Treatment of persistent shoulder pain

                              Dr. KS Dhillon

Persistent shoulder pain is a common clinical problem and it is often associated with limited range of motion and decreased function [1,2]. An estimated 20 percent of the population will suffer shoulder pain during their lifetime [3]. Shoulder pain is second only to low back pain in patients seeking care for musculoskeletal ailments. There are several causes of such persistent pain and these include glenohumeral osteoarthritis, rotator cuff tears, subacromial impingement, tendinitis, adhesive capsulitis, and subacromial bursitis [4].

Damage or dysfunction affecting one component of the shoulder can lead to secondary pathological changes, in other areas of the shoulder leading to persistent pain [4,5]. A rotator cuff tear, for example, can lead to mechanical and degenerative changes in the glenohumeral joint and that can result in symptomatology [4,6,7].

Effective treatment depends on an accurate diagnosis of the cause of the shoulder pain. The causes of the shoulder pain can include the following diagnosis, rotator cuff disorders, adhesive capsulitis, acromioclavicular osteoarthritis, glenohumeral osteoarthritis, and shoulder instability.

The initial treatment involves activity modification and analgesic medications. If no improvement occurs or if the initial presentation is very severe, a trial of physical therapy that focuses on the particular diagnosis is indicated. 

Combined local anesthetic and steroid injections can be used alone or in combination with physical therapy. The site of the injection depends on the diagnosis and it can be into the shoulder joint, subacromial space, or into the acromioclavicular joint. Injections into the glenohumeral joint are usually done under fluoroscopic guidance. 

Treatment Overview

A systematic review of randomised controlled trials of interventions for painful shoulder showed little evidence for or against the most common treatments of chronic shoulder disorders [8]. This is mainly because of a lack of well-designed clinical trials. Nevertheless, most patients with chronic shoulder disorders can initially be treated conservatively with a combination of activity modification, physical therapy, medications, and steroid injections if necessary.

The outcome of this approach is satisfactory in majority of the patients [9,10].  

Activity Modification

A simple treatment for reducing shoulder pain is activity modification.  Recommendations are based on the underlying diagnosis. Avoidance or reduction of overhead activity is the mainstay of treatment for patients with glenohumeral osteoarthritis, rotator cuff pathology, and adhesive capsulitis because this avoids the painful arc between 60 to 120 degrees. Heavy loading of the shoulder should be avoided in patients with glenohumeral osteoarthritis to reduce pain. Certain activities such as bench pressing, kayaking, and overhead throwing should be avoided in patients with an unstable shoulder. In patients with acromioclavicular osteoarthritis cross-body shoulder adduction, such as the motion performed in the golf swing or weight lifting, should be limited to prevent pain. 

Medications

Pain control with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or short-term opiate medication is imperative to allow for the progression of treatment. Although NSAIDs are widely used to treat pain, there is no conclusive evidence to support the use of NSAIDs over simple analgesia in the treatment of chronic shoulder pain [11]. The risks and benefits of each class of drugs should be considered before its use [4].

Physical Therapy

Physical therapy includes several types of treatment. There are several modalities to alleviate pain such as heat and ice, ultrasound, hyperthermia, and iontophoresis. Stretching and strengthening exercises improves overall shoulder function and relieves pain. 

The type of physical therapy will depend on the underlying etiology. Little evidence exists for the use of these therapeutic modalities alone [12]. A Cochrane review showed that strengthening and stretching exercises provide improved short-term recovery and long-term function in patients with rotator cuff disease [12].

Calis et al [13] carried out a study to compare the efficacy of sodium hyaluronate injection with the most common treatment methods, such as intraarticular steroid injection, and physical therapy modalities in patients with adhesive capsulitis. They found that physical therapy provided the best results as compared to other treatment modalities.

For success of physical therapy, the underlying diagnosis must be known and the patient must actively participate in the rehabilitation process on a daily basis.

Injections

Corticosteroid injections combined with a local anesthetic are administered if patients have a poor response to initial treatment for chronic shoulder disorders. The injection has to be directed toward the area of underlying pathology, such as the subacromial space, glenohumeral joint, or acromioclavicular joint. 

The role of subacromial injection for rotator cuff disease is an area of controversy as well as active research. There are two systematic reviews that found little evidence to support or refute the use of subacromial injections and there are two systematic reviews that found it to be beneficial for rotator cuff tendinitis and shoulder pain. There is another review that suggested a possible small benefit [14-18]. 

There are several studies that have found subacromial injections to be beneficial,  for short-term decrease in pain and increase in function [17,18,19,20].

A study by Koh KH [21] to assess the efficacy and safety of corticosteroid injections for adhesive capsulitis showed that corticosteroid injection is superior to placebo and physiotherapy in the short-term (up to 12 weeks), but there is no difference in outcomes between corticosteroid injection and oral nonsteroidal anti-inflammatory drugs at 24 weeks.

A systematic review of corticosteroid injections into the shoulder for adhesive capsulitis by Shah N [22] provided convincing evidence based on 3 high-quality studies in which use of multiple corticosteroid injections had beneficial effect on pain reduction, improved function and increased range of movements.

According to the American Academy of Orthopedic Surgeons (AAOS), there is moderate evidence to support the use of a single injection of steroids with local anesthetic for short-term pain relief and improvement in shoulder function in patients with rotator cuff tears [23].

In patients with adhesive capsulitis, intra-articular injections of steroids decrease pain and increase function, particularly in combination with physical therapy for stretching [18,24].

The AAOS does not recommend the use of intra-articular steroid injections for glenohumeral osteoarthritis [25]. The AAOS has no recommendation for use of hyaluronic acid injection in patients with glenohumeral osteoarthritis [4]. 

The AAOS endorses the use of steroid injection into the acromioclavicular joint for osteoarthritis despite few studies demonstrating its effectiveness [25]. 

Surgery

Most patients respond to conservative treatment for shoulder pain. Those patients who do not respond to conservative treatment, surgical treatment may be required. Patients with continued instability or disabling pain that is not responsive to conservative treatment may require surgical treatment [4,25,26]. 

Treatment of Specific Conditions

1. Acromioclavicular osteoarthritis

Acromioclavicular osteoarthritis is a common condition and it can produce chronic shoulder pain. It can be associated with subacromial impingement syndrome of the shoulder. The mainstay of treatment is pain control and activity modification [25]. Pain control may be obtained with the use of NSAIDs or other analgesics. If there is a failure to obtain pain relief with analgesics, corticosteroid injections can be used. Corticosteroids are usually effective in short-term pain control for more severe cases [27]. Failure to improve or maintain function with conservative treatment may warrant surgical treatment. Resection of the distal clavicle is often effective in relieving the pain symptoms [28,29]. 

2. Adhesive capsulitis

The treatment of adhesive capsulitis can be challenging. Long-term follow-up studies show that adhesive capsulitis resolves spontaneously over one to two years without intervention [25,30]. The aim of treatment is to decrease the duration of symptoms. The treatment essentially involves activity modification to decrease pain, anti-inflammatory or analgesic medications, and a physical therapy regimen for stretching and mobilizing the shoulder, both with the therapist and at home.

In the event of no progress or slow progress after six weeks, an intra-articular steroid injection can be given. An intra-articular injection of corticosteroid has shown short-term benefits in reducing pain and disability at the six-week follow-up [31]. The accuracy of injection is improved with the use of a fluoroscope. If a dye is injected it can confirm the position of the needle. The dye will also provide an arthrogram, that can rule out other concomitant pathologies such as a rotator cuff tear. The need for surgical intervention is rare. Arthroscopic capsular release is usually not necessary. A manipulation of the shoulder under anesthesia may sometimes be required.

3. Rotator cuff disorders

Shoulder pain due to rotator cuff pathology can usually be treated successfully with conservative modalities [32,33]. The conservative treatment involves activity modification, physical therapy, and the use of anti-inflammatory or analgesic medications. The aim of physical therapy is to improve the strength, range of motion, and proprioception of the shoulder. If there is no improvement after several weeks, a subacromial corticosteroid injection may provide significant pain control that will allow range of motion to improve with physical therapy [34]. 

If the clinical assessment demonstrates that the rotator cuff is intact, a three to six-month trial of conservative treatment is usually adequate. For small rotator cuff tears also, a six to 12 weeks of nonoperative treatment is reasonable. Large retracted rotator cuff tears, sometimes seen in patients with a history of trauma or dislocation often need surgical intervention. These patients usually present with severe pain and significant supraspinatus, infraspinatus, and subscapularis weakness. Surgical treatment can be open, mini-open, or arthroscopic decompression and rotator cuff repair.

4. Glenohumeral osteoarthritis

Glenohumeral osteoarthritis is not a common condition and is a less common source of chronic shoulder pain. Glenohumeral osteoarthritis can produce significant pain and disability. The aim of treatment is to maintain overall function with adequate pain control. Pain control is obtained with anti-inflammatory or analgesic medications. If pain, however, is not adequately controlled, an intra-articular steroid injection may be given. There is, however, little evidence to support the use of steroid injection, and its use is not endorsed by the AAOS [25].

Physical therapy can help maintain shoulder function. Patients with shoulder osteoarthritis often have joint incongruity and aggressive attempts at increasing the range of motion can be counterproductive. The aim should be to maintain a functional, pain-free range of motion of the shoulder. 

In patients with advanced osteoarthritis who have severe disability, surgery may be required. Capsular release and arthroscopic debridement, hemiarthroplasty, and total shoulder arthroplasty are surgical options available [35]. There are, however,  no clinical trials or systematic reviews comparing conservative versus surgical treatment outcomes.

5. Glenohumeral joint instability

Glenohumeral instability leading to chronic shoulder pain may be related to an old dislocation of the shoulder or repetitive overuse in a young athlete with some ligamentous laxity. The initial treatment should focus on activity modification and an aggressive muscle strengthening program. Strengthening of the rotator cuff muscle and scapular stabilizer muscles can be very useful, particularly for athletes with traumatic instability of the shoulder [36]. Surgery has to be carried out if there is a failure to improve with conservative treatment or there is recurrent dislocation or subluxation. 

Sodium hyaluronate for treatment of shoulder pain

The role of hyaluronate (HA) treatment for chronic painful shoulder has not yet been elucidated although HA injections are commonly used. There is little evidence to support their use. None of the published studies have proven undeniable efficacy of HA for the treatment of chronic shoulder pain.

Saito et al [37] carried out a meta-analysis of randomized controlled trials that compared the efficacy of HA injections with that of placebo. The authors concluded that the meta-analysis provided evidence that HA injections are a valuable alternative to other conservative methods for treatment of chronic shoulder pain. The authors admitted that there were limitations of this meta-analysis. They said that only a few conclusions could be drawn from the meta-analysis because of the relatively small number of studies included. They empahasized the need of additional investigations on the use of HA injections for shoulder pain.

Furthermore, in the article by Saito et al, the term periarthrities was used and a precise diagnosis was not made and the exact cause of shoulder pain was not established. Furthermore the HA injection was given at different sites. These facts makes the study less effective. The diagnosis and treatment should be more homogenous to provide potentially useful information for therapeutic recommendations.

Blaine et al [38] carried out a randomized, controlled trial to study the efficacy of sodium hyaluronate in the treatment of persistent shoulder pain. This was a multicentre study. The study included 660 randomized patients with moderate to severe shoulder pain that was refractory to standard treatment. They had three treatment groups namely the three-injection hyaluronate group, five-injection hyaluronate group, and phosphate-buffered saline solution group.

The majority (about 60%) of the patients in each treatment group had a diagnosis of osteoarthritis as the etiology of shoulder pain. Two thirds of these patients had concurrent shoulder abnormalities such as a partial or complete rotator cuff tear and/or adhesive capsulitis. The authors found that although the primary end point of this study was not achieved, the overall findings, including secondary end points, indicate that sodium hyaluronate is effective and well tolerated for the treatment of osteoarthritis and persistent shoulder pain that is refractory to other standard nonoperative interventions. The patients were not followed beyond twenty-six weeks, it is unclear how long the clinical benefit would have been maintained in these patients. The lack of fluoroscopic guidance may be considered a limitation of the study.

There, however, were glaring conflicts of interest in this study. The authors received editorial support in the preparation of this manuscript that was funded by the study sponsor i.e the manufacturers of sodium hyaluronate.

Harris et al [39] carried out a systematic review to study the efficacy of intra-articular hyaluronate injections for the treatment of adhesive capsulitis. The systematic review showed that sodium hyaluronate injection into the glenohumeral joint significantly improves shoulder range-of-motion, constant scores, and pain at short-term follow-up following treatment of adhesive capsulitis. They also found that isolated intra-articular hyaluronate injection has equivalent outcomes as compared to intra-articular corticosteroid injection. The study also showed that the improvement in range-of-motion following isolated hyaluronate injection was greater than control; however, the difference was not significant. There were several limitations in this study and one of the significant limiting factor in this review was the very short-term follow-up duration.

Prognosis

The prognosis of chronic shoulder pain depends to a large extent on the underlying cause of the pain. Generally, the pain responds well to conservative treatment [40,41]. Symptoms of gradual onset, more severe pain at presentation and prolonged symptoms are associated with a worse outcome for protracted recovery [42,43]. Generally, the speed of recovery in patients with chronic shoulder pain is slow. There are two prospective studies involving patients with chronic shoulder pain that have shown complete recovery at one month in 23 percent of patients, and at 18 months in 59 percent of patients [9,10].

Conclusion

Persistent shoulder pain is a common clinical problem. An estimated 20 percent of the population will suffer shoulder pain during their lifetime There are several causes of such persistent pain and these include glenohumeral osteoarthritis, rotator cuff tears, subacromial impingement, tendinitis, adhesive capsulitis, and subacromial bursitis. 

Effective treatment depends on an accurate diagnosis of the cause of the shoulder pain. Most patients respond to conservative treatment that involves activity modification, analgesic medications, and physical therapy. Failure to respond to these treatment modalities would be an indication for steroid injections. HA injections have no established role in the treatment of chronic shoulder pain. Surgery is rarely indicated.

Generally, the prognosis is good in most patients. Most patients recover within one to 18 months.

References

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13.  Calis M, Demir H, Ulker S, Kirnap M, Duygulu F, Calis HT. Is intraarticular sodium hyaluronate injection an alternative treatment in patients with adhesive capsulitis? Rheumatol Int. 2006 Apr;26(6):536-40. doi: 10.1007/s00296-005-0022-2. Epub 2005 Aug 10. PMID: 16091920.
14.  Koester MC, Dunn WR, Kuhn JE, Spindler KP. The efficacy of subacromial corticosteroid injection in the treatment of rotator cuff disease: a systemic review. J Am Acad Orthop Surg. 200715(1):3–11.
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16.  Arroll B, Goodyear-Smith F. Corticosteroid injections for painful shoulder: a meta-analysis. Br J Gen Pract. 200555(512):224–228.
17.  Johansson K, Oberg B, Adolfsson L, Foldevi M. A combination of systematic review and clinicians' beliefs in interventions for subacromial pain. Br J Gen Pract. 200252(475):145–152.
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19.  Winters JC, Sobel JS, Groenier KH, Arendzen HJ, Meyboomde Jong B. Comparison of physiotherapy, manipulation, and corticosteroid injection for treating shoulder complaints in general practice: randomised, single blind study. BMJ. 1997314(7090):1320–1325.
20.  van der Windt DA, Koes BW, Devillé W, et al. Effectiveness of corticosteroid injections versus physiotherapy for treatment of painful stiff shoulder in primary care: randomised trial. BMJ. 1998317(7168):1292–1296.
21.  Koh KH. Corticosteroid injection for adhesive capsulitis in primary care: a systematic review of randomised clinical trials. Singapore Med J. 2016 Dec;57(12):646-657. doi: 10.11622/smedj.2016146. Epub 2016 Aug 29. PMID: 27570870; PMCID: PMC5165171.
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               Treatment of fibromyalgia

                               Dr. KS Dhillon

Introduction 

Fibromyalgia is a common, debilitating, and often overlooked, clinical syndrome. It affects about 2% of the population with a peak incidence in middle-aged women (90.6%) [1]. Fibromyalgia overlaps with other functional somatic disorders, such as chronic fatigue syndrome, irritable bowel syndrome, and temporomandibular joint dysfunction [2]. Fibromyalgia commonly co-occurs with anxiety and mood disorders. Research shows that, although functional somatic disorders are related and potentially interact with psychological conditions, they are usually independent [3]. Fibromyalgia is characterised by features of widespread somatic pain and deep tissue tenderness. This results from sensitisation of neural pain pathways [4]. 

The patients can also have a variable combination of sleep disturbance, fatigue, cognitive dysfunction as well as psychological distress. These symptoms can be present despite the absence of objective abnormalities on clinical examination.

There is an incomplete understanding of this syndrome's pathogenesis. There is increasing evidence for a mechanism-based management approach to this syndrome [5,6]. These are likely to be more effective if introduced early, and this makes it important to make an early timely diagnosis. 

Pathophysiology

Fibromyalgia usually develops spontaneously [7]. It is likely to represent a maladaptive, stereotypical, biological response of the body to the cumulative effects of physical or psychological stress in people who are genetically predisposed to it [8]. It is also associated with psychiatric and musculoskeletal disorders, and that leads to poorer outcomes [9,10]. It can also occur after an infection.

The prevalence of fibromyalgia is increased in people with chronic medical disorders [11]. Fibromyalgia is primarily derived from pathophysiology within the central nervous system, where there is disordered sensory processing. There is growing evidence to suggest that fibromyalgia may comprise multiple pathogenetic subsets, including originating partly within the peripheral nervous system [4,12,13]. With time, most cases of fibromyalgia evolve out of persistent regional pain [14].

Diagnosis

The fibromyalgia diagnostic criteria [15] have evolved from the recognition that fibromyalgia is a spectrum disorder, both with regards to spatial distribution of symptoms and pain severity. Diagnosing fibromyalgia can be challenging.

The condition should be considered as a possibility in all patients with persistent musculoskeletal pain, fatigue, or sleep disturbance, especially when such symptoms are out of proportion to the severity of any background chronic illness [16]. 

A practical, validated, self-assessment tool based on the diagnostic criteria has been developed [17] to quantitate the symptoms of fibromyalgia [18,19] (Table 1).

Scores above certain thresholds [19] yield reasonable sensitivity and specificity compared to the original classification criteria [20]. Other disorders that fully explain the patient's symptoms have to be excluded [21]. Examination for deep tissue tenderness, which was required by the old criteria, is now not needed. Investigations are needed to exclude treatable comorbidities and potential differential diagnoses, such as thyroid dysfunction [22].

                 Fibromyalgia survey questionnaire

I. Using the following scale, indicate for each item the level of severity over the past week by checking the appropriate box.

0: No problem

1: Slight or mild problems; generally mild or intermittent

2: Moderate; considerable problems; often present and/or at a moderate level

3: Severe; continuous, life-disturbing problems

Fatigue [ ] 0 [ ] 1 [ ] 2 [ ] 3

Trouble thinking or remembering [ ] 0 [ ] 1 [ ] 2 [ ] 3

Waking up tired (unrefreshed) [ ] 0 [ ] 1 [ ] 2 [ ] 3

II. During the past 6 months have you had any of the following symptoms?

Pain or cramps in the lower abdomen [ ] Yes [ ] No

Depression [ ] Yes [ ] No

Headache [ ] Yes [ ] No

III. Joint/body pain

Please indicate below if you have had pain or tenderness over the past 7 days in each of the areas listed below.

Please make an X in the box if you have had pain or tenderness. Be sure to mark both the right side and left side separately.

[] Shoulder, left [ ] Upper leg, left [ ] Lower back

[ ] Shoulder, right [ ] Upper leg, right [ ] Upper back

[ ] Hip, left [ ] Lower leg, left [ ] Neck

[ ] Hip, right [ ] Lower leg, right

[ ] Upper arm, left [ ] Jaw, left [ ] No pain in any of these areas

[ ] Upper arm, right [ ] Jaw, right

[ ] Lower arm, left [ ] Chest

[ ] Lower arm, right [ ] Abdomen

IV. Overall, were the symptoms listed in I–III above generally present for at least 3 months? [ ] Yes [ ] No

Table 1

Management

Spontaneous recovery usually does not occur. The main aim of treatment is to improve symptoms, function, and quality of life [23]. The treatment is individually tailored. It is multimodal, multidisciplinary, and combines both pharmacological and non-pharmacological approaches [5].

 

Non-pharmacological approach

The medical treatment of fibromyalgia is usually only partially successful [5], hence health professionals need to give their patients sustained support to become active self-managers. This is the most important intervention to enable the patient to live successfully with this debilitating multidimensional disorder.  Self-management skill training is best delivered within a small group setting where education, training, coping skills, and cognitive behavioural approaches are explored [24]. Thereafter, skills can be consolidated by trained peer mentors [25]. For health professionals, an open and patient-centered communication style is recommended [26].

Among non-pharmacological therapies, exercise and psychoeducational approaches have the greatest evidence of efficacy [5]. Biomechanical assessment and subsequent exercise monitoring by a physical therapist is desirable. A referral to a psychologist should be considered in all patients, especially in those who are more psychologically distressed.

Pharmacological approach

Drug therapy has a supportive role in the management of symptoms. Some patients do not tolerate and others do not benefit from drugs. All drugs are started at low doses and gradually the dose is increased. The drugs are used to manage the patient's predominant symptoms such as pain, sleep disturbance, and psychological distress. The drugs are stopped if they provide no benefit.

Antidepressants

Traditionally low-dose amitriptyline has been the first-line drug for treating pain and sleep disturbance in patients with fibromyalgia. The evidence supporting the use of amitriptyline is of low quality. 

A Cochrane Database Systematic  Review by Moore et al [27] showed that there was no first‐tier evidence on the efficacy of amitriptyline in fibromyalgia. There was some second-tier evidence that amitriptyline at 25 or 50 mg daily was better than placebo. About 64% of participants taking amitriptyline had adverse effects. Only about 38% of participants benefited from the use of amitriptyline. About 5% withdrew because of lack of efficacy with amitriptyline. Tolerance development and weight gain limit the use of amitriptyline. 

Serotonin and noradrenaline (norepinephrine) are mediators of descending inhibition in the nervous system. Their concentrations are reduced in patients with fibromyalgia. Hence, it is justified to have a trial of a serotonin noradrenaline reuptake inhibitor. In trials conducted by the manufacturers, there is low-quality evidence that Duloxetine at 60 mg per day is effective in the treatment of fibromyalgia [28].

Milnacipran as well inhibits the reuptake of serotonin and noradrenaline (norepinephrine). It can be used to treat fibromyalgia. The recommended dose is 100 mg daily in divided doses. There is some high-quality evidence which shows that it has modest efficacy [29].

Antiepileptic drugs

In patients with fibromyalgia, the concentrations of the pain facilitatory neurotransmitters glutamate and substance P in the central nervous system are elevated. These transmitters are the targets of gabapentin and pregabalin which have potential pain modulatory, sleep-promoting, and anxiolytic actions. 

A Cochrane Database Systematic  Review by Nurcan Üçeyler et al [30] showed that anticonvulsant, pregabalin, demonstrated a small benefit over placebo in reducing pain and sleep problems in patients with fibromyalgia. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide, and levetiracetam in patients with fibromyalgia. 

Other drugs

There is weak evidence that NSAIDs are ineffective in the treatment of patients with fibromyalgia [5]. There is no trial evidence of efficacy for paracetamol used alone. There is preliminary evidence from randomized controlled trials of the efficacy of tramadol [31], pramipexole [32], and memantine [33]. Pure mu-opioid receptor agonists, such as codeine, oxycodone, and fentanyl are contraindicated because of poor clinical response and increased risk of opioid-induced hyperalgesia [31].  

Conclusion

Fibromyalgia can produce profound, multidimensional disability, and multidisciplinary management is required. A systematic, patient-centered approach can produce meaningful improvements in patient's symptoms, function as well as quality of life. Non-pharmacological treatments have an important role to play. Some drugs can complement an active rehabilitation program. There is some evidence for the use of amitriptyline, pregabalin, duloxetine, and milnacipran for the treatment of fibromyalgia. However, not all patients will benefit from these drugs. Patients should be monitored for adverse events resulting from the use of these drugs.

References

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     Platelet Rich Plasma for Osteoarthritis

                             Dr. KS Dhillon

What is Platelet Rich Plasma?

Platelet Rich Plasma (PRP) is an autologous concentration of human platelets in a small volume of plasma. Here the platelet concentration is higher, usually up to five times higher, than the normal platelet concentration in a healthy person’s blood.

Preparation of Platelet Rich Plasma

PRP is prepared by differential centrifugation. In differential centrifugation, the acceleration force is adjusted to sediment certain blood cellular constituents based on different specific gravity.

The first centrifugation is to separate red blood cells (RBC). This is followed by a second centrifugation that concentrates platelets, which are suspended in a small volume of final plasma. 

Whole blood is initially collected in tubes that contain anticoagulants. The first spin is performed at constant acceleration to separate RBCs from the remaining whole blood volume. After the first spin, the whole blood separates into three layers: an upper layer that contains mostly platelets and white blood cells (WBC), an intermediate thin layer that is known as the buffy coat that is rich in WBCs, and a bottom layer that consists mostly of RBCs. To obtain pure PRP (P-PRP), the upper layer and superficial buffy coat are transferred to an empty sterile tube. To produce leucocyte-rich PRP (L-PRP), the entire layer of buffy coat and a few RBCs are transferred. 

The second spin step is then performed. It aids in the formation of soft pellets (erythrocyte-platelet) at the bottom of the tube. The upper portion that is composed mostly of PPP (platelet-poor plasma) is removed. Pellets are homogenized in the lower 1/3rd (5 ml of plasma) to create the PRP [1].

There are many commercially marketed PRP systems that facilitate the preparation of ready to apply platelet-rich suspensions in a reproducible manner. All operate on a small volume of drawn blood (20-60 mL) [1]. 

Effect of platelet-rich plasma

There is some evidence that PRP has the potential to have a regenerative effect on certain body tissues, besides the main role that platelets play in haemostasis [2]. PRP contains alpha granules. About 70% of the growth factors in the alfa granules will be secreted in the first 10 min, and almost all the stored amount will be released in the first hour [3]. The growth factors activate the cells that are responsible for tissue healing and bone and cartilage regeneration [4].

The joint destruction in patients with osteoarthritis (OA) occurs as a result of an imbalance in the equilibrium between the breakdown and repair of the joint tissue. A combination of cellular changes and biomechanical stresses causes several secondary changes in the joint. Research has identified a number of biochemical pathways that can be targeted therapeutically through biological intervention [5] and platelet-rich plasma (PRP) is one such intervention.

Platelets contain and release numerous growth factors that promote healing, dampen inflammation, and reduce pain [6,7,8]. These blood-derived products are also used to enhance chondrogenesis [9,10], treat bone injuries [11,12], tendon injuries [13,14], and ligament injuries [15,16], and have recently emerged as a potential treatment for knee OA [17].

Studies comparing intra-articular PRP injections to other means of non-surgical intervention for knee OA report benefits for patients receiving PRP. The positive clinical response in patients with OA is mainly due to the anti-inflammatory effects of PRP rather than due to increased anabolic and reparative effects on articular cartilage [17,18]. These reports are, however, inconclusive because of the high variability in the available PRP preparations, and the lack of consensus and standardization of treatment protocols [19]. 

PRP for Osteoarthritis

Most clinical guidelines do not recommend the use of platelet-rich plasma (PRP) for knee osteoarthritis (OA). This is because there is a lack of high-quality evidence on efficacy of PRP for the treatment of knee OA. The guidelines in fact emphasize the need for rigorous studies. Despite this lack of evidence, the use of PRP in knee OA is increasing [20].

Bennell et al [20] carried out a randomized clinical trial to find out the effect of intra-articular injection of platelet-rich plasma (PRP) in patients with mild and moderate OA of the knee and compared its effect to placebo saline injection into the knee. The clinical trial included 288 adults aged 50 years or older with mild to moderate radiographic knee osteoarthritis. Half of the subjects had PRP injections and the other half had placebo injections. Of the 288 subjects, 269 (93%) completed the trial. After 12 months, treatment with PRP vs placebo injection resulted in a mean change in knee pain scores of −2.1 vs −1.8 points, respectively. The mean change in medial tibial cartilage volume was −1.4% vs −1.2%, respectively. Neither comparison was statistically significant.

The authors concluded that intra-articular injection of PRP, compared with injection of saline placebo, did not result in a significant difference in symptoms or joint structure at 12 months. Their findings do not support the use of PRP for the management of knee OA.

Dório et al [21] carried out a randomized, double-blind, placebo-controlled trial to assess the efficacy of platelet-rich plasma and plasma in the treatment of symptomatic knee osteoarthritis. Sixty-two participants were allocated to treatment groups of which 57 (92%) were female, with a mean age of 65 years and a mean BMI of 28.0 Kg/m2.

They found that PRP injected with a 2-week interval, and plasma were not superior to placebo for pain and function improvement in knee OA over 24 weeks. The main drawback of this study was the relatively small sample which may have influenced the outcome. The PRP group had a higher frequency of mild transitory increase in pain.

Khoshbin et al [22] carried out a systematic review with quantitative synthesis to assess the efficacy of Platelet-Rich Plasma in the treatment of symptomatic knee osteoarthritis. There were six Level I and II studies that satisfied their inclusion criteria (4 randomized controlled trials and 2 prospective nonrandomized studies). There were a total of 577 patients in the studies with 264 patients (45.8%) in the treatment group (PRP) and 313 patients (54.2%) in the control group (hyaluronic acid [HA] or normal saline solution [NS]). The mean age of patients receiving PRP was 56.1 years compared with 57.1 years for the group receiving HA or NS. 

The main findings of this systematic review were that multiple sequential intra-articular PRP knee injections (2 to 4 injections) improved functional outcome scores (WOMAC and IKDC) at a minimum of 24 weeks. However, no benefit of PRP over control treatment was found for other pain measures (VAS) or overall patient satisfaction scores.

The American Academy of Orthopaedic Surgeons (AAOS) evidence-based clinical practice guideline on treatment of knee OA does not recommend the use of PRP for the treatment of knee OA. The evidence rating is inconclusive which means that there is a lack of compelling evidence that has resulted in an unclear balance between benefits and potential harm [23].

The National Institute for Health and Care Excellence (NICE) guidelines on the use of PRP for knee OA states that the current evidence on platelet-rich plasma injections for knee osteoarthritis raises no major safety concerns. However, it states that the evidence on efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, with consent, and for audit or research [24]. 

Conclusion

Most clinical guidelines and scientific publications do not recommend the use of platelet-rich plasma (PRP) for knee osteoarthritis (OA). This is because there is a lack of high-quality evidence on efficacy of PRP for the treatment of knee OA. Despite this lack of evidence, the use of PRP in knee OA is increasing. 

The guidelines and studies in fact emphasize the need for rigorous studies. Despite this call for more rigorous studies, there is a glaring lack of such studies in the scientific literature.

References

1. Dhurat, Rachita, and Ms Sukesh. “Principles and Methods of Preparation of Platelet-Rich Plasma: A Review and Author's Perspective.” Journal of cutaneous and aesthetic surgery vol. 7,4 (2014): 189-97. doi:10.4103/0974-2077.150734.
2. Lee KS, editor. Platelet-rich plasma injection. Seminars in musculoskeletal radiology. New York: Thieme Medical Publishers; 2013.
3. Spaková T, Rosocha J, Lacko M, Harvanová D, Gharaibeh A. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil. 2012 May;91(5):411-7. doi: 10.1097/PHM.0b013e3182aab72. PMID: 22513879.
4. Say F, Gurler D, Yener K, Bulbul M, Malkoc M. Platelet-rich plasma injection is more effective than hyaluronic acid in the treatment of knee osteoarthritis. Acta Chir Orthop Traumatol Cechoslov. 2013;80(4):278–283.
5. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013;41(2):356–364. doi: 10.1177/0363546512471299.
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7. Andia, I. & Mafulli, N. Platelet-rich plasma for managing pain and infammation in osteoarthritis. Nat. Rev. Rheumatol. 9, 721–730. https://doi.org/10.1038/nrrheum.2013.141 (2013).
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9. Xu, Z. et al. Comparative evaluation of leukocyte- and platelet-rich plasma and pure platelet-rich plasma for cartilage regeneration. Sci. Rep. 7, 43301. https://doi.org/10.1038/srep43301 (2017).
10. Barlian, A., Judawisastra, H., Ridwan, A., Wahyuni, A. R. & Lingga, M. E. Chondrogenic diferentiation of Wharton’s Jelly mesenchymal stem cells on silk spidroin-fbroin mix scafold supplemented with L-ascorbic acid and platelet rich plasma. Sci. Rep. 10, 19449. https://doi.org/10.1038/s41598-020-76466-8 (2020).
11. Rof, A., Di Matteo, B., Krishnakumar, G. S., Kon, E. & Filardo, G. Platelet-rich plasma for the treatment of bone defects: from pre-clinical rational to evidence in the clinical practice. A systematic review. Int. Orthop. 41, 221–237. https://doi.org/10.1007/ s00264-016-3342-9 (2017).
12. Yin, N. et al. Platelet-rich plasma enhances the repair capacity of muscle-derived mesenchymal stem cells to large humeral bone defect in rabbits. Sci. Rep. 10, 6771. https://doi.org/ 10. 1038/s41598-020-63496-5 (2020).
13. Filardo, G., Di Matteo, B., Kon, E., Merli, G. & Marcacci, M. Platelet-rich plasma in tendon-related disorders: results and indications. Knee Surg. Sports Traumatol. Arthrosc. 26, 1984–1999. https://doi.org/10.1007/s00167-016-4261-4 (2018).
14. Zhang, J. et al. Selectively activated PRP exerts diferential efects on tendon stem/progenitor cells and tendon healing. J. Tissue Eng. 10, 2041731418820034. https://doi.org/10.1177/2041731418820034 (2019).
15. Koch, M. et al. Partial anterior cruciate ligament ruptures: advantages by intraligament autologous conditioned plasma injection and healing response technique-midterm outcome evaluation. iomed. Res. Int. 2018, 3204869. https://doi.org/10.1155/2018/ 3204869 (2018).
16. Krismer, A. M. et al. Biologic response of human anterior cruciate ligamentocytes on collagen-patches to platelet-rich plasma formulations with and without leucocytes. J. Orthop. Res. 35, 2733–2739. https://doi.org/10.1002/jor.23599 (2017).
17. Gato-Calvo, L., Magalhaes, J., Ruiz-Romero, C., Blanco, F. J. & Burguera, E. F. Platelet-rich plasma in osteoarthritis treatment: review of current evidence. Ter. Adv. Chronic Dis. 10, 2040622319825567. https://doi.org/10.1177/2040622319825567 (2019).
18. Andia, I. & Mafulli, N. Platelet-rich plasma for managing pain and infammation in osteoarthritis. Nat. Rev. Rheumatol. 9, 721–730. https://doi.org/10.1038/nrrheum.2013.141 (2013).
19. Chu, C. R. et al. Optimizing clinical use of biologics in orthopaedic surgery: consensus recommendations from the 2018 AAOS/NIH U-13 conference. J. Am. Acad. Orthop. Surg. 27, e50–e63. https://doi.org/10.5435/JAAOS-D-18-00305 (2019).
20. Bennell KL, Paterson KL, Metcalf BR, et al. Effect of Intra-articular Platelet-Rich Plasma vs Placebo Injection on Pain and Medial Tibial Cartilage Volume in Patients With Knee Osteoarthritis: The RESTORE Randomized Clinical Trial. JAMA. 2021;326(20):2021–2030. doi:10.1001/jama.2021.19415.
21. Dório et al. Efcacy of platelet-rich plasma and plasma for symptomatic treatment of knee osteoarthritis: a double-blinded placebocontrolled randomized clinical trial BMC Musculoskelet Disord (2021) 22:822.
22. Khoshbin et al. The Efficacy of Platelet-Rich Plasma in the Treatment of Symptomatic Knee Osteoarthritis: A Systematic Review With Quantitative Synthesis. Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 29, No 12 (December), 2013: pp 2037-2048. 
23. American Academy of Orthopaedic Surgeons. Treatment of Osteoarthritis of the Knee – 2nd Edition Evidence-Based Clinical Practice Guideline at   https://www.aaos.org/globalassets/quality-and-practiceresources/osteoarthritis-of-the-knee/osteoarthritis-of-the-knee-2nd-editiion-clinical-practice-guideline.pdf. 
24. Platelet-rich plasma injections for knee osteoarthritis. Interventional procedures guidance [IPG637]Published: 23 January 2019 at https://www.nice.org.uk/guidance/IPG637/chapter/1 -Recommendations.