A Protocol for Ozone Enhanced Regenerative Injection Treatment of Ligamentous Spinal Pain
Richard Gracer, M.D.
Proliferative Therapy, also known as prolotherapy or Regenerative Injection Therapy (RIT), is the injection of mild inflammation producing substances onto ligaments and/or tendons, most commonly at their origins and insertions. This causes cytokine release, which along with other mechanical and neurologically mediated processes starts a fibroblastic reaction that is akin to the natural healing process. This, under the proper conditions, results in the creation of new, stronger, flexible, and less pain sensitive ligaments and/or tendons. RIT has been developed principally in the United States, although James Cyriax, MD, the British "Father of orthopedic medicine" was a proponent of its use for treatment of ligamentous laxity in the thoracic and lumbar spines.
Ozone has been used for medical purposes for over 50 years, predominantly in Italy and Germany. Its effects have been studied both in local injection and in whole blood, which after ozone exposure is reinfused into the patient. Its overall effect is to act as an oxidative "shock" that activates the antioxidant systems and causes release of cytokines and other immune stimulating factors. These effects have been shown effective in the treatment of spinal pain, arthritis, infectious disease, macular degeneration, healing vascular skin ulcerations, as well as other problems. There is some evidence that ozone treatment may stimulate stem cell formation.
Both of these therapies work on the same systems from different angles. It is logical that combining the two approaches would augment their effects and could actually be synergistic. Frank Shallenberger, MD has pioneered what he calls "Prolozone", a combination of local intramuscular injection of an ozone/oxygen mixture with a mild form of RIT. The ozone acts locally on the nearby ligamentous structures, amplifying the proliferant effect. What I am proposing is to treat blood extracorporeally and then inject this "activated" blood onto the ligaments and tendons that are to be treated with RIT. The RIT proliferant would be injected a few days later, allowing it to stimulate tissue that is already primed to react.
This paper reviews in more detail the effects of each of these treatment modalities and then outlines a treatment protocol that would take advantage of the possible synergism of RIT and ozone cellular activation.
RIT has been evaluated by randomized trials and found to be effective for the treatment of low back pain, as well as many other musculoskeletal disorders. ** The Florida Academy of Pain Medicine produced a position paper supporting the use of this treatment modality. A position paper committee of interventional pain physicians was formed and undertook a comprehensive review of pertinent literature. The committee reviewed 78 specific articles and nine text books, as well as 51 relevant articles and chapters from other text books. They concluded that "RIT is a safe and effective treatment modality that is very useful in a significant number of pain syndromes arising from ligament and tendon diathesis, as well as other clearly delineated pain problems." Yelland arrived at a similar conclusion in another analysis in Spine 2003.
In recent years there has been increased interest in the mechanism of inflammation and its relationship to chronic illness involving such disparate tissues as the coronary arteries, joint degeneration, inflammatory arthritis (rheumatoid, psoriatic, lupus and others), inflammatory bowel disease(Crohn's disease and ulcerative colitis), Alzheimer's disease, and even "normal" aging. This research has resulted in a greater understanding of the commonality of body system functions in that similar processes are involved in all of these maladies, leading to specific treatments that are making immense improvements in the course of many of these problems. It has also shown that there is a delicate equilibrium between various normal processes, which when out of balance can one the one hand can cause inflammatory damage and on the other can allow infection or failure of tissues which need "maintenance."
As we become older there is a gradual and to some extent, natural degeneration of the moving parts of the body due to ongoing recurrent mechanical stresses, failure of tissue repair with aging, and inflammation. The ligaments, tendons, and cartilage become dehydrated and weaker. This results in laxity and secondarily, abnormal mechanical stress. Abnormal shearing and torsion forces gradually cause joint dysfunction. These cause a progressive separation of the ligaments from the periosteum. The space that this creates is filled with new bone formation. These bits of bone are the osteophytes that are a hallmark of degenerative arthritis. The increased joint play and abnormal forces also result in increased and abnormal wear of the cartilaginous joint surfaces, causing joint space narrowing, the other most common finding seen in degenerative arthritis of hips, knees, ankles, wrist and hand joints, and shoulders. The facet, sacroiliac joints, and the intervertebral disks and are also affected by this process. One would think that there would be increased joint range due to laxity and loss of cartilage, but the opposite is true. The osteophytes and joint laxity result in a reduced range of motion (in a specific pattern for each joint) which causes abnormal strain on other contiguous structures, which themselves become increasingly dysfunctional, causing the process to spread to sometimes quite remote structures, which can cause further abnormal stresses and so on.
At times ligamentous injury can start a rapid degenerative cascade with both local and remote sequelae. In others a subtle injury at young age can result in problems later in life, often in areas that are remote to the original injury. It is also very common for seemingly minor variations in gait and coordination to cause gradual dysfunctions. There are genetic differences which can cause premature osteophytic changes in the metacarpal and phalangeal joints. Other common genetic predispositions cause ligamentous laxity of varying degrees, the best known and most severe of which are Marfan and Ehler-Danlos syndromes. These lead to the degenerative cascade and propensity to injury.
Injured structures often develop abnormal C-fibers, which can cause pain without appropriate painful stimulation. (This is a major cause of disc pain.) In addition there is increased neural firing by proprioceptive receptors. All of this stimulation to spinal cord structures causes "wind up", a type of remodeling and hypersensitization of the normal pain pathways that we see in chronic pain. The result is allodynia (pain from what is usually non painful stimulation) and increased sympathetic nervous system activity. This itself causes a decrease in blood supply and further diffuse pain tract stimulation that often crosses the midline and dermatomes. What results is a chronic pain syndrome the source of which can be difficult to unearth, and which can be very difficult to treat successfully.
By modifying the local milieu both on cellular, neurologic, and mechanical levels RIT can attack many of the abnormalities described above.
RIT is effective for these conditions by effecting repair and tightening of the lax structures. In addition, RIT has a neurolytic effect ablating the aberrant C-fibers that are often present in painful structures. The result is decreased sympathetic tone allowing better local circulation and a more normal cytokine environment. The increased blood flow brings increased nutrition and hydration. With these changes comes increased range of motion and decreased pain.
An easy analogy that illustrates this concept is to a door and hinges. If a hinge of a door is loose, the problem that we see may be with the door's opposite edge hitting the door frame. If one lifts the door back into place, it may be fine temporarily (for example, treating spinal joint dysfunction with manipulation), but the next time it opens, the same problem will recur. Applying oil to either the hinge or the frame may lubricate and allow less stress for a while (for example using a local steroid injection), but this is also only a temporary solution. What we need to do is fix the hinge!
This new knowledge has also led to new nutritional and pharmacologic strategies which aim at modifying inflammation and stimulating repair. These include reducing carbohydrates in the diets of those with insulin resistance, consumption of highly purified fish oil (a source of DHA and EPA, critical omega-3 fatty acids), use of glucosamine, chondroitin sulfate, and methyl sulfonyl methane (MSM), vitamin supplementation including vitamin C and various other micronutrients, amino acids (including lysine and praline) and minerals, and correction of underlying hormone deficiencies (thyroid, sex hormone, and growth hormone).
The addition of ozone stimulation to the reparative system is a potential enhancement that merits trial and study.
In the United States ozone is known as a toxic pollutant causing damage to the pulmonary system, as well as irritation to the eyes, nasal passages and skin. It is clear that ozone should never be inhaled because the cells that line the respiratory tract have minimal oxidative protective power. Ozone exposure can cause severe irritation and even pulmonary edema. Prolonged exposure to ozone can be deadly. This has understandably slowed its acceptance as a possible medical treatment modality. Non medical uses of ozone include water purification and a variety of industrial uses in which it acts as a powerful oxidant.
Ozone is a powerful oxidant. Upon contact with body fluids ozone dissolves and then reacts immediately with a variety of bodily constituents. These include fatty acids, antioxidants, various proteins, and carbohydrates. There is a build up of lipid peroxides and a chain reaction that results in the elaboration of many cytoactive compounds. Alpha tocopherol (vitamin E), glutathione, uric acid (an important and potent antioxidant), ascorbic acid, and bilirubin quench this reaction both in cell walls and in plasma.
One of the first signs of significant cytotoxicity in blood is hemolysis, which is easy to clinically monitor. When whole blood is exposed to the low and carefully controlled concentrations of ozone that are used medically, the naturally occurring antioxidants listed above protect the cells. Careful research has shown that there is neither cellular damage nor hemolysis, although there is potent stimulation of the antioxidant system and depletion of both the lipophylic cellular membrane and the hydrophilic plasma dissolved antioxidants. There also are many reactive compounds such as lipid peroxides produced in the plasma. Other studies show that leukocytes that are washed with saline and then exposed to the small concentrations of ozone used medically rapidly die. This demonstrates that the naturally occurring antioxidants that are found in whole blood prevent cellular damage.
In the medical procedure called major auto hemotherapy (MAHT) blood is taken out of the patient, carefully exposed to controlled concentrations of ozinated oxygen, and then reinfused into the patient. The activated cells and biologically active compounds are diluted in the blood preventing any toxic effect. As they spread into the general circulation they initiate multiple biologic reactions, influencing the whole body. This activation is a "shock" which stimulates the immune system and stimulates healing. It is important to differentiate this type of intermittent shock from the constant low level stresses caused by disease and other chronic environmental factors that can cause oxidative damage and result in chronic disease.
Other forms of medical ozone treatment include exposure of ulcerations to the gaseous form, rectal insufflation, and application of ozinated water and olive oil.
Ozone is also injected intraarticularly for treatment of arthritis, intramuscularly for musculoskeletal problems. It has been studied in several centers demonstrating efficacy for treatment of shoulder rotator cuff injuries. The ozone reacts locally after it dissolves in body fluids. "Prolozone" treatment utilizes this action after local intramuscular injection.
The most carefully studied use of ozone treatment for the musculoskeletal system is its injection into intervertebral discs for treatment of disc protrusions and increased discal chemical sensitivity. There is an ongoing multicenter European study, coordinated through the University Of Milan School Of Medicine, collecting data for this treatment. Data available to date shows a very significant positive result.
The most authoritative and complete discussion of this subject is found in the excellent and authoritative textbook, Oxygen-Ozone Therapy by Velio Bocci, MD and there is a growing body of medical literature outlining these changes emanating from several European countries.
What I propose is to use ozone activated whole blood to stimulate and activate the areas to be treated with RIT.
Wound Healing and RIT
Most proliferant solutions contain between 12.5% and 25% glucose and 0.5 to 1.0% lidocaine. The hyperosmotic glucose causes swelling and cellular rupture. The glucose itself is a growth factor which facilitates healing. Glycerin is often added to this mixture and acts in a similar way to glucose. Phenol is another common ingredient. It ensures sterility and is also is neurolytic, destroying the bare C-fibers found in painful connective tissue. (The proliferant used in the two double blind controlled studies was P2G, a solution of 12.5% glucose, 12.5% glycerin, 1.25% phenol, and 0.5% lidocaine) Sodium morrhuate, derived from fish oil, is often added to the proliferant mixture. It is FDA approved for sclerosing varicose veins and acts as a direct stimulant to the inflammatory process. It is often used to augment the proliferative effects in refractory cases, although there are many physicians who now use it as part of their routine proliferant mixture.
Injection of a proliferant causes low level inflammation. This results in early phase (Phase I) granulocyte activity and release of inflammatory cellular contents. This phase lasts about three days. Over the next 10 days or so macrophages predominate (Phase II). They release chemotactic factors, which attract fibroblasts and act as growth factors. Over the next several days collagen starts to form, giving strength to the tissue (Phase III). At first this is a soupy mixture without structure. Soon, however, a matrix forms, on which collagen is deposited. Macrophages are still active and they uptake some of this new material. Over time the collagen predominates and there is a gradual dehydration of the matrix with more orderly collagen fibers. This eventually leads to new, stronger connective tissue. The whole process may take several months. During this time period external forces affect the eventual outcome of the final tissue fiber both as to length, strength as well to orientation and flexibility. This works much in the same way as the bone remodeling that occurs after fracture. The elegance of this process is that the "body decides" which ligaments to strengthen depending upon the physical needs in each individual This is why it is important to advise RIT patients to stretch and stay active during therapy.
The current RIT protocol calls for a series of proliferant injections at least one week apart. By repeatedly starting and then restarting the inflammatory cascade with regularly scheduled injections, better and more effective healing takes place, the fibrous network is more extensive and the actual healing process is stronger and most likely, more prolonged. The rationale for ozone use is to support the phase II and III healing phases.
Discussion of RIT and Ozone Activation
The easiest way to deliver ozone to the ligamentous treatment areas is to inject it IM into the paravertebral muscles at the L4-5 level, the gluteus medius muscles adjacent to the sacroiliac joints, and directly into the SI joint if possible. This is now being used as part of the Prolozone" process. There is certainly some effect on the inflammatory/healing process as the ozone dissolves in the extracellular fluid and forms oxidative reactive products, as discussed above. This contemporaneous injection of ozone with the proliferant certainly stimulates the acute proliferant effect, but is not effective to help the longer term phases II and III of the healing process. In addition the types of growth factors that are released by blood cells during autohemotherapy are probably not present in significant quantities.
The use of platelet rich plasma (PRP) was considered in that the platelets themselves release chemotactic and growth factors. It was thought that using this purer form of blood product would result in a better result. Upon further consideration the fact that this procedure is difficult to perform and that the red blood cell products themselves should provide increased efficacy eliminated this proposal.
Exposing whole blood to a high dose of ozone and physically shaking it results in all of the products described above for PRP, but also includes the products of hemolysis, which are themselves stimulants for the healing process. In addition, the catabolism of hemoglobin induces the elaboration of heme-oxygenase, the enzyme which breaks down hemoglobin from its tetramer with a central bound iron. This is the initial catabolic step of an enzymatic process which results in the formation of bilirubin. It also causes increased production of carbon monoxide (CO), which stimulates the formation of nitric oxide (NO). These are now known to be important factors for increased perfusion and local cellular growth. This along with the other trophic effects of this form of ozone treatment should stimulate and sustain Phases II and III of the healing process. It was therefore chosen as the best and easiest form of ozonated blood (OB) to use for this protocol.
The question is when this ozone activation would best be employed. These substances if injected locally to the ligamentous areas that are to be treated should stimulate and augment the local cellular inflammatory/trophic reactions. OB could be injected before the first proliferant injection in order to "prime" the area for cellular proliferation. The proliferant would be injected two to three days later. Since proliferants cause cellular damage by osmotic and/or chemical means, injecting the plasma with the proliferant would be counterproductive in that the active organic substances present in the OB could be damaged. Therefore the OB should be injected in between the proliferant treatments. In addition the OB could strengthen and prolong the healing process. Injection of intramuscular ozone/oxygen mixture (OOM) as described by Shallenberger could also be employed at the time of the proliferant injection.
The following proposed schedule for using RIT and ozinated oxygen together uses the above rationale to best exploit the effects of both treatments.
The first injection should be a strong proliferant (such as a P2G and sodium morrhuate mixture) to start the inflammatory/healing process. OB would be injected four to seven days after each proliferant. OOM injections would be performed at the time of the proliferant treatment. The follow up injections would be P2G alone, as this proliferant is less likely to interfere with the trophic processes already underway.
It is very difficult to design a randomized, blinded, controlled research protocol with the power to differentiate between the various groups that would be needed to completely study this complicated process. The arms would include a control with no or sham treatment, an RIT only arm, an OB only treatment arm, and an ozone and RIT combined arm. In previous studies of RIT the injection of lidocaine and even normal saline as placebo showed significant proliferant activity. There were also problems with truly double blinding the placebo arm.
What I propose is to perform a pilot study of patients who are candidates for RIT. This should reveal clinical patterns that will be useful in deciding upon patient types that would benefit from this combination. A more definitive study could follow, although funding for this type of research is limited.
RIT itself is under intense study aiming at FDA approval for P2G. The animal studies are completed and the human controlled trials are to start in the near future. The information that will result from these studies can be used to augment results of RIT/OB treatment. Perhaps a carefully designed study that would use the same entry criteria could use this data for a type of control group and RIT only group.
- On day 1 a standard RIT injection procedure will be performed using a P2G sodium morrhuate mixture.
- A total of 20cc at 15-20 gamma of OOM, will be injected IM into the lumbosacral area immediately after the RIT procedure. This will be divided into bilateral injections into the paravertebral muscles at the L4-5 level and over the SI joints.
- One week later ten to twenty ml. of blood will be mixed with an equal volume of OOM at 80 or higher gamma. This OB is then to be shaken and then injected onto the usual RIT injection points in the lumbosacral spine.
- A standard RIT injection procedure will be performed using a P2G the next week
- The next week the OB injection will be repeated.
- This sequence will be repeated for a total of 5 of each treatment types (over 10 weeks).
- If practical major AHT or peroxide treatments weekly to increase and support the healing response.
- Patients will be chosen and evaluated and results reported in the same fashion as both the previous double blind studies of RIT and the ongoing University of Milan discolysis study.
This study will be certified by and FDA registered Investigational Review Board.
Please contact your physician to answer any specific questions or to explain anything that is not clear.
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