A reader recently asked me to take another look at a product for producing and administering platelet rich plasma (PRP). This is a subject I haven’t covered since 2013, when I wrote about a small study looking at the use of PRP for arthritis in dogs. Since that time, there has been a huge increase in the amount of laboratory and human-focused research into the use of platelets as a form of “regenerative medicine.” Much like stem cells, which I have written about more often, PRP is used to treat a wide range of conditions, such as arthritis, connective tissue injuries, wounds, and many others. Like stem cell therapies, there is a plausible rationale for PRP and some encouraging pre-clinical research, but the marketing and use of both approaches have outpaced the clinical research by quite a bit.
The basic principle is that platelets, and other components of blood, contain growth factors, compounds that reduce inflammation, and a host of other agents that could be useful in managing pain and in promoting healing. Studies looking at PRP and some of these components certainly find evidence of physiologic activity that might, in principle, be beneficial to patients. Anyone who has followed this blog or read my book, however, will know that such laboratory studies frequently fail to accurately predict what will happen in the real world of the clinic. Living patients are much more complex and varied than tissue in a test tube, and studies in rats or human cell culture don’t always reflect what happens in living dogs and cats.
The actual clinical research on PRP in veterinary species is sparse and not robust. The best evidence is in horses, and here is the conclusion of a systematic review of some of this research (for treatment of musculoskeletal lesions):
Most experimental studies revealed positive effects of PRP. Although the majority of equine clinical studies yielded positive results, the human clinical trials’ results failed to corroborate these findings. In both species, beneficial results were more frequently observed in studies with a high risk of bias. The use of PRP in musculoskeletal lesions, although safe and promising, has still not shown strong evidence in clinical scenarios.
There are a handful of clinical studies in dogs:
- Prostatic cysts– This was an uncontrolled study. Ten dogs had their cysts injected with PRP, and eventually they all resolved, but there was no comparison with other treatment or no treatment, so the significance of this in uncertain.
- Corneal ulcers– This was a randomized, controlled trial adding PRP to conventional therapy for uncomplicated corneal ulcers. No difference was seen in healing between the groups.
- Supraspinatus tendinopathy-Another uncontrolled study in which ten dogs were treated and some got better while others didn’t. No real conclusion can be drawn from this.
- Wound healing– This was a small study using three dogs. Eight small (6mm) wounds were created on each dog, and some were treated with PRP while others were not. The authors reported faster healing in the PRP-treated wounds, but there was no blinding, and the assessment of the wounds was subjective, so risk of bias is high.
- Skin flaps-Another lab study in beagles. Here skin flaps were created on both sides of several dogs, one treated with PRPR and the other not. Some measures of wound healing differed between the treatments and others did not, though the difference in survival of the flaps was pretty large. Again, no blinding was involved, so the risk of bias is high.
- Bone healing-Some more poor beagles had bone screws placed and some were treated with PRP while others were not. No difference in bone healing was seen.
- Bone Healing-This time, dogs had a defect surgically created in their radius and then fixed in place, and healing was compared between dogs treated with PRP or untreated. There was a difference in bone healing between the groups, and again some controls for bias were missing. Other lab studies in animals looking at bone healing have found some evidence of benefits, but the conclusions are tentative due to the paucity of studies.
Overall, the research in dogs is promising but limited, and the most recent review concludes:
The growing development and use of PRP preparations in wound healing and tissue repair in people will require the development of new randomized controlled studies with large sample sizes to establish therapeutic efficacy.
Unsurprisingly, there is even less research on PRP in cats, and no conclusions at all can be drawn about the effectiveness of PRP in this species.
As usual, when the veterinary research is limited, we turn to studies in humans to see whether a therapy is likely to be helpful. While the quantity and quality of human research is inevitably higher than that in dogs and cats, the results cannot reliably be assumed to apply to other species, so such studies can only suggest, not prove the potential benefits of PRP in veterinary patients.
The human clinical trial research is vast, with almost 300 systematic reviews currently listed on Pubmed. The conclusions of these reviews are varied, with some claiming proven benefits while others suggest more research is needed for reliable conclusions or that PRP is not helpful for the condition being evaluated. And many of these reviews apply to conditions that are not relevant to veterinary species.
I have collected below a sample of the more recent systematic reviews in conditions that might be a target for PRP therapy in veterinary species. This is not an exhaustive list, merely a sample illustrating the variety of conclusions reached about the meaning of the human clinical trial literature.
PRP is a plausible therapy, and there is reason to believe it could be helpful for veterinary patients with arthritis, connective tissue and muscle injuries, wounds, and other conditions. However, the clinical trial in humans is encouraging but not consistently positive, and there is very little clinical research in veterinary species. Much of the veterinary research consists of small studies with significant methodological limitations, which means we cannot confidently conclude what conditions, if any, might benefit from treatment with PRP.
As with many veterinary therapies that are insufficiently tested, PRP involves a variety of commercial products which vary in ways which might be significant for their effectiveness but which haven’t been specifically tested in most, if any, of the conditions for which they are marketed.
Few significant signs of harm have been seen in the preliminary PRP research, so risks are likely small, though our confidence in this conclusion must also be limited by the absence of strong research evidence.
Systematic Reviews of Clinical Trials in Humans
Regardless of the positive results obtained in several studies, it is important to take into consideration that many of the referred studies were not randomized and/or blinded controlled trials[11,88,114] and therefore should be regarded with caution. In fact, in a recent meta-analysis, from 10 manuscripts selected for the study, presented high risk of bias . The high heterogeneity among studies is another critical limitation of PRP . In addition, many of these studies suggest that autologous PRP is a safe treatment; however, the potentially negative effects of PRP were not fully investigated at this point.
Acute Muscle Injury
The promising biological rationale, the positive preclinical findings, and the successful early clinical experience of PRP injections are not confirmed by the recent high-level RCTs. Therefore any benefit in terms of pain, function, return to sport, and recurrence using PRP injections for the treatment of acute muscle injuries is not supported. Due to the bias in the studies, the heterogeneity of the findings, and the limited sample size, the evidence should be considered to be of low or very low quality.
There is slight evidence for the potential benefits of intra-articular injections of PRP in patients with TMJ-OA. However, a standardized protocol for PRP preparation and application needs to be established.
The results of this meta-analysis, which documents the very marginal effectiveness of PRP compared to controls, does not support the use of PRP as conservative treatment in orthopaedics.
Intra-articular PRP injections probably are more efficacious in the treatment of knee OA in terms of pain relief and self-reported function improvement at 3, 6 and 12 months follow-up, compared with other injections, including saline placebo, HA, ozone, and corticosteroids.
In patients with symptomatic knee OA, PRP injection results in significant clinical improvements up to 12 months post injection. Clinical outcomes and WOMAC scores are significantly better after PRP versus HA at 3 to 12 months post injection. There is limited evidence for comparing leukocyte-rich versus leukocyte-poor PRP or PRP versus steroids in this study.
Rotator Cuff Injury-
The results of this meta-analysis do not support the use of platelet-rich plasma/platelet-rich fibrin matrix in patients with rotator cuff injuries.
On the basis of the current evidence, PRP injections reduced pain more effectively than did placebo injections in OA of the knee (level of evidence: limited due to a high risk of bias). This significant effect on pain was also seen when PRP injections were compared with hyaluronic acid injections (level of evidence: moderate due to a generally high risk of bias). Additionally, function improved significantly more when PRP injections were compared with controls (limited to moderate evidence). More large randomised studies of good quality and low risk of bias are needed to test whether PRP injections should be a routine part of management of patients with OA of the knee.
Lateral epicondylitis and rotator cuff injuries-
This review shows that PRP may reduce pain associated with lateral epicondylitis and rotator cuff injuries.
PRP intra-articular injection of the knee may be an effective alternative treatment for knee OA, especially in patients with mild knee OA. Although some studies suggested that the effect of PRP was no better than HA, we found that it was no worse. A large, multicenter, randomized trial is needed to further assess the efficacy of PRP treatment for patients with knee OA.
Literature to date concludes that intra-articular platelet-rich plasma injections of the hip, performed under ultrasound guidance to treat hip osteoarthritis, are well tolerated and potentially efficacious in delivering long-term and clinically significant pain reduction and functional improvement in patients with hip osteoarthritis. Larger future trials including a placebo group are required to further evaluate these promising results. Level of evidence: Level I, a systematic review of level I studies.
This systematic review demonstrated no long-term statistically significant improvement in patient validated outcomes and secondary outcomes both in patients with knee OA or following TKA for OA. However PRP has been shown to have short to medium-term benefits in pain control after TKA and activities of daily living in patients with OA.
There is good evidence to support the use of a single injection of LR-PRP under ultrasound guidance in tendinopathy. Both the preparation and intratendinous injection technique of PRP appear to be of great clinical significance.
Although the results of the included studies showed that arthrocentesis or arthroscopy with PRP or PRGF, saline, or HA injections all reduced pain and increased mouth opening, the evidence was of very low quality. Further studies are needed to confirm these preliminary results showing that PRP or PRGF with arthrocentesis or arthroscopy significantly improved pain but did not increase MMO compared with findings in the control or HA groups.
IA-PRP is a viable treatment for knee OA and has the potential to lead to symptomatic relief for up to 12 months. There appears to be an increased risk of local adverse reactions after multiple PRP injections. IA-PRP offers better symptomatic relief to patients with early knee degenerative changes, and its use should be considered in patients with knee OA.
The current best available evidence suggests that CSI improves functional outcomes and pain relief in the short term, while AB and PRP are the most effective treatments in the intermediate term.
Degenerative joint disease-
The analysis showed an increasing number of published studies over time. Preclinical evidence supports the use of PRP injections that might promote a favourable environment for joint tissues healing. Only a few high-quality clinical trials have been published, which showed a clinical improvement limited over time and mainly documented in younger patients not affected by advanced knee degeneration.
The main finding of this study was the paucity of high-level literature regarding the application of PRP in the management of patellar and Achilles tendinopathy. However, the clinical data currently available, although not univocal, suggest considering PRP as a therapeutic option for recalcitrant patellar and Achilles tendinopathies.
Evidence from the current literature, although limited, suggests that the use of PRP may result in an earlier return to sport among patients with acute grade I or II muscle strains without significantly increasing the risk of reinjury at 6 months of follow-up. However, no difference in time to return to sport was revealed when specifically evaluating those with a grade I or II hamstring muscle strain.
The currently limited available evidence on PRP for nonoperative treatment of chronic rotator cuff disease suggests that in the short term, PRP injections may not be beneficial. When directly compared with exercise therapy, PRP does not result in superior functional outcomes, pain scores, or range of motion. However, interpretation of this literature is confounded by the lack of reporting of the cytology and characteristics of PRP.
After knee replacement-
Current meta-analysis indicates that PRP is associated with increasing the ROM after TKA in short term and long term. What’s more, PRP can also decrease the WOMAC score and pain intensity without increasing the occurrence of infection.
Platelet-rich plasma is a safe and promising therapy in the treatment of recalcitrant PT. However, its superiority over other treatments such as physical therapy remains unproven. Further RCTs are required to determine the relative effectiveness of the many available treatments for PT and to determine the subgroups of patients who stand to gain the most from the use of these therapies.
Corticosteroid injections provide rapid therapeutic effect in the short-term with recurrence of symptoms afterwards, compared to the relatively slower but longer-term effect of platelet-rich plasma.
Local corticosteroid injections demonstrated favorable outcomes compared with those of local PRP treatments for lateral elbow epicondylitis during the short-term follow-up period (4 weeks and 8 weeks post-treatment). Otherwise, at the long-term follow-up (24 weeks post-treatment), PRP injections had improved pain and function more effectively than corticosteroid injections.
PRP intra-articular injections of the knee may be an effective alternative treatment for knee OA. However, current studies are at best inconclusive regarding the efficacy of the PRP treatment. A large, multicenter randomized trial study is needed to further assess the efficacy of PRP treatment for patients with knee OA.
In short-term outcomes (?1 year), PRP injection has improved functional outcomes (WOMAC total scores, IKDC score and EQ-VAS) when compared to HA and placebo, but has no statistically significant difference in adverse events when compared to HA and placebo. This study suggests that PRP injection is more efficacious than HA injection and placebo in reducing symptoms and improving function and quality of life. It has the potential to be the treatment of choice in patients with mild-to-moderate OA of the knee who have not responded to conventional treatment.
Epicondylitis, Plantar fasciitis-
The use of PRP yields statistically and clinically better improvement in long-term pain than does CS in the treatment of EE. The use of PRP yields statistically and clinically better long-term functional improvement than that of CS in the treatment of PF.
Although the results of this review show promise for the use of PRP in chronic tendinopathy, the analysis highlighted the need for more controlled clinical trials comparing PRP with placebo.
Meta-analysis showed superior efficacy for rehabilitation exercises. PRP injection had no effect on acute hamstring injury. Limited evidence was found that agility and trunk stabilisation may reduce re-injury rates. The limitations identified in the majority of RCTs should improve the design of new hamstring RCTs.
This meta-analysis demonstrated that PRP injection provided adjuvant efficacy to arthrocentesis or arthroscopy in pain reduction for temporomandibular joint osteoarthritis in the long term. Furthermore, PRP injection significantly reduced pain better compared with HA injection, saline injection, or no injection.
The results of this systematic review and meta-analysis suggest that PRP is superior to HA for symptomatic knee pain at 6 and 12 months. ACP appears to be clearly superior over HA for pain at both 6 and 12 months. There were no advantages of PRP over HA for clinical outcomes at both 6 and 12 months.