The Effects of Platelet Rich Plasma Versus Prolotherapy on Pain and Function in Rotator Cuff Tendinopathy: A Randomized Clinical Trial
Phase: PHASE1
Conditions: Rotator Cuff Tendinosis, Supraspinatus Strain, PRP
Sponsor: University of Malaya

 
 
 
 
 
TITLE: 
 
The Effects of Platelet-Rich Plasma vs Prolotherapy Injection on 
Functional and Pain Scores in Supraspinatus Tendinopathy: A 
Randomized Controlled Trial. 
 
 
 
 
 
 
 
 
 
 
DATE: 23RD AUGUST 2019 
 
 
 
 
 
 
 

 
 
 
 
The Effects of Platelet-Rich Plasma vs Prolotherapy Injection on Functional and Pain 
Scores in Supraspinatus Tendinopathy: A Randomized Controlled Trial. 
A) Background 
Shoulder pain and dysfunction are frequently encountered in the clinical setting. It is a 
complex problem and affects the person's ability to carry out daily activities and work. The 
point prevalence of shoulder pain varies from 14% to 21% in the general population 1,2.  A 14-
years follow up study showed the prevalence of shoulder pain increased by 8.5% from the 
1990s to 20043.  In primary care, the common causes of shoulder pain and disability are rotator 
cuff disorders, glenohumeral disorders and acromioclavicular joint disease4. Rotator cuff 
tendinopathy is defined as “pain and weakness, most commonly experienced with movements 
of shoulder external rotation and elevation, as a consequence of excessive load on the rotator 
cuff tissues"5. The pathology of rotator cuff tendon injury is in a continuum from 
underloaded/overloaded tendon to reactive tendinopathy, tendon disrepair and finally 
degenerated tendon6. Understanding of the pathological and repair process will enhance the 
management of a patient with such pathology.  
Treatment options ranges from conservative, which consist of non-invasive such as 
rehabilitation to more invasive injection procedure and finally, surgical treatment. A systematic 
review showed limited evidence that surgery is more effective in treating rotator cuff tear than 
conservative treatment alone7. At an early stage, the use of anti-inflammatory, exercise and 
electrotherapeutic modalities are to control the inflammatory phase of tendon disease. 
However, despite the treatment above, recalcitrant tendinopathy may manifest because, once 
damaged, the biological and biomechanical properties of tendon tissue never completely 
restored. Healing times in chronic tendinopathies are prolonged as tendons are relatively less 
vascular and local blood flow is less than verged delivered to the muscles. Thus, in recent years, 
the use of platelet rich plasma and prolotherapy has been emerging as a treatment option for 
rotator cuff tendinopathy8. Platelet rich plasma with its supraphysiologic platelet concentration 
has the potential to release biologically active proteins that promote cellular recruitment, 
growth and morphogenesis. Tendon healing is thought to be stimulated via enhanced fibroblast 
migration and proliferation, increased the tissue vascularization and collagen deposition9.  
Prolotherapy is an injection of small volumes of an irritant such as dextrose into the 
insertion sites of the damaged tendon, which promotes the growth of normal tissue. Studies 
hypothesize that the injected substance mimics the natural healing processes by facilitating a 

 
 
 
 
local inflammatory cascade, which triggers the release of growth factors and collagen 
deposition10. Both interventions showed a good outcome for the treatment of rotator cuff 
tendinopathy.  
 
Hypothesis: 
1. Participants treated with prolotherapy injection showed a significantly higher clinical 
and functional scores compared to control group 
2. Participants treated with platelet-rich plasma injection showed a significantly higher 
clinical and function scores compared to control group 
 
Problem statements: 
Platelet rich plasma and prolotherapy have been the option treatment for tendinopathy, 
particularly in lateral epicondylitis and Achilles tendinosis. However, the study on the 
rotator cuff is still limited. No study compares the effect of PRP to prolotherapy is 
available. Furthermore, the reviews on the factors that may influence the outcome were 
minimal.  
 
 
 

 
 
 
 
Literature Review 
 
Traditionally, the first-line management of rotator cuff tendinopathy included anti-
inflammatory approach by using NSAIDs or corticosteroid. However, several studies 
demonstrate little or no inflammation is present in tendinopathy. Histopathologic changes 
associated with tendinopathy include degeneration and disorganization of collagen fibers, 
increased cellularity, and minimal inflammation. Macroscopic changes include tendon 
thickening, loss of mechanical properties, and pain. PRP and prolotherapy are believed to kick 
start the inflammatory process and promote tendon healing11.  
 
The study on the role of PRP for rotator cuff healing is limited. Most of the study assess 
the clinical effect of PRP injection after arthroscopic rotator cuff repair 14,15. Besides that, 
majority systematic reviews on the use of PRP not only limited to rotator cuff problem but 
included other tendinopathies including lateral epicondylitis and Achilles tendinopathies. 
Moreover studies, vary in PRP preparation methods and PRP class (leukocyte poor vs 
leukocyte rich PRP) as well as the volume of PRP injected into the tendons (ranges from 1 ml 
to 5 ml). Studies also differs in the use of platelet activation, and the use of lignocaine before 
injection 12,16,17. In general, the PRP was more efficient than control in reducing tendinopathy 
pain, with an effect size of 0.47 (95% CI 0.22 to 0.72, p<0.001), signifying a moderate 
treatment effect9.  
 
The use of prolotherapy is based on the hypothesis that hypertonic dextrose solutions 
in the extracellular matrix provide local tissue irritation that initiates an acute inflammatory 
response and improves fibroblast proliferation and subsequent collagen synthesis, which 
provides healing and tissue renewal18. Previous studies differes in the types of prolotherapy 
used for rotator cuff tendinopathy. Various substances were used by previous studies which 
include dextrose, phenol-glycerine-glucose (P2G), and sodium morrhuate. Results of the 
studies were inconsistent, ranging from no effect19 to some functional improvement20 and pain 
reduction13.  
 
A recent systematic review comparing the effectiveness of injection therapies in rotator 
cuff pathology concludes: “corticosteroid was more effective only in the short-term in both 
pain reduction and functional improvement. Network meta-analysis indicated that prolotherapy 
significantly reduced pain compared with placebo in the long-term [over 24 weeks, SMD: 2.63, 
95% confidence interval (CI): 1.88-3.38]; meanwhile PRP significantly improved shoulder 

 
 
 
 
function compared with placebo in the long-term (over 24 weeks, SMD: 0.44, 95% CI: 0.05-
0.84)”. 21 
 
B) Research Objective: 
1. To investigate the effects of platelet rich plasma injection on clinical and functional 
outcome for the treatment of rotator cuff tendinopathy. 
2. To investigate the effects of prolotherapy injection on clinical and functional outcome 
for the treatment of rotator cuff tendinopathy. 
3. To compare the effect of platelet rich plasma vs prolotherapy injections for the 
treatment of rotator cuff tendinopathy 
4. To analyses the factors that may result in the different outcome between PRP and 
prolotherapy intervention. 
 
C) Methodology 
Research Plan 
This study will implement a three-armed double-blind, randomized control trial design.  The 
study will run for 2 years. Recruitment will be for 12 months with a final follow-up at 6 months 
post treatment.  
 
Recruitment centers and participant 
Participants will be recruited at the University Malaya Medical Centre from Sports Medicine 
clinic, Orthopedic clinic, Rheumatology clinic and Primary Care clinic. Interested participants 
will undergo an eligibility assessment before recruitment.  
Inclusion criteria are:  
1) Individual age 18 and above 
2) Shoulder pain more than 6 weeks3 months 
3) Diagnosis of painful rotator cuff tendinopathy by Sports Physician/ Orthopaedic Sports 
Surgeon: by clinical test and ultrasound 
 

 
 
 
 
Exclusion criteria are: 
1) Patients with the following medical conditions: autoimmune rheumatology disease, 
immunocompromised, blood disorder (thrombocytopenia and anemia). 
2) Patients with the following shoulder conditions: referred pain from cervical, recent 
shoulder surgery, shoulder instability and dislocation, complete rotator cuff tear, 
Adhesive capsulitis, grade III acromion (Biligani classification) based on the 
radiological finding. 
3) Patient with the following medications: anti-coagulant treatment, steroid injection in 
less than 2 months 
4) Patient with the following laboratory findings: Haemoglobin level less than 10 g/L 
and/or platelet count less than 100,000/μL 
5) Unable to follow study protocol 
 
Sample size calculation and estimation 
The sample size was estimated based on the primary outcome of functional score. Improvement 
was defined by a decrease in the mean Shoulder Pain and Disability Index (SPADI) of 17.7 ± 
3.7 in the platelet-rich plasma group11 and 16.12 ± 12.8211 for prolotherapy. For this study, the 
sample size was calculated after taking into account the desired statistical significance level set 
at 5%, and the power of the study set at 80%, with type I error rate of less than 0.05 is permitted 
and a false-negative rate of less than 0.20. The sample size is calculated using the G*Power 
version 3.1.9.2 software11. With the assumption of 30% drop out, hence, to detect a difference 
in the functional outcome, a minimum of 30 patients in each group is required.  
 
Procedures 
Informed consent will be obtained from the patients before intervention. All 
participants are required to complete the functional questionnaire (name of the functional 
questionnaire = SPADI??). Participants will be assessed by Sports Physician for eligibility. 
Subsequently, ultrasound assessment will be performed by one musculoskeletal (MSK) 
radiologist or a Sports Physician with more than 10 years’ experience in performing MSK 
ultrasound.  Blood will be sent for full blood count test to assess the hemoglobin and platelet 
levels. A plain shoulder radiography (indicate views that will be ordered) will also be 

 
 
 
 
performed to exclude Type III acromion. Electromyogram and strength testing will be done at 
the first visit for all patients.  
Patients who fulfilled the study criteria will be randomly assigned using computer-
generated block randomization to receive either PRP, prolotherapy or normal saline injections. 
On the procedure day, blood will be withdrawn from all the patients to ensure blinding of 
participants. A covered syringe contains the solutions will be prepared by the investigator to 
ensure its content is not visible. The procedure will be performed under ultrasound guidance 
with the patient sitting on a chair, in a modified crass position. All shoulder injection will be 
performed by a co-investigator who are not involved in outcome measure assessment of 
patient’s progress. Post injection, the patients will be advised to rest, and avoid vigorous 
shoulder activities. The patients are allowed to take paracetamol if the pain is intolerable (up 
to 1000mg every 6 hourly. Patient are required to record the amount of paracetamol that they 
take.  
During the follow up, the Sports Physician and or radiologist who assess the patient at 
baseline will repeat the assessment. The involved physician will not be informed of the 
intervention received by the participants. (Refer to Figure 1: Flowchart of the study). 
Intervention 
Platelet rich plasma: We will use a commercially available kit (YCELLBIO Kit). The 
autologous PRP will be prepared in accordance with the manufacturer’s guideline. Fifteen (15) 
ml blood will be collected, according to a standard PRP kit; this volume can produce 
approximately 3 mL of PRP. Two milliliters of the PRP will be delivered to the injured area 
under ultrasound guidance.  
Prolotherapy: We will dilute dextrose 50% in bacteriostatic water to get 16.5 % solution. One 
to two ml of the dextrose solution will be injected into the area of painful tendinosis under 
ultrasound guidance.  
All participants will receive single injection. The injection will be under ultrasound guided 
intralesional.  
 
 
 

 
 
 
 
 
Outcome measures 
Study assessments will include the following assessment at baseline, 3 weeks, 3 months and 6 
months. 
• Clinical outcome: Range of movement and special test for rotator cuff 
• Functional outcome: Shoulder Pain and Disability Index (SPADI) questionnaire  
• Pain: Visual analogue score (VAS) 
• Ultrasound assessment characteristics: tendon thickening, changes in the normal 
contour and echotexture lost in the fibrillar pattern, hypoechoic changes, swelling, 
neovascularization, and partial tear. 
• Biomechanics analysis: dynamometer for strength and electromyogram of 
periscapular muscle 
 
Statistical Analysis 
The primary outcome of the study which consist of the mean difference in pain and shoulder 
function will be analyzed with independent T-test. For secondary outcome, range of movement, 
strength, ultrasound findings and electromyogram result independent T-test will be used for 
continuous data and Fisher exact test for categorical data.  
 
 

 
 
 
 
D) Expected Results/Benefit 
i. 
Novel theories/New findings/Knowledge 
Platelet rich plasma and prolotherapy is a treatment of choice for recalcitrant 
supraspinatus tendinopathy. However, the effect may be influenced by several factors 
such as clinical examination at presentation and ultrasound findings.  
ii. 
Specific or Potential Applications: 
PRP and prolotherapy can result in improvement of shoulder function in patients with 
chronic shoulder pain. The costs are cheaper compared to surgery.  
 
 

 
 
 
 
Appendix 1: Flowchart of the study: 
 
 
 
 
 
Patient selection 
from relevant clinic 
in UMMC 
Screening 
 in accordance to 
Inclusion Criteria 
Baseline:  
1. Informed consent 
2. Baseline: clinical assessment, blood 
investigations, ultrasound assessment, EMG 
and dynamometer 
Patient allocation 
Blood will be withdrawn 
from all patients 
30 patients for PRP 
30 patients for 
Prolotherapy 
Assessment at 3 weeks 
1. Functional assessment: SPADI 
2. Pain: VAS 
3. Clinical examination 
Figure 1: Flowchart of research activity 
Assessment at 3 months and 6 months:  
1. Functional assessment: SPADI 
2. Pain: VAS 
3. Clinical examination 
4. Ultrasound 
5. Electromyogram & Dynamometer 

 
 
 
 
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Appendix 1 
SHOULDER PAIN AND DISABILITY INDEX (SPADI) 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Appendix 2 
PATIENT’S FORM 
Patients’ History 
 
Name:  
RN:  
 
 
 
 
 Age: 
 
Gender: Male/ Female 
    
 
 Ethnics: Malay/ Chinese/ Indian/ Others _______________ 
Occupation:  
Job description: 
__________________________________________________________________________________________
__________________________________________________________________________________________
__________________________________________________________________________________________
__________________________________________________________________________________________ 
Smoker: No / Yes 
Medical Illness: No/ Yes 
__________________________________________________________________________________________
__________________________________________________________________________________________
__________________________________________________________________________________________ 
Medication: 
__________________________________________________________________________________________
__________________________________________________________________________________________
__________________________________________________________________________________________ 
 
 

 
 
 
 
 
Clinical Examination 
Height:   
 
Weight:   
 
 
 
BMI: 
 
Dominant Hand: Right/ Left 
Involved Side: Right/ Left/ Bilateral 
Range of movement (goniometer): 
ROM 
Degrees 
ROM 
Degrees 
Forward flexion 
 
Internal Rotation (hand at side) 
 
Extension 
 
Internal rotation (90) 
 
Abduction 
 
External rotation (hand at side) 
 
Adduction 
 
External Rotation (90) 
 
 
Painful site (most tender area) 
Non-specific anterior 
 
Supraspinatus fossa 
 
Non-specific posterior 
 
AC joint  
 
Greater tuberosity 
 
Others: 
 
Bicipital groove 
 
 
 
 
Special Test: 
 
 
Description 
Empty can (Jobe’s test) 
+ / - / NA 
 
Full can test 
 
 
Resisted external  
 
 
Gerber’s lift off test 
 
 
Hawkin’s Kennedy 
 
 
Neer’s Sign 
 
 
Drop arm test 
 
 
Other test with positive findings: 
 
 
 
 
 
 

 
 
 
 
 
Handheld (Commander dynamometer test) 
 
T1      T2        T3        Avg 
 
  T1     T2      T3       Avg 
Forward flexion 
 
 
 
 
Internal Rotation (hand at side) 
 
 
 
 
Abduction 
 
 
 
 
Internal rotation (90°) 
 
 
 
 
Abduction 30° 
 
 
 
 
External rotation (hand at side) 
 
 
 
 
Adduction 
 
 
 
 
External Rotation (90°) 
 
 
 
 
*T- Trial 
  Avg- Average