, and dosage were barriers to a critical evaluation, and further research is necessary to understand the action of PRP.
Two 2020 systematic reviews draw different conclusions. Hurley et al.47 reviewed nine RCTs (n=239) and reported statistically significant differences in VAS scores in favor of PRP at one through 12 months. They report at one and three months no difference in AOFAS scores, but favorable towards PRP at 6 and 12 months. The authors conclude evidence to suggest PRP may lead to greater improvement in pain and function for chronic plantar fasciitis and conclude there is level 1 evidence to support its use. However, the authors acknowledge significant heterogeneity, limiting the results of a meta-analysis and high risk of bias among the majority of included studies. Another 2020 systematic review included thirteen randomized controlled trials reported significant superiority of PRP in outcome scores when compared to corticosteroids (VAS:MD= -0.85, p=<0.0001, I2= 85%; AOFAS: MD= 10.05, p=<0.0001, I2= 85%) whereas there is no statistical difference in well-designed double-blinded trials (VAS:MD=0.15, p=0.72, I2= 1%; AOFAS: MD=2.71, p=0.17, I2= 0%). In comparison of PRP to placebo, the pooled mean difference was -3.75 (p=<0.0001, 95% CI= -4.34 to -3.18). In conclusion, the authors state there is no superiority of PRP compared to corticosteroids in well-designed double-blind studies. The advantage of PRP seen in some literature may be due to the lack of blinding in these studies. The report is a trend to the improvement of PRP compared to placebo.48 The heterogeneity was also significantly reduced in the double-blinded randomized control trials allowing more meaningful conclusions.
RCTs of 24 patients with an injection of PRP vs. saline into Achilles Tendinopathy (AT) demonstrated no significant difference at three months in the Victorian Institute of Sports Assessment-Achilles (VISA-A) score.49 A 1-year follow-up of 54 patients in a similar trial also found no improvement.50
Patellar tendinopathy is a condition characterized by anterior knee activity related pain, most commonly found in athletes who engage in jumping sports. A well-designed multisite single-blind study randomized 57 athletes with patellar tendinopathy to LR-PRP, LP-PRP, and saline ultrasound guided injections. All participants received one injection followed by six weeks of supervised rehabilitation training three times per week. Study retention was 93% at 12 weeks and 79% after one year. Using the outcome measure, Victorian Institute of Sport Assessment-patellar (VISA-P), there was no significant difference in mean change in VISA-P score, pain, or global rating of change among the three treatment groups at 12 weeks or any other time point.51 A SR/MA addressed 70 studies of patellar tendinopathy treatment involving 2530 patients, reported in 22 studies on eccentric exercise, extracorporeal shockwave therapy (ESWT), and PRP. Eccentric exercise therapies obtained the best results (P < 0.05) at short-term (< 6 months, mean 2.7 +/- 0.7 months). However, multiple injections of PRP obtained the best results (P < 0.05), followed by ESWT and eccentric exercise, at long-term follow-up (>/=6 months, mean 15.1 +/- 11.3 months).52
A different SR looked at 15 studies comparing eccentric training, PRP, CS, and ESWT. With or without core stabilization or stretching, eccentric training improved symptoms by 61% in the VISA-P score with a 95% confidence interval. Results from ESWT demonstrated 54% improvement, and PRP studies 55% improvement with similar confidence intervals. Finally, CS injection provided no benefit.53
In summary, RCTs and SR/MA findings have been mixed and have generally found that PRP did not have a statistically and/or clinically significant impact on pain or functional outcomes. In RCTs that have found significantly improved pain outcomes for PRP injections, critical relevancy gaps and study conduct limitations preclude reaching strong conclusions based on their findings. The evidence is insufficient to determine the benefit of PRP on health outcomes for patellar tendinopathy.
Surgical Augmentation of Repairs
Most RCTs with surgical repair of rotator cuff or Achilles tendon have not demonstrated any clinically significant benefit.54-57 A MA of 8 Level I or Level II studies of rotator cuff surgery comparing preoperative and postoperative risk for retears and gain in functional outcome showed no statistically significant differences between those treated with PRP and those without such an intervention.58 An additional MA of Level II and Level III studies by Saltzman et al.59 came to similar conclusions. A Cochrane review by Moraes et al.60 on platelet-rich therapies for musculoskeletal soft tissue injuries identified 2 RCTs and two quasi-randomized studies (total n = 203 patients) specifically on PRP used in conjunction with anterior cruciate ligament (ACL) reconstruction. Pooled data found no significant difference in International Knee Documentation Committee (IKDC) scores between the PRP and control groups. The evidence is insufficient to determine the benefit of PRP on health outcomes for surgical augmentation of repairs.
Primary Treatment for Osteoarthritis
Osteoarthritis (OA) is a common disease involving joint damage, inadequate healing response, and progressive deterioration of the joint architecture. Presently, intra-articular injections of CS or viscosupplementation with HA remain the mainstay of conservative treatment. The evidence for using PRP for this condition includes multiple RCTs and systematic reviews. Most trials have compared PRP with HA for knee osteoarthritis, though HA as a comparator is questionable because the evidence demonstrating the benefit of HA for osteoarthritis is not robust.
Systematic reviews have generally found that PRP was more effective than placebo or HA in reducing pain and improving function. However, systematic review authors have noted that their findings should be interpreted with caution due to important limitations, including significant statistical heterogeneity, questionable clinical significance, and a high risk of bias in study conduct.61 One retrospective study compared PRP to HA in 190 patients between January 2014 and October 2017. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), VAS, and ROM were measured before injection, at 15 days, six months, 12 months, and at last follow-up. HA treated patients experienced a higher arthroplasty rate (36.0% vs. 5.3%, p < 0.001), lower ROM, worse VAS and WOMAC score, and increased risk of any arthroplasty occurrence (log-rank < 0.001) than PRP patients.61
A 2014 systematic review of 10 randomized and non-randomized trials of PRP for OA of the knee found intra-articular PRP injections were more effective for pain reduction (mean difference (MD) -2.45; 95% CI -2.92 to -1.98; p-value < 0.00001 and MD -2.07; 95% CI -2.59 to -1.55; p-value < 0.00001, single and double PRP injections, respectively) compared with placebo at 6 months post injection. Intra-articular PRP injections were compared with hyaluronic acid and showed a statistically significant difference in favor of PRP on pain reduction based on the VAS and numeric rating scale (standardized mean difference -0.92; 95% CI -1.20 to -0.63; p-value <0.00001) at six months post injection. Almost all trials revealed a high risk of bias.62
A similar SR/MA in 2020 of 18 studies (all level 1) met inclusion criteria, including 811 patients undergoing intra-articular injection with PRP (mean age, 57.6 years) and 797 patients with HA (mean age, 59.3 years). The mean follow-up was 11.1 months for both groups. Mean improvement was significantly higher in the PRP group (44.7%) than the HA group (12.6%) for WOMAC total scores (P < 0.01). Of 11 studies based on the VAS, six reported PRP patients to have significantly less pain at the latest follow-up when compared with HA patients (P < 0.05). Of 6 studies based on the Subjective IKDC outcome score, three reported PRP patients to have significantly better scores at the latest follow-up when compared with HA patients (P < 0.05). Finally, LP-PRP was associated with significantly better Subjective IKDC scores vs. LP-PRP (P < 0.05).63
Park and colleges64 conducted an RCT to evaluate the efficacy of inter-articular PRP injections in knee osteoarthritis as compared with hyaluronic acid (HA) injection and to determine if clinical efficacy is associated with its biological characteristics. This RCT enrolled 110 symptomatic knee osteoarthritis patients who received a single injection of leukocyte-rich PRP or HA. Outcomes were assessed at baseline, six weeks, three and six months after injection. Authors reported PRP showed significant improvement in IKDC subjective scores at six months vs. HA. No significant differences were observed between the clinical outcomes in other groups. The proportion of individuals who scored above the minimal clinically important difference (MCID) for VAS at six months was significantly greater in the PRP group (P=0.044). Adverse events did not differ between the groups. Strengths of this study include RCT design, clearly defined protocol for and PRP preparation and administration, and standardized tools for pain assessment. Limitations include lack of placebo group and lack of radiological imaging. While it makes valuable contribution comparison to other studies with confounders such as leucocyte rich vs. poor, number of injections, type of preparation kit, underlying medical conditions, adjunctive therapies were not addressed.
To address these differences several authors have attempted to use systematic review/meta-analysis approach to pool data. Three meta-analysis comparing the literature on the effectiveness and safety of PRP and HA in patients with adult knee osteoarthritis were reviewed. Tan et al reviewed twenty-six RCTs with 2430 individuals and reported PRP significantly reduced patient pain and improved function as comparted to HA.65 Chen et al.66 reviewed 14 RTCs comprised of 1350 patients, and Han et al.67 report on fifteen RCTs comprised of 1314 individuals both reporting PRP injections reduced pain more effectively than HA injections. All three trials reported no significant difference in adverse events between the two groups. However, meta-analysis cannot adequately address these factors as they have not been adequately investigated in the trials included in the analysis. The fundamental issues as multiple confounders such as the source of stem cells, most effective delivery method, role of surgery and type and amount of PRP used are not addressed in high-quality studies.68 This significant heterogeneity subsequently affects the reliability of conclusions. Additionally, despite the seemingly large body of evidence, it is important to note that some RCTs were included in multiple SR/MAs.
A recent prospective study compared the efficacy of intra-articular injections of PRP and HA with a control group of NS solution for knee OA. This was a randomized, dose-controlled, placebo-controlled, double-blind, triple-parallel clinical trial. A total of 87 osteoarthritic knees (53 patients) were randomly assigned to 1 of 3 groups receiving three weekly injections of either LP-PRP (31 knees), HA (29 knees), or NS (27 knees). WOMAC score and IKDC subjective score were collected at baseline and at 1, 2, 6, and 12 months after treatment. All three groups showed statistically significant improvements in both outcome measures at one month; however, only the PRP group sustained the significant improvement in both the WOMAC score (63.71 ± 20.67, increased by 21%) and IKDC score (49.93 ± 17.74, increased by 40%) at 12 months. The conclusion was that intra-articular injections of LP-PRP could provide clinically significant functional improvement for at least one year in patients with mild to moderate OA of the knee.69
Osteoarthritis of the hip can also be a source of chronic pain. A 2021 double-blind, randomized pilot study of leukocyte-poor PRP compared to low-molecular weight hyaluronic acid for symptomatic osteoarthritis of the hip was reported on thirty-four patients with hip OA. The patients were randomized to three weekly PRP injections or hyaluronic acid, and conversion to total hip arthroplasty or hip resurfacing procedure was the primary outcome with pain scores as the secondary outcome. They reported fewer patients converted to surgical management and lower pain score in the PRP group (n=19) within six months; however, an additional 15.8% of the PRP patients with improvements went on the surgical management within the first year.70 Limitations include a sample size too small for statically significant findings, lack of placebo group, short-term follow-up, and risk of bias. A 2021 systematic review using GRADE methodology evaluated the effectiveness of PRP in the management of hip OA. Four trials (334 participants, 340 hips) were included, and all were marked as “moderate risk of bias”. PRP's superiority against comparative treatments was reported in one study, longer-term evaluations from four to twelve months showed diverse results, and only one study reported significantly better results for PRP. The authors recognize considerable heterogenicity and small sample sizes among the studies, which were considered moderate to low quality. They conclude while PRP may be beneficial and safe for hip OA at mid-term follow-up, further research with high-quality designs, larger sample sizes, and comparison to standard treatments are imperative.71
However, evidence is still limited due to the overall high risk of bias in previous trials and great variability between studies regarding the number of injections (generally 1 to 4), the interval between injections, preparation of the PRP, and volume injected. Furthermore, the typical length of follow up was only one year or less. There is also uncertainty regarding whether individuals with less severe OA may benefit more from this intervention compared with individuals with more advanced structural damage. Additionally, it is unclear whether LR-PRP or LP-PRP should be utilized, though the latter appears to have an advantage. Larger controlled studies comparing PRP with placebo and alternatives other than HA are needed to determine the efficacy of PRP for knee OA. Further studies are also needed to determine the optimal protocol for delivering PRP. At present, the evidence is insufficient to determine the effects of PRP on health outcomes for OA.
Primary Treatment for Chronic Low Back Pain
Low back pain (LBP) is now regarded as the first cause of disability worldwide, causing morbidity and socioeconomic loss.72 Conventional treatments include physical therapy, CS injection, medial bundle branch block (MBBB), and surgery. Intervertebral disc (IVD) degeneration is an important pathogenesis of LBP. Several animal studies have shown that the injection of PRP into degenerated IVDs effectively restores structural changes (IVD height) and improves the matrix integrity of degenerated IVDs as evaluated by MRI and histology.73 Recently, a small number of studies have promoted PRP injection as a relatively safe means of treating patients with degenerative disc disease who have failed other means of managing their LBP. A small number of prospective trials have suggested there may be some benefit to using PRP injection in the treatment of pain or functional decline caused by facet joint arthropathy.74
A 2016 double-blinded, randomized controlled trial compared PRP (n=29) to control (contrast agent) (n=18) for moderate to severe lumbar discogenic pain unresponsive to conservative treatment. While data were collected for one-year patients randomized to the control group, 15/18 crossed over to PRP at eight weeks. They concluded superiority of PRP to the control group. Limitations included the comparative analysis was modified, limited follow-up for the control group, underpowered to detect the demonstrated difference in functional rating index score at eight weeks between the study groups, no data collection on cell counts or biochemical analysis of the PRP, and there was no routine radiologic follow-up to see if morphologic disk changes occurred with clinical improvement.75
A 2016 study of forty patients with chronic low back pain of sacroiliac joint origin was randomized to corticosteroids with lidocaine or leukocyte-free PRP injections and evaluated at two, four, and six weeks and three months. They reported lower pain scores at both six weeks and three months in the PRP group, concluding PRP is an effective treatment.76 Limitations of this study include short follow-up time, disease scoring not performed, risk of bias, and small sample size. This study was included as the only RCT in a 2020 systematic review, along with two case series, using GRADE to evaluate evidence and concluded very low-quality evidence. The authors include inconsistent reporting of demographics, patient diagnosis and selection, PRP preparation, storage and administration, and co-interventions as limitations in the literature.77
A 2020 study of 50 patients with low back pain secondary to sacroiliac joint (SIJ) were injected with platelet-rich plasma into the sacroiliac joint under ultra-sound guidance. Oswestry Disability Index (ODI) and Numeric Rating Scale (NRS) were measured at baseline, two weeks, four weeks, three months, and six months after injection. Authors concluded ultrasound-guided PRP injections into the SIJ were a safe and effective for reducing functional disability and decreasing low back pain. They report most effects are seen at two to four weeks, with sustained functional improvement and pain relief at six months. The authors reported missed follow-up visits, selection of participants were recruited from a single site, and the need for longer follow-up as study limitations.78
A non-randomized comparator study by Bise et al.79 looked at the efficacy of interlaminar computed tomography (CT) guided epidural PRP and CS injections in 60 patients. Utilizing the NRS and function with the Oswestry Disability Index (ODI) before and six weeks after treatment. At six weeks, there was found to be no statistical difference between the two groups.
The American Society of Interventional Pain Physicians reviewed the evidence for PRP usage in LBP. They found Level III evidence for intradiscal injections of PRP. In contrast, the evidence is considered Level IV for lumbar facet joint, lumbar epidural, and sacroiliac joint injections of PRP (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis.72 The evidence is insufficient to determine the benefit of PRP on health outcomes for chronic LBP.
Contractor Advisory Committee (CAC) Evidentiary Meeting 3/10/2021
CGS Administrators hosted and Noridian Healthcare Solutions participated in a CAC meeting to review the evidence on platelet-rich plasma for non-wound indications on 3/10/2021. Audio, transcript and voting results are available at: https://www.cgsmedicare.com/partb/medicalpolicy/lcd_discussion_recordings.html. Subject matter experts (SMEs) from podiatry, orthopedic, physical medicine, rehabilitation, anesthesiology, and rheumatology were represented. All literature submitted by the SMEs to supplement the reference list was reviewed. Case reports or series and studies with less than twenty-five patients were reviewed but not included in the evidence review due to being very low-quality evidence. The SMEs agreed there is sufficient evidence that the use of PRP injections into joints/tissue for non-wound conditions is safe, voting 4.75/5 (range 3-5) for safety and 5/5 that it is as safe as the current standard of care treatments. They were slightly less confident for repeat injections voting 3.75/5 (range 3-5) for safety.
The effectiveness of PRP was more controversial. The panel was overall favorable, voting 3.5/5 (range 2-5). There is evidence to support PRP's efficacy. The discussion often focused on anecdotal experience rather than an assessment of the literature. In the evaluation of the evidence, the panel voted 2.7/5 (range 1-3) that there is evidence for standardized protocols. The SMEs submitted no societal guidance or evidence-based protocols. The voting on disease-specific etiologies was incomplete as several SMEs did not vote on the disease processes outside of their clinical expertise. Overall, the SMEs felt that PRP was safe and effective or potentially effective but acknowledged the limitations in the evidence. The lack of standardized protocols was the most significant point. The concentration of leukocytes (rich or poor) was of particular concern as effectiveness may vary depending on the concentration of leukocytes used, which is not reconciled in the literature. Additional points of concerns included variations in injection technique, type or lack of imaging, frequency and number of injections, different instruments to distill the product, different activating agents, preparations and additives, injection into variable locations including different potential responses depending on tissues type such as joints, tendons or muscle, and the degree of arthritis and underlying comorbidities that can impact response. In terms of the literature, the panel members acknowledge that assessing the variability of different protocols, various locations of injections, lack of long-term safety or effectivity data, heterogenicity in existing studies, and lack of controls or variable controls creates barriers to the assimilation and interpretation of the existing evidence. While the panel was enthusiastic for PRP as a potential treatment option, even the anecdotal experiences shared to demonstrate the variability in practices and lack of evidence-based guidance for use at this time.