Abstract
Background
Platelet-rich plasma (PRP) and autologous blood are commonly used therapies for lateral epicondylitis, but the evidence from randomized, placebo-controlled trials is conflicting. Thus, it is still unclear if patients benefit from these treatments.
Questions/purposes
In the setting of a randomized, placebo-controlled trial, we compared PRP, autologous blood, and saline injections in the treatment of lateral epicondylitis with respect to: (1) VAS pain scores, and (2) functional outcomes (DASH score and grip strength) 1 year after treatment.
Methods
We performed a parallel-group, randomized, controlled participant- and assessor-blinded study including adults with clinically diagnosed lateral epicondylitis. We defined lateral epicondylitis as pain in the lateral humeral epicondyle area exacerbated during resisted wrist extension and epicondyle compression. The participants were recruited from a secondary referral center, after not responding to initial nonoperative treatment. Patients with other concomitant upper-limb symptoms and surgical treatment of the elbow were excluded. Randomization sequence was generated with computer software and concealed from the investigators. We randomized 119 participants to receive an injection of PRP, autologous blood, or saline (1:1:1) in the proximal insertion of the extensor carpi radialis brevis muscle; 40 participants received PRP, 40 received autologous blood, and 39 received a saline injection. To prepare the PRP, we collected venous blood with a syringe kit followed by centrifugation, whereas autologous blood group received unprepared blood injection. Two unblinded investigators gave injections while the participant was unable to see the injection. There was no formal postinjection rehabilitation protocol and the use of NSAIDs was similar between different treatment arms. 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 VAS scale (without specification as to whether the pain was activity related or at rest; range 0-10; a higher score indicates worse pain; the minimum clinically important difference [MCID] on the 10-cm scale was 1.5 cm), from baseline to 52 weeks. The secondary outcomes were the DASH score (range 0-100; a higher indicates a poorer outcome, and the MCID was 10.2 points) and grip strength. All patients were included in the analyses, and analyses were performed using the intention-to-treat principle. There was no crossover between treatment groups. At 52 weeks, nearly all (95% [38 of 40]) participants in autologous blood group were available for analysis whereas 78% (31 of 40) and 82% (32 of 39) were available in PRP and saline groups. This study was registered at ClinicalTrials.gov and funded by the local hospital district. With 40 patients in each group, we had 80% power to detect a clinically important improvement in pain (1.5 cm on the 10-cm VAS pain scale).
Results
There were no clinically important differences in the mean VAS pain or DASH scores among the groups at any timepoint. At 52 weeks, the mean difference in the VAS score for pain was -0.2 (95% CI -1.5 to 1.1; p = 0.75) for PRP versus saline and 0.5 (95% CI -0.7 to 1.7; p = 0.40) for autologous blood versus saline. The corresponding mean differences in the DASH score were 0.0 (95% CI -9.2 to 9.2; p > 0.99) and 7.7 (95% CI -1.3 to 16.7; p = 0.09) and those for grip strength were 1.4 kg (95% CI -3.3 to 6.1; p = 0.56) and -0.2 kg (95% CI -5.0 to 4.5; p = 0.92). No complications occurred because of the injections.
Conclusions
PRP or autologous blood injections did not improve pain or function at 1 year of follow-up in people with lateral epicondylitis compared with those who were given a saline injection. However, because the 95% CIs did not exclude the MCID in VAS scores for autologous blood versus saline at 52 weeks, it is possible that a larger study could identify a between-group difference that we missed, but the effect size of that difference (based on our findings), even if present, is likely still to be small. Until or unless future randomized trials convincingly show a benefit either to PRP or autologous blood injections, we recommend against their use in patients with lateral epicondylitis.
Level of Evidence
Level II, therapeutic study.
Introduction
Lateral epicondylitis, also known as tennis elbow, is a common enthesopathy typically affecting middle-aged people. This upper-extremity condition affects up to 1% to 3% of people between 40 and 55 years old daily [32], and it is associated with functional disability, physiological distress, and prolonged absences from work [1, 36, 37]. Several etiologies have been suggested, but as with many other degenerative musculoskeletal conditions, the exact pathophysiology explaining pain remains unknown [8, 27]. The current consensus suggests that symptoms are related to enthesopathy originating at the extensor carpi radialis brevis muscle [11, 15, 24]. Histologically, immature and disorganized connective tissue (collagen), abnormal activation of connective tissue cells, and formation of neovascularization are found in the tendinous insertion of extensor carpi radialis brevis [11, 15, 24].
Currently, there is no evidence that any treatment, including surgery, is better than placebo or no treatment in the management of lateral epicondylitis [17, 18, 29]. Platelet-rich plasma (PRP) and autologous blood are widely used therapies for lateral epicondylitis, showing promising results in animal tendon injury models and initial clinical series [4, 21, 22, 25, 35]. While PRP seems to outperform corticosteroid injections [2], it has failed to show superiority over placebo consistently [5, 16, 21, 22, 30, 35]. Due to conflicting findings, systematic reviews have arrived at varying conclusions regarding its efficacy, some considering evidence as strong against, some as supportive [6, 9, 10, 12, 20]. Despite the data from several previous efficacy trials, it remains unclear if patients with lateral epicondylitis benefit from PRP or autologous blood injections.
Because the efficacy of any treatment should first be established by comparing it to placebo rather than other treatments, and because the comparisons of PRP or autologous with placebo-injections have yielded conflicting results, we compared PRP, autologous blood, and saline injections in the treatment of lateral epicondylitis with respect to: (1) VAS pain scores, and (2) functional outcomes (DASH score and grip strength) 1 year after treatment in a randomized, controlled trial.
Patients and Methods
Study Design
We conducted this randomized, controlled, single-center, three-arm (PRP, autologous blood, and saline), parallel-group superiority trial. The local institutional review board approved the study protocol, and the study was conducted in accordance with the principles of the Declaration of Helsinki. All participants gave written informed consent and the study was registered at ClinicalTrials.gov (NCT01851044).
Our primary theory was that PRP and autologous blood injections relieve pain more effectively at 52 weeks follow-up than a saline injection in people presenting with clinical findings consistent with lateral epicondylitis.
Recruitment
We enrolled adult patients who had lateral elbow pain for more than 3 months and were dissatisfied with the results of initial nonoperative treatment. All had symptoms and clinical findings consistent with the symptoms of lateral epicondylitis. The diagnostic criteria were lateral elbow pain, maximum point of tenderness in the insertion of the extensor carpi brevis, and pain exacerbated during gripping, resisted wrist extension, and compression of the epicondyle.
Patients were recruited between March 2011 and January 2017 from a secondary care hospital to which they had been referred from primary public health care, occupational health care, private health care, or other hospitals. The exclusion criteria were other concomitant upper-limb symptoms and previous surgical treatment of the elbow (Table 1).
Table 1.
Eligibility criteria
Randomization and Blinding
Eligible patients were informed about the study, and if they agreed to participate, we obtained informed consent. After collecting baseline data, we randomized the patients using sequentially numbered, sealed, opaque envelopes. The randomization sequence was prepared with computer software by a person (H-ML) not otherwise involved in the study, and the sequence was unknown to all study personnel.
The investigators (JL, KK) who administered the injections also prepared the injection and thus were not blinded. All other hospital staff and persons responsible for treating the participants after the injection were blinded to the allocation. The investigator opened a sealed opaque envelope containing allocation code after venous blood was collected from the participants.
The participants were blinded to the treatment throughout the study period. They underwent the same aftercare and follow-up regimens regardless of the treatment group, and the investigator who administered the treatment did not participate in follow-up examinations.
Interventions
We collected blood from the asymptomatic arm of all participants using the Arthrex ACP® Double Syringe Kit (Arthrex Inc, Naples, FL, USA). The investigator (JL, KK) withdrew approximately 15 mL of venous blood from the cephalic vein of each participant. Anticoagulants were not used because the injection was administered within 30 minutes of blood withdrawal in all patients. If the treatment arm was randomized as PRP or saline, the investigator placed the syringe in a centrifugation container and a suitable counterweight was placed on the opposite site. If the treatment arm was randomized as autologous blood, centrifugation was performed with two counterweights. The blood was therefore saved for the injection. Thus, all participants received a similar treatment pre-injection protocol. For centrifugation, we used Hettich Rotofix A32 (Andreas Hettich GmbH & Co.KG, Tuttlingen, Germany) with a swing-out rotor (220 V) at 1500 rpm for 5 minutes for all samples.
After centrifugation, the smaller syringe of the kit was filled with 4 mL to 6 mL of PRP. Based on a previous study [34], the mean concentration of platelets in the PRP kit was 3613/µL × 103/µL, which was 1.99 x larger than the volume of venous blood. The investigator asked the participant to close their eyes and not open them until the injection was finished and the investigator gave permission. Then the investigator cleaned the skin and injected PRP, autologous blood, or saline with a 22 G x 1.5 G (0.70 mm x 40 mm) needle into the insertion of the extensor tendons at the lateral epicondyle. After covering the injection site with a bandage, the investigator disposed of the syringe, needle, and all equipment, and instructed the participants to open their eyes. No specific postinjection regimen was given to patients. However, the patients were advised to use NSAIDs if pain persisted at the injection site.
Outcomes
During the follow-up period, participants visited the hospital at 4, 8, 12, 26, and 52 weeks after the injection. All outcomes were measured during every visit.
The primary outcome measure of the study was pain measured with the VAS, ranging from 0 (no pain) to 10 (extreme pain); the question did not specify whether pain was activity related or at rest. Based on existing evidence, we regarded 1.5 as the minimum clinically important differences (MCID) for the VAS score for pain [13].
The secondary outcomes included the DASH score (range 0-100; a higher score indicates a worse outcome; MCID 10.2 [13]), grip strength measured with a JAMAR-type hydraulic hand dynamometer (Model SH5001, Saehan Corp, Changwon City, South Korea, kg; higher grip strength indicates a better outcome), use of NSAIDs (categorized as daily, several times a week, weekly, and rarely) and cumulative weeks of sick leave during the follow-up period (more sick leave indicates a worse outcome).
Study Flow
We screened 128 patients, nine of whom were excluded or declined to participate (Fig. 1). The groups were not different at baseline with regard to age, duration of symptoms, duration of sick leave, VAS scores for pain, DASH scores, and grip strength (Table 2). During the follow-up period, 10 participants discontinued the study and eight were lost to follow-up (Fig. 1). Baseline data were not different between participants completing the study and those who were lost to follow-up or discontinued the treatment (see Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/CORR/A305). There were no adverse effects in any groups. One participant in each group underwent surgery and two participants in the PRP group received additional injections (corticosteroid and botulinum toxin A) during the follow-up period (see Appendix Table 2, Supplemental Digital Content 2, http://links.lww.com/CORR/A306). There was no crossover between treatment groups. At 52 weeks, 95% (38 of 40) of participants in the autologous blood group were available for analysis whereas 78% (31 of 40) and 82% (32 of 39) were available in PRP and saline groups, respectively.
Fig. 1.
This diagram shows the study inclusion process. aExcluded because of bilateral symptoms (n = 2), other upper-limb problems (n = 3), or systemic disease (n = 1). bPatients refused to participate because they could not participate in follow-up visits. Participants discontinued treatment because they could not participate in follow-up visits (n = 2) or the reason was unknown (n = 8). The number of participants in each group may vary between follow-up points due to missing data.
Table 2.
Characteristics of participants at the beginning of the study
Statistical Analysis
To detect an effect size of 0.60 (MCID 1.5 ± 2.5 points) with a power of 80% (alpha = 0.05), 40 patients were recruited per group. All participants were included in the analysis as randomized regardless of discontinuation of treatment, loss to follow-up, or treatment conversion (intention-to-treat principle).
To estimate between-group differences, we calculated improvement in the VAS score for pain, DASH score, and grip strength from baseline to 4, 8, 12, 26, and 52 weeks after the injection. These improvements were compared using one-way ANOVA. We reported between-group differences in improvement from baseline with 95% CIs at every timepoint. Additionally, we performed a sensitivity analysis comparing improvement from baseline of the VAS score, DASH score, and grip strength with imputed data for those participants who were missing or discontinued the study (see Appendix Table 3, Supplemental Digital Content 3, http://links.lww.com/CORR/A307).
Table 3.
Outcomes of the study
Continuous data are reported as the mean ± SD when normally distributed or as the median (interquartile range) when the distribution was skewed. Outcome measures were analyzed with a t-test, ANOVA, or Kruskal-Wallis test, as appropriate. We considered a p value of 0.05 to indicate statistical significance. RStudio 1.1.463 (Boston, MA, USA) was used for all statistical analyses.
Results
Pain
With the numbers available, we found no differences between the PRP and the saline control groups in terms of improvement of VAS pain scores at 52 weeks (2.7 ± 2.4 versus 3.0 ± 2.5; mean difference -0.2 [95% CI -1.5 to 1.1]; p = 0.75), nor between autologous blood injections and saline controls (2.1 ± 2.1 versus 3.0 ± 2.5; mean difference 0.5 [95% CI -0.7 to 1.7]; p = 0.40) (Table 3). VAS pain scores decreased in all treatment groups through the study (Fig. 2A).
Fig. 2.
These graphs show the main outcomes of (A) VAS score for pain, (B) DASH score, and (C) grip strength.
Function
We found no between-group differences in functional endpoints between either of the active-treatment groups and saline controls at any timepoint (Table 3). The DASH score (Fig. 2B) decreased and the grip strength increased (Fig. 2C) in every treatment group during the follow-up. Accumulation of sick leave did not differ among the PRP (median 1 week, range 0-38 weeks), autologous blood (median 0 weeks, range 0-55 weeks), and saline (median 0 weeks, range 0-56 weeks) groups (p = 0.65). The use of NSAIDs was not different between the groups, and only four or five participants per group used NSAIDs daily at 52 weeks (Table 3).
The sensitivity analysis did not substantially affect the results (see Appendix Table 3, Supplemental Digital Content 3, http://links.lww.com/CORR/A307).
Discussion
PRP and autologous blood are widely used therapies for lateral epicondylitis, although their efficacy has not been established. Several previous randomized controlled trials have compared PRP or autologous blood against other therapies [14, 33], but among the studies that compared their efficacy against placebo, which we believe is the most relevant comparison in this setting, conclusions have varied widely [5, 16, 19, 22, 23, 38, 40]. Thus, it remains unclear if these treatments provide benefits to people with lateral epicondylitis. In this randomized controlled placebo-controlled trial, we sought to determine whether PRP or autologous blood can decrease pain or improve function in patients with lateral epicondylitis. We found no evidence that PRP or an autologous blood injection is superior to a saline injection. Specifically, we found no between-group differences in pain or function over the 52-week span of this study. This adds to the growing body of evidence that these treatments likely do not work [16, 19, 23, 40]. In light of that, we recommend against the use of these treatments in patients with lateral epicondylitis.
Limitations
Although pain did not improve with autologous blood injections compared with a saline injection, the 95% CIs overlapped MCID at the 26-week and 52-week follow-up points. This means that we cannot rule out the beneficial effect of autologous blood injection with high confidence; we trust that future meta-analyses will decrease this uncertainty. If there is a beneficial effect, our confidence intervals suggest it would likely be very small, likely below the MCID, and almost certainly would not justify the costs of these interventions. The attrition rates may explain the wide confidence intervals (see Appendix Table 4, Supplemental Digital Content 4, http://links.lww.com/CORR/A308). Although attrition may bias the comparison, PRP and saline groups had comparable proportions of patients with complete follow-up as well as comparable reasons for missing data. Furthermore, we did not control blinding after the treatment. Because all patients were blinded during injection, the aftercare was similar, and the investigators giving the injections did not participate in the follow-up, we believe that risk for inadvertent unblinding is small.
Pain
In experimental tendon injury models, PRP demonstrated the potential to accelerate tendon injury healing [4]. However, experimental tendon injuries in animal studies may not be comparable to degenerative tendinopathy in humans. After positive effects were observed in animal models, PRP was tested in clinical series with promising results in relieving pain experienced by patients [21, 25, 35]. In contrast, randomized controlled studies have found inconsistent evidence with respect to PRP’s effects regarding reducing pain, with a couple of trials suggesting a benefit [5, 22], while most others found no difference from a placebo injection [16, 19, 23, 40]. Mishra et al. [22] observed positive findings in a subgroup of participants at a follow-up point that was not planned a priori, and the report evoked substantial criticism [3]. Furthermore, Behera et al. [5] did not report whether they concealed the allocation sequence and whether the participants were blinded. These methodological shortcomings may have caused an overestimation of the treatment effect [28, 31, 39]. Our results suggest that PRP likely has no clinically important pain-relieving benefit for patients with lateral epicondylitis. We found no difference between PRP and saline groups, and even the point estimates were smaller than the MCID. This is convincing evidence that the treatment did not improve patients’ pain. Furthermore, the CIs suggest that there is unlikely to be a clinically important difference (more than 1.5).
At 52 weeks, we found no difference in pain improvement between autologous blood and saline. However, the CIs overlapped the MCID at the 26-week and 52-week follow-up intervals, suggesting imprecision. Wolf et al. [38] performed a randomized, blinded study with autologous blood, corticosteroid, and saline injections. During a 6-month follow-up period, they did not find any difference in the VAS score for pain between autologous blood and saline. VAS scores for pain were higher in the autologous blood group than in the saline group throughout the follow-up period. However, the study included only 34 patients, and it may have been underpowered. The results are in line with those of the present study.
Three trials have compared PRP with autologous blood in patients with lateral epicondylitis [7, 26, 35]. Two trials found no difference in pain relief of PRP compared with autologous blood [7, 26], whereas one trial reported a clinically unimportant difference at one timepoint in favor of PRP (1.2, range 0-10 for pain at 6 weeks) [35]. Because neither PRP nor autologous blood showed benefits over the saline injection in this study, we did not compare them.
Function
Likewise, PRP or autologous blood injections provided no functional benefit over saline injections in patients treated for lateral epicondylitis. The previous evidence about functional benefit of PRP injections is very similar compared with pain scores: while one study reported improvement for function [5], three studies found no benefit [19, 23, 40]. In the present study, the CIs overlap the MCID, suggesting imprecision at 8 weeks (that is, a clinically important difference cannot be excluded based on our data). A meta-analysis pooling data from all well-controlled randomized studies might help determine whether there is a transient short-lived benefit.
With respect to our secondary outcomes, we found no differences among our study groups in terms of grip strength, pain medication use, and accumulation of sick leave, which supports our primary conclusion that PRP offers no important benefits to people with this condition. The CIs for grip strength were relatively narrow, excluding differences greater than 6.5 kg. Although the MCID for grip strength is not known in this population, even the possible differences that might be present at the extremes of our CIs seem rather small.
Conclusions
The results of this randomized controlled trial do not support the use of PRP or autologous blood injections in the treatment of clinically diagnosed lateral epicondylitis. There was comparable improvement in symptoms and participation in work among patients in all groups. We recommend against using PRP or autologous blood injections in the treatment of lateral epicondylitis unless a future meta-analysis or a large, rigorously conducted randomized study finds clinically meaningful benefits.
Acknowledgments
We thank Hanna-Mari Laiho BHC, of Tays Hatanpää Hospital and Tampere University Hospital in Tampere, Finland, for performing the randomization sequence of the study.
Footnotes
One of the authors certifies that he (OVL) has received a grant, during the study period, an amount of USD 10,000 to USD 100,000, from Competitive Research Funding of the Pirkanmaa Hospital District (Grant number: 9S031).
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.
Each author certifies that his or her institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.
This work was performed at Hatanpää Hospital, Tampere University Hospital, Tampere, Finland.
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