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12 Articles in Volume 18, Issue #4
A New Frontier in Migraine Management: Inside CGRP Inhibitors & Migraine Prevention
Assessment of Patients with Rheumatoid Arthritis or Osteoarthritis
Biosimilars in Rheumatology: How Popular Will They Be?
Case Studies in Regenerative Cellular Therapy: Tendinopathy and Osteoarthritis
Commentary: Make the Easy Choice for Care
Editorial: The Emergence of Trackable Pill Technology: Hype or Hope?
Editorial: The Practicality of Pain Acceptance
How to Avert Government Scrutiny When Prescribing Opioids
Letters to the Editor: DEA and Prescribing, the War on Statistics, Failing Treatments, Patients' Options
Meet the Migraine Game-Changers
Platelet-Rich Plasma and Stem Cell-Rich Prolotherapy for Musculoskeletal Pain
With concerns over opioids, could novel receptors be useful?

Platelet-Rich Plasma and Stem Cell-Rich Prolotherapy for Musculoskeletal Pain

In the updated second edition of Free Yourself From Chronic Pain and Sports Injuries, PPM Editorial Advisory Board Member Donna D. Alderman, DO, shares the fundamentals of how and why prolotherapy regenerative medicine works.

Many people have heard the term “platelet-rich plasma” in news stories in connection with athletic injuries, however, not all may realize that when platelet-rich plasma (PRP) is injected into and around a joint, it is actually a type of prolotherapy. In fact, PRP has been used as a formula in prolotherapy since around 2005. The approach has been shown to be effective not only for older injuries but also for recent ones, making it ideal for athletic injuries. It has also successfully been used in the treatment of osteoarthritis (OA) and helpful for cartilage repair.

Not All Platelet-Rich Plasma Is Equal

As the use of PRP has grown, so has the demand for, and availability of, PRP–concentrating machines and methods; several manufacturers now make these systems. There are also doctors who “do it themselves” using a regular type of centrifuge rather than one of the systems developed for this purpose. The basic differences among these various methods are: 1) the amount of concentration of platelets (how many times a person’s normal levels (called “baseline” levels); and 2) the presence and number of red or white blood cells.1

Platelet Concentration

There is debate in the medical community about what is the best platelet concentration or cell type for different conditions; however, most data supports a platelet concentration of four to six times a patient’s normal level (baseline) for most musculoskeletal problems.2 More specifically, since the average normal patient’s platelet count is 250,0000 platelets per microliter, this means that the magic number is 1.0 million to 1.5 million platelets per microliter (four to six times normal baseline). This concentration has shown better tissue regeneration when compared to lower platelet concentrations. It also seems that much higher concentrations could have an inhibitory effect,3 which may decrease effectiveness.4 Therefore, four to six times baseline has become the most commonly used concentration for PRP, and this concentration range is known as “high-density.” Remember that platelets work by sending out biochemical messages so that nearby available stem cells will come and help repair injured areas. It has been found that when high-density PRP is used, there is a stronger stem-cell response when compared to whole blood or PRP with lower platelet concentrations.

Red and White Blood Cells

The other difference between PRP is the number of red and white cells. Keep in mind that most of the red cells are already removed in the making of PRP: whole blood is 94% red cells as compared to only 5% red cells in PRP. However, even though the remaining red cells are greatly diminished, it is believed that any red cells may still cause unnecessary aggravation after treatment. One issue has been that removing too many red cells may greatly reduce platelet levels since some platelets are within the red cell layer. Fortunately, recent developments in technology now permit the ability to remove most of the red cells while still maintaining high platelet counts. Another issue is that with prolotherapy, clinicians may prefer this additional red blood cell irritation to “wake up” certain tissue types that are not healing. Therefore, both formulas are used in prolotherapy—the low red cell (“yellow”) and the regular red cell (“red”)—depending on the area treated, intended result, physician and/or patient choice, and treatment plan.

Regarding white blood cells, some physicians argue that white cells may cause too much pain and should be reduced, especially in joints.5 However, typically, white cells constitute only 1% of both whole blood and PRP, and therefore a very small percentage of the treatment formula. Also, white cells are very difficult to remove without seriously sacrificing platelet numbers.6 Most physicians also agree that white cells are important and improve wound healing; furthermore, white cells have antibacterial properties that are thought to potentially help reduce infection risk from, or after, the procedure (as long as done under appropriate sterile conditions of course).7 Therefore, it is generally agreed in the medical community that white cells are desirable and should remain in platelet-rich plasma formulas.8

Cortisone versus Platelet-Rich Plasma

Cortisone injections are commonly recommended for the treatment of joint pain. However, the use of cortisone is controversial because it tends to break down, rather than repair, joints and connective tissue, especially if done repeatedly. Current evidence now supports platelet-rich plasma to be more effective than cortisone for treatment of joint and connective tissue issues,9 especially long term. A well-designed, two-year, randomized, controlled, blind trial, with a significant test group of 100 patients investigated cortisone versus PRP injections for elbow tendon problems. The researchers concluded that PRP reduced pain and increased function significantly, exceeding the effect of corticosteroid injection even after two years.10 A similar study in 2017 agreed.11 These two treatments were also compared for use in chronic, severe plantar fasciitis and concluded: “PRP was more effective and longer lasting than cortisone injection."12 Platelet-rich plasma has also been found to be a “superior treatment option” versus cortisone for lumbar facet (low back joint) injections, with longer lasting effectiveness.13

PRP versus Dextrose Prolotherapy

Both PRP and dextrose prolotherapy have been shown to stimulate natural healing.14 Both can be effective, and both should be considered in the treatment plan for connective tissue repair. PRP prolotherapy, however, may be deemed more appropriate in cases where the tissue or joint has become degenerated, there is osteoarthritis present or the problem is older and more chronic. When platelet-rich plasma is the formula used in prolotherapy, it provides not only needed irritation (concentrated platelets are aggravating) but also growth factors that provide a jump-start on healing. Using PRP is like adding fertilizer to newly planted seeds versus just planting the seeds; the condition of the “soil” can help to determine which formula is the best choice. Platelet-rich plasma may also be preferred over dextrose in cases of a tendon sheath or muscle injury; these areas are occasionally, but not typically, treated with dextrose.

Another factor to consider is that PRP is a more aggressive formula than dextrose; therefore, it can be more aggravating and uncomfortable for the patient afterward. In addition, the cost of PRP prolotherapy is higher than for dextrose prolotherapy because of the additional materials needed. Another difference is that PRP prolotherapy seems to stimulate multiple healing episodes, sometimes creating more “ups and downs” in pain levels during the weeks following a treatment. With dextrose, on the other hand, there is usually only an initial period of discomfort, although there are variations from patient to patient. As a general rule, fewer treatments are needed with PRP than with dextrose. The bottom line is there are several factors to consider, and the determination of which type of prolotherapy to use is made on an individual basis after careful evaluation and discussion between the doctor and the patient of all factors, including patient preference.

Introducing Biocellular Prolotherapy

Biocellular (stem cell-rich) prolotherapy is the most advanced and aggressive form of prolotherapy. It is used either when other forms of prolotherapy have stopped working, or as a first procedure when a condition is severe. This approach is called “stem cell-rich” because tissue used is rich in stem cells, specifically “adult” stem cells. Because tissue used is taken from the body, it is further referred to as “autologous.” The two main tissue sources used stem-cell rich therapy are either adipose or bone marrow. Like other forms of prolotherapy, both chronic and acute problems can be treated. Biocellular prolotherapy is especially well suited for sports injuries because of its tendency to encourage repair using new, normal tissue rather than weaker scar tissue.

Adipose & PRP: Better Together

Studies have shown that using PRP and adipose tissue together “significantly improves” regeneration versus using adipose cells alone.15 When adipose is used as the stem-cell source, PRP is thus typically used at the same time since this combination has been shown to work synergistically in multiple studies.16 In one study, using adipose-derived cells with PRP versus PRP alone on Achilles tendon injuries showed tendon strength for the adipose/platelet-rich plasma group to be greater, with a statistically higher production of collagen and growth factors.17 Therefore, typically, adipose and PRP are done together during a biocellular procedure.

The Choice of Biocellular Formula: Adipose vs Bone Marrow

The choice of which stem-cell source to use in biocellular prolotherapy depends on several factors, including the condition being treated, the age of the patient, the physician’s background and training, and the patient’s preference. While adipose and bone marrow formulas have demonstrated similar treatment capabilities, there does appear to be functional differences between them. Some animal and laboratory studies indicate that bone marrow may be preferred and more efficient for osteochondral (bone and cartilage) regeneration.18 However, adipose has shown an excellent ability to stimulate cartilage regeneration,19 and there are many studies that indicate similar chondrogenic (ability to make cartilage) potential between bone marrow-derived and adipose-derived mesenchymal stem cells, or MSCs.20 In a recent case report, a patient received surgery for a cartilage defect, which is the traditional treatment.

This particular patient had a condition called osteochondritis dissecans and that treatment surgery failed. The patient then received an injection of autologous adipose-derived MSCs into the area. The result was structural and functional improvement, as well as reduction of pain level.21

In multiple studies, both adipose and bone marrow stem cells have shown the ability to change the microenvironment more favorably toward healing and to decrease “bad” inflammation while promoting “good” inflammation and blood supply, helping to reduce pain and stimulate repair. However, adipose is considered by some researchers to be better in this ability.22 There are also several advantages that adipose has over bone marrow for ligament, tendon, and muscle repair,23 especially in certain joints. For these reasons, adipose is becoming the preferred choice for connective tissue injury.

When to Use Stem Cell-Rich Prolotherapy: An Algorithm

Biocellular prolotherapy may be the preferable treatment for chronic or degenerative conditions where cellular depletion is suspected and a more aggressive approach is needed or preferred.24 In many cases, prior to doing biocellular treatment, a clinician will recommend one or two dextrose and/or PRP treatments to prime the area and see how much improvement can be obtained, and then advance to biocellular if needed. The decision of which formula to use must be evaluated on a case-by-case basis, considering the problem to be addressed, the particular injury site, and the person’s medical history—in addition to the individual’s age and health status. Only after a thorough evaluation by a physician trained in these techniques, and an extensive discussion of a patient’s needs and expectations, can the best decision be made to determine the optimal course of treatment. To get an idea of how a treatment plan is mapped out, see the Figure below.

Figure 1: Typical Prolotherapy treatment algorithm

In conclusion, medical treatment must make sense for the individual patient and account for all risks. While one cannot always predict the outcome, one can do enough research to make an intelligent decision.

For more on the use of regenerative medicine in treating musculoskeletal pain, see Dr. Alderman’s full book, available at familydoctorpress.com and on Amazon.

*Excerpt printed with permission from the author; references are taken directly from source and renumbered for flow. 

Last updated on: April 12, 2019
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