Introduction
Due to the chronicity of the clinical manifestations of the rotator cuff impingement
syndrome, there is a need to find new therapies that collaborate to improve pain management.
Platelet-rich plasma (PRP) is an evolving treatment modality that has been gaining
prominence in primary care, rehabilitation and sports medicine. Platelet-rich plasma
is a concentrated platelet solution prepared with autologous blood, which makes this
treatment safe for clinical use.[1] Platelet-rich plasma acts by the modulation of bioactive factors in the injured
region, increasing the regeneration potential.[2] It increases the production of type I collagen and the proliferation of tenocytes,
transforming growth factor beta-1 (TGF-β1), platelet-derived growth factor (PDGF),
vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), while
also stimulating the synthesis of ligament matrix.[3]
[4]
[5]
[6]
Corticosteroid injections are commonly administered in tendinous lesions.[7] Subacromial application is considered a cheap and effective therapeutic option,
but the side effects of corticosteroids cause concern in clinical practice. Tendinous
ruptures following local injections of corticosteroids have also been found in the
repetition of the treatment or even after single application.[8] In addition, other noninfectious complications may occur, including nerve atrophy,
hypopigmentation of the skin, dystrophic calcification around the joint capsule, hyperglycemia
and inhibition of the pituitary hypothalamic axis for 1 to 2 weeks after application.[9]
The current literature regarding PRP, as this is a new modality of treatment, is limited
due to the lack of standardization of study protocols, PRP preparation techniques
and methods of measuring clinical improvement, so new research needs to be performed
for the concrete understanding of this modality of therapy.
The aim of this study is to analyze the therapeutic efficacy of subacromial infiltration
of PRP in patients with rotator cuff impingement syndrome compared with subacromial
corticosteroid injection.
Methods
This clinical trial is a double-blind, randomized, controlled, interventional study
of patients with rotator cuff impingement syndrome. The patients were randomized into
blocks and assigned to receive treatment with PRP or to receive corticosteroid injection.
The sample consisted of 51 patients, 25 in the corticoid group and 26 in the PRP group.
The number of patients in the sample estimated to have a confidence interval of 95%,
and power of 80% to detect a difference of 15 points in the DASH score, with a standard
deviation (SD) of 10 was 20.4 for each group. To allow for a conservative withdraw
of ∼ 20%, we recruited a total of 51 patients. No imputation protocol was implemented
regarding sample loss. The block randomization was performed using the online engine
sealedenvelope.com, which generated a list of patient admission number and corresponding
treatment. The researcher responsible for patient admission was not aware of the randomization
or group allocation, and the order of admission was followed thoroughly.
Platelet-rich plasma was obtained through 15 ml of the patient's peripheral blood
that underwent a double centrifugation protocol (1,500 rpm for 6 minutes, then 3,500 rpm
for 15 minutes in a Coleman 80–2C Macro Centrifuge) and manual platelet separation
with micropipettes, including the buffy coat and then transferred to test tube for
concentration. The outcome is ∼ 3 ml of PRP, transferred to syringe for injection.
All materials used were sterile and disposable. The corticosteroid used was betamethasone
dipropionate. To maintain the double-blind characteristic, peripheral blood was collected
from all patients, and the nature of the treatment was hidden from both the patient
and care provider. One of the researchers was responsible for patient allocation,
preparation of the treatment and assuring double blindness. The injections were made
in the subacromial space through a posterior approach after anesthesia with 1% lidocaine,
and they were not guided by ultrasound. All participants were instructed to rest the
injected shoulder for 24 h. No changes to medication or rehabilitation program were
recommended.
To evaluate the therapeutic response, the tools used were: University of California
Los Angeles (UCLA) shoulder rRating scale, Constant-Murley Shoulder Outcome Score
(CMS), and The The Disabilities of the Arm, Shoulder and Hand (DASH) outcome measure.
The patients were evaluated before the procedure, and at 1, 3, and 6 months after
the intervention. All patients were informed regarding possible side-effects throughout
the follow-up period.
The inclusion criteria used were: age between 18 and 70 years old, positive Neer impingement
test; no previous treatment of intravenous (IV), injectable, or oral corticosteroids
in the last 12 months; hemoglobin ˃11 g/dl; platelet count ˃150,000/mm3, and signature of the informed consent form. The exclusion criteria were: association
with adhesive capsulitis, complete rupture of the rotator cuff in ultrasonography
(all other forms of tendinopathy were included), and use of oral or parenteral corticosteroids
during the study.
This research was fully conducted at the deCós Day Hospital, in Aracaju, Brazil. Patient
recruiting and follow-up were conducted from October 2015 to July 2016 and ended after
6 months follow-up of the last recruited patient. The data were tabulated and analyzed
in the Statistical Package for Social Sciences (SPSS), version 19.0 (IBM Corp., Armonk,
NY, USA).
In this research, the confidentiality and privacy of the participating professionals
were assured, ensuring that the information of the questionnaire was not used to the
detriment of the people involved. All patients signed an informed consent form. This
study was approved by the research ethics committee of Tiradentes University - CEP/UNIT
(CAAE: 49144515.90000.5371) and is registered in The Brazilian Registry of Clinical
Trials—ReBEC (UTN: U1111–1195–9769).
Results
The mean age of the patients in this sample was 53 years old. A total of 64% of the
patients were female, with pain in the right shoulder (45%), weighing an average 72 kg
and measuring 1.6 m, and with a body mass index (BMI) of 28 kg/m2. The epidemiological profile of the sample is characterized in [Table 1]. Of the patients studied, only 40 returned for evaluation after 1 month of treatment
(19 in the corticoid group and 21 in the PRP group); 27 completed 3 months of treatment
(10 in the corticoid group and 17 in the PRP group), and 22 patients completed 6 months
of treatment (10 in the corticoid group and 12 in the PRP group). No imputation protocol
was implemented in this study, and all data acquired was utilized in data analysis.
Table 1
|
Treatament received
|
|
|
|
PRP
|
Corticoid
|
Total
|
p-value
|
|
Age – n (%)
|
|
|
|
|
< 35 years old
|
1 (4)
|
1 (4)
|
2 (4)
|
0.41
|
|
36–45 years old
|
4 (15)
|
4 (16)
|
8 (16)
|
|
|
46–55 years old
|
9 (35)
|
8 (32)
|
17 (33)
|
|
|
56–65 years old
|
10 (38)
|
6 (24)
|
16 (31)
|
|
|
> 65 years old
|
2 (8)
|
2 (8)
|
4 (8)
|
|
|
Not informed
|
0 (0)
|
4 (16)
|
4 (8)
|
|
|
Total
|
26 (49)
|
25 (51)
|
51 (100)
|
|
|
Mean ± SD
|
53.2 ± 9,4
|
53 ± 11
|
53.1 ± 10
|
|
|
Gender – n (%)
|
|
|
|
|
|
Male
|
11 (42)
|
7 (28)
|
18 (36)
|
0.433
|
|
Female
|
15 (57)
|
18 (72)
|
33 (64)
|
|
|
Affected side – n (%)
|
|
Right shoulder
|
11 (44)
|
21 (80)
|
23 (45)
|
0.015
|
|
Left shoulder
|
11 (44)
|
5 (20)
|
16 (31)
|
|
|
Anthropometric data – Mean ± SD
|
|
Height (m)
|
1.6 ± 0.1
|
1.6 ± 0.1
|
1.6 ± 0.1
|
0.054
|
|
Weight (Kg)
|
72.2 ± 13.7
|
71.8 ± 16.3
|
72.0 ± 14.7
|
0.196
|
|
BMI (Kg/m2)
|
28.4 ± 3.7
|
27.6 ± 5.0
|
28.0 ± 4.3
|
0.258
|
The values obtained through the questionnaires at the time before the intervention
and after 1, 3, and 6 months were compared between the groups using the independent
Student t-test and the Mann-Whitney test, and are shown in [Table 2].
Table 2
|
Tratament received
|
|
|
|
PRP
|
Corticoid
|
CI 95%
|
p-score
|
|
DASH outcome
|
|
|
|
|
Admission
|
53.3
|
54.5
|
[-52.9; 21.35]
|
0.135
|
|
1 month
|
32.5
|
22.9
|
[-37.01; -0.85]
|
0.205
|
|
3 months
|
23.5
|
20.2
|
[-104.76; 44.08]
|
0.235
|
|
6 months
|
21.6
|
17.7
|
[-14.14; 18.57]
|
0.824
|
|
UCLA shoulder rating scale
|
|
Admission
|
13.4
|
14.9
|
[-3,.02; 6.19]
|
0.926
|
|
1 month
|
23
|
23.9
|
[-4.45; 6.07]
|
0.832
|
|
3 months
|
29.3
|
29.6
|
[-9.54; 10.16]
|
0.898
|
|
6 months
|
27
|
27.6
|
[-8.53; 9.73]
|
0.005
|
|
Constant shoulder score
|
|
|
|
|
Admission
|
45.9
|
49.8
|
[-5.04; 12.80]
|
0.049
|
|
1 month
|
55.4
|
58.8
|
[-4.43; 11.12]
|
0.503
|
|
3 months
|
59.8
|
68
|
[-5.39; 21.74]
|
0.848
|
|
6 months
|
62.9
|
56.9
|
[-21.45; 9.42]
|
0.228
|
When comparing the results of the DASH outcome measure after 1, 3, and 6 months of
treatment with the preintervention values, we identified a statistically significant
difference (p < 0.05) in both PRP and corticoid groups at all moments studied, as shown in [Fig. 1]. Through the evaluation of the progression of the UCLA shoulder rating scale ([Fig. 2]), we also identified that there were statistically significant differences (p < 0.05) when comparing the scores at admission to the scores at 1 and 3 months of
treatment in both groups.
Fig. 1 Evolution of the Disabilities of the Arm, Shoulder and Hand (DASH) score of patients
with rotator cuff tendinopathy after 1, 3, and 6 months of treatment with corticosteroids
and platelet-rich plasma. (p-value shown represents statistical difference from that of admission). Abbreviations:
DASH, Disabilities of the Arm, Shoulder and Hand; PRP, platelet-rich plasma.
Fig. 2 Evolution of the University of California Los Angeles UCLA shoulder rating scale
of patients with rotator cuff tendinopathy after 1, 3, and 6 months of corticosteroids
and platelet-rich plasma treatment. (p-value shown represents statistical difference from that of admission). Abbreviations:
UCLA, University of California Los Angeles; PRP, platelet-rich plasma.
In the CMS, the difference between the values obtained during the follow-up of the
PRP group was statistically significant after 1 month (p < 0.05), but it was not statistically significant at 3 months (p = 0.07) and at the 6 months' follow-up (p = 0.103) in comparison to the score at admission, as shown in [Fig. 3]. In the corticoid group, there was a statistically significant difference after
1 and 3 months of treatment (p < 0.05). However, there was no statistically significant difference after 6 months
(p = 0.760) in comparison to the admission score. For statistical evaluation of progression
among the treatment groups, the Student t-test with paired samples and the Wilcoxon test were applied.
Fig. 3 Evolution of the Constant-Murley shoulder outcome score (CMS)of patients with rotator
cuff tendinopathy after 1, 3, and 6 months of corticosteroids and platelet-rich plasma
treatment. (p-value shown represents statistical difference from that of admission). Abbreviation:
PRP, platelet-rich plasma.
Discussion
This randomized, controlled, double-blind, longitudinal study demonstrates the effects
of treatment with a single infiltration of corticosteroids and PRP in the therapeutic
process of rotator cuff tendinopathy.
In the present study, the patients who received PRP showed a mean difference of 20.8
points in the DASH score during the first month of follow-up, which already shows
a significant improvement in pain and limb function in the short term (difference
greater than 15 points).[10] On the other hand, the patients in the corticoid group had a mean difference of
31.6 points, which shows that both groups presented a significant reduction (p < 0.05) of the short-term DASH score. The DASH scores remained significant in relation
to admission even after 3 and 6 months of follow-up.
The group of patients that received corticosteroids, apparently, had a better response
to pain and function at the 1 and 3 months follow-ups. At 6 months of follow-up, both
groups presented similar results. Nevertheless, the differences presented between
the groups at the 3 moments were not statistically significant (p > 0.05). The positive and significant results in the DASH outcome measure symbolize
that in both treatment modalities there was an improvement in the daily challenges
associated with the painful shoulder in the patients' own perception, as well as a
decrease in symptoms, and a lower influence of these symptoms on the psychosocial
and occupational spheres.
The clinical improvement observed in the group that received PRP in this study was
also observed by other authors. A longitudinal study[11] on the use of PRP in rotator cuff tendinopathy identified a gradual improvement
in the visual analytical scale at 8 and 52 weeks of treatment. The authors used a
different form of measurement of the therapeutic response, but noticed a gradual reduction
of the symptoms, a finding also observed in the current research through the decreasing
values in the DASH score.
The other scores used in this study showed similar results. The UCLA shoulder rating
scale uses an association of subjective pain and function variables with objective
variables of shoulder function to assess the therapeutic response after a procedure
through pain, function, movement, strength, and patient satisfaction parameters. The
therapeutic response was significant at 1 and 3 months of treatment (p < 0.05), but the difference from the admission score was not significant at 6 months
(p = 0.138), which can be explained by the low number of participants who finished the
study. One study[12] used intraoperative PRP in arthroscopic repairs of complete ruptures of the rotator
cuff and found that PRP has positive results in the CMS and UCLA scores.
The CMS is a more objective questionnaire that measures the shoulder function through
the range of motion and strength, with less relevance of the symptoms in the final
score. The results of the CMS show that a measurable improvement in the shoulder function
was only identified in the 1st month after treatment with PRP up to 3 months after corticosteroid use, and, in the
latter, there was a general worsening of function in relation to admission. When compared
with the results found by another study[12], the findings of the current study appear to be less significant, but this fact
is probably associated with the association of surgical treatment with the PRP used
by the authors. Platelet-rich plasma has been shown[13] to have improvement in several parameters of the CMS, including pain and range of
motion up to 3 months after injection, showing similar results when compared with
the present study.
A systematic review meta-analysis[14] has studied the efficacy of PRP on tendon and ligament healing using 37 articles.
In this study, PRP groups showed significantly less pain in the long-term follow-up
when compared with the control groups. This finding may correlate to the current study,
when considering the long-term worsening found in the CMS in the corticoid group,
while the PRP effects have shown more durability.
A prospective, randomized, controlled study[15] compared PRP and corticosteroid injection in 40 patients with partial rotator cuff
tears. Both groups showed statistically significant better scores when compared with
the baseline before injection. And when comparing the groups, the PRP group showed
significantly better results at the 12 weeks evaluation, with no difference after
6 months.
In contrast, another comparative[16] study of the use of PRP and prednisone in the treatment of rotator cuff syndrome
concluded that even though both treatments had positive results, their findings showed
that patients who received corticoid had a significantly better clinical response
than those who received PRP, both at 6 weeks and at 6 months. The present study agrees
with both studies when showing positive results with both treatments; however, our
findings agree with those of Shams et al when considering PRP equivalent or non-inferior
when compared with corticosteroid injections. The present study concurs with the data
found by Say et al regarding the short-term response, but disagrees with the long-term
response, since the difference at 6 months between the two groups was not significant.
This divergence has been prevalent in PRP literature, and these varying results may
have been due to the different preparation protocols, the corticoid used, or the methodology
of the study. New studies are still necessary for further understanding.
A randomized, double-blind, controlled clinical trial[17] was conducted with the use of PRP in the treatment of chronic tendinopathy of the
rotator cuff. The authors found that there was no significant difference between the
use of PRP and placebo in the Western Ontario Rotator Cuff (WORC) index, Shoulder
Pain and Disability Index (SPADI) and visual analogue scale (VAS) scores throughout
the study, concluding that PRP was no more effective than placebo in improving quality
of life, pain, dysfunction, or range of motion. This study stands against the use
of PRP to treat this condition, with a level 1 of evidence. This supports the hypothesis
that corticosteroids may not have value in the long-term treatment of rotator cuff
tendinopathies, since through the comparison performed in this study there was no
significant difference between the therapeutic responses of corticosteroids and PRP.
The authors also identified that there was a therapeutic improvement in the two groups
studied, and hypothesized that improvement would also be observed if there was a group
that was not submitted to any procedure, since just physical exercise is already associated
with short and long term improvement of the rotator cuff tendinopathies.[18]
The apparent improvement of patients that underwent subacromial infiltrations may
also be associated with the dry needling performed to maintain the double-blind character
of the investigations.[19] Authors identified an unexpected positive result in patients that received dry needling,
which is explained as a stimulus to regeneration through extravasation of blood and
subsequent local inflammatory reaction. Dry needling, although limited, is a mechanism
that is similar to the use of PRP.
Despite the positive results with the subacromial use of corticosteroids, evidence
in the literature does not value the use of this drug in rotator cuff diseases. A
review[20] identifies two studies that favored the use of corticosteroids, two studies that
did not observe a significant difference between corticoid and placebo, and a study
favoring placebo results. In addition, there are studies[20]
[21] that have investigated the association of corticosteroids with NSAIDs compared with
the use of NSAIDs alone, with no significant difference found between the two groups,
suggesting that similar or better therapeutic responses can be achieved without exposing
the patient to the possible side effects of corticosteroid injections.
Patients who underwent corticosteroid injections had to seek health services more
frequently than patients who had only motor physical therapy during a 1 year follow-up
due to persistence or relapse of symptoms, requiring new rounds of injections.[22] These findings are comparable to those encountered in the current study in the 6-month
evaluation of the CMS and UCLA shoulder rating scale, since there was a decrease in
these scores, symbolizing worsening of symptoms in relation to the previous evaluation
and possibly indicating the need for new applications or other adjunctive therapy.
Due to its autologous characteristic, PRP is a safe treatment for clinical use.[1] The patients in the current study did not report any side effects during the whole
follow-up period beyond the expected local pain up to 24 hours of the application,
which is expected from the needle injection in the period after the end of the local
anesthetic effect.
The limitations found in this study were: absence of a placebo group for comparison
with the natural history of the disease, and the absence of complete 6-month follow-up
of all patients in the sample. This work still opens the possibility of being optimized
with protocols of PRP preparation, better concentrations and reproducibility. Current
studies seem to indicate that multiple PRP applications may have value in increasing
the clinical response to this treatment. The application of three doses of PRP has
been shown to be significant in the treatment of early stages of osteoarthritis[23] and chronic patellar tendinopathy[24], and this pattern can also be repeated for rotator cuff tendinopathies. In addition,
PRP has been studied[25] to be used in conjunction with corticosteroid, as PRP does not affect the effects
of dexamethasone on tenocytes and its antiinflammatory effect, showing that these
treatments may have a synergic clinical response regarding pain and tissue regeneration.
The efficacy of PRP as a therapeutic modality still needs to be better clarified,
but its characteristics make it a promising therapy in the treatment of rotator cuff
tendinopathy. Corticosteroids, although well studied when their efficacy and side
effects, remain rising concern in its chronic use in clinical practice.
Conclusion
This study concludes that subacromial injections of autologous PRP and corticosteroids
have a positive and similar clinical response in the treatment of rotator cuff tendinopathies.
When analyzing scores that consider the range of motion and strength, the patients
only found significant results in the short term (1–3 months), and, in the corticosteroid
group, functional worsening was observed at 6 months. These findings suggest that
PRP is a safe treatment and may be a useful tool in the therapeutic arsenal against
rotator cuff diseases, especially by avoiding possible adverse effects associated
with the use of corticosteroids.
