By Douglas Lobay, BSc, ND

THE LOBAY VIEWPOINT

I could see the bright neon lights of Las Vegas in the distance as I hobbled up the stairs on the tarmac to my connecting flight.  I had just returned from a weekend seminar with the Dr. Dietrich Klinghardt on prolotherapy in Albuquerque, New Mexico. It was November 1994, and I was just three years graduated from Bastyr College of Naturopathic Medicine. I was now practicing as a licensed naturopathic physician in British Columbia. I was eager for practical knowledge and skills that I didn’t acquire in school.  I was enthusiastic to learn some invasive naturopathic treatments with one of the gurus of chronic pain treatment.  It was a small, intimate group of about thirty practitioners at an airport hotel meeting room. The revered Dr. Klinghardt explained his approach to neural therapy, prolotherapy, and chronic pain.  He asked for volunteers to demonstrate his techniques. At some point I stuck up my hand and said I had a bad knee.  He examined my knee, confirmed my suspicion and proceeded to inject my knee with a P2G solution of phenol, glycerin, and glucose.  He peppered my anterior cruciate ligament attachment to the tibia plateau. He told me it was okay to use a stationary bicycle at the hotel after the treatment and to take it easy.  Some inflammation and swelling would be normal for a few days after the treatment.  After leaving Albuquerque, I really felt the inflammation for a few days.  Needless to say, my knee got better and the prolotherapy treatment was a key part of my recovery.

I have bad knees.  I played competitive hockey when I was younger and my knees took the brunt of many hits.  I originally injured one knee, can’t remember which one, when I was playing squash as an undergraduate student at the University of British Columbia in Vancouver. Running, planting, pivoting and twisting and snap. I tore my anterior cruciate ligament. I saw a sports medicine doctor and he recommended surgery. I had arthroscopic surgery and it seemed to help.  Another time I was taking judo classes and had a match with bigger, stronger opponent. My other knee gave out and pop I tore my meniscus. I later had arthroscopic surgery on that knee.  As I pass the half century mark, I still play old-timer’s hockey and recreational tennis. I am particularly fond of taking good care of my aging knees as I get older.

More recently I injured my knee while playing mixed doubles tennis at the Lakeview Heights Tennis Club.  My knee was inflamed, swelled up, and was painful to walk on for a while.  I used a cane, applied ice, lathered copious amounts arnica cream and took a combination of over-the-counter and herbal anti-inflammatory medicine mainly as turmeric. I was pretty sure that I had a meniscal tear.  I went to a walk-in-clinic, was examined by a doctor and went for some obligatory knee x-rays.  The x-rays showed some narrowing joint space and some age-related degeneration. When the acute swelling had diminished, I embarked on an aggressive rehabilitation program that included swimming, biking, and the use of some physiotherapy devices that I had at the office. In the true spirit of “physician heal thyself,” I gave myself a series of generalized intra-articular prolotherapy injections with hyaluronic acid and procaine.  While I am not advocating that anyone should give themselves intra-articular knee injections, I can attest that it was only slightly unnerving—after all I have given numerous shots like this to many of my patients. The shots seemed to help a lot, decreased the pain almost immediately and accelerated healing to the point at which I am now back playing tennis.

Prolotherapy is a generic term that involves the use of proliferants to help stimulate growth of new connective tissue in cartilage, ligaments, and tendons. Proliferants include any substance that would help to proliferate or stimulate the growth of new tissue.  Substances used as proliferants include dextrose or glucose, saline, glycerin, phenol, sodium morrhuate or a mixture of the sodium salts of the saturated and unsaturated fatty acids of cod liver oil, dimethylsulfoxide, glucosamine sulphate, growth hormone, hyaluronic acid, plasma rich platelets (PRP) and other minerals and substances.  Some of the substances such as phenol and sodium morrhuate are strongly irritating and provoke inflammation.  Other substances such as hyaluronic acid and PRP tend to be less irritating and less inflammatory.  Prolotherapy is a quintessential natural healing therapy.

Synovial fluid is a thick viscous straw-colored fluid that lubricates joint space between two bones.  A typical knee joint contains between 0.5 to 4.0 milliliters of this fluid.  The fluid can expand and contract depending on internal and external pressure, temperature and other rheological factors.  The purpose of synovial fluid is to lubricate the joint between two bones, reduce friction, and act as a shock absorber.  Synovial tissue is considered to be a sterile environment that can also supply nutrients and remove waste products and act as a molecular sieve.  The synovial lining is composed of several cells, including chondrocytes, fibroblasts and monocytes.  Chondrocytes produce collagen proteins that line the surface of bones in a joint. Lubricin is a glycoprotein produced by chondrocytes that coats and protects the outer surface of joint collagen. Fibroblasts produce hyaluronic acid and monocytes are active in removing debris produced in the joint space.  Hyaluronic acid is a disaccharide polymer of repeating units of glucuronic acid and N-acetyl glucosamine.  Synovial fluid is also composed of a filtrate of blood plasma mixed with hyaluronic acid and lubricin and different proteinase and collagenase enzymes. With osteoarthritis or degenerative joint disease there is a breakdown of the connective tissue, including collagen and hyaluronic acid and deterioration of the quality of synovial fluid lining the joint space.¹

A search of the medical research database PubMed revealed over 28,000 listings on hyaluronic acid. I found that some of the most informative articles on this site belong to the area of veterinary medicine.  Hyaluronic acid is widely used on horses, dogs, rabbits, sheep, and other animals with arthritic degeneration.  The biochemistry and pharmacology of hyaluronic acid has been studied more extensively in this group.  Intra-articular injections of hyaluronic acid appear to be safe and effective in the treatment of degenerative arthritis in animals and humans.¹

Hyaluronic acid (HA) is a large, heavy molecule that exists with different molecular weights.  Hyaluronic acid is typically measured in Daltons.  A Dalton is a unit of atomic mass that is exactly 1/12 the weight of a carbon-12 atom. Native hyaluronic acid usually exists between 4 to 10,000 kilodaltons in joint space. Hyaluronic acid is composed of repeating units of glucuronic acid and N-acetylglucosamine in different chain lengths. Different lengths and size of the chain account for the different atomic weights of the molecule. Injectable hyaluronic acid can be made from animal tissues such as shellfish and rooster combs but is more typically made from bacterial production commercially. Injectable hyaluronic acid can exist in different molecular weights. Low molecular weight hyaluronic acid ranges from 500 to 730 kilodaltons.  Intermediate molecular weight hyaluronic acid ranges from 800 to 2000 kilodaltons.  High molecular weight hyaluronic acid ranges greater than 6000 kilodaltons.  Some studies suggest that injectable high molecular weight hyaluronic acid is more effective than smaller subunits.  All weights seem to have beneficial effects.¹

Some commercially available injectable hyaluronic acid products include Hyalgan, Orthovisc and Synvisc.  The exact ingredients and weights of the hyaluronic acid are proprietary and non-disclosed. Some compounding pharmacies will make up generic hyaluronic acid preparations.  The compounding pharmacy I am currently using makes up an intermediate molecular weight hyaluronic acid at 10 milligrams per milliliter.¹

Animal studies show that injectable hyaluronic acid can directly improve lubrication of synovial fluid shortly after injection.  Also, local hylauronidases break down some of the hyaluronic acid into smaller chains and subunits which can then be reassembled into nascent hyaluronic acid. Injectable hyaluronic acid has been shown to decrease inflammatory cytokines like prostaglandin E2, interleukin-1 beta and tumor necrosis factor; decrease oxidative stress; decrease chondroctyte and fibroblast apoptosis; increase fibroblast and chondroctye growth factors; decrease proteolytic enzyme activity; and block pain receptors.  These effects summarily improve joint lubrication, preserve joint function, and prevent degenerative deterioration.¹ 

An overview of hyaluronic acid injections showed improved lubrication, anti-inflammatory activity, chondro-protective effects.  Hyaluronic acid further significantly reduced pain in the affected joints.  It was further suggested that HA should be mixed with other drugs or substances to maximize potential benefits.  Additionally, it was noted that HA was generally non-toxic and biodegradable.²  Seventeen papers, including seven randomized controlled trials and ten cohort studies, evaluated intra-articular HA injections for knee osteoarthritis.  Repeated injections of HA appear to be safe, effective, and well tolerated for most patients.³  In one randomized controlled trial with eighty patients, low molecular weight HA injections were compared to high molecular weight HA injections.  Both solutions showed about the same benefits in terms of reduced pain and inflammation and improved range of motion.  There was no clear benefit of one molecular weight of HA compared to the either one.⁴

In one larger study, three hundred and sixty patients with osteoarthritis of the knee were divided into four treatment groups.  One group received just plasma rich platelets (PRP) injections, one group received just HA injections, a third group received PRP plus HA injections and a fourth group received normal saline injections.  The group that received the combination of PRP plus HA simultaneously showed the best improvement in terms of pain reduction and joint healing.  Decreased cytokines, decreased tumor necrosis factor, decreased interleukin-1 beta, increased interleukin-6, and increased vascular endothelial growth factor were observed. Side effects to the treatments were closely monitored and were noted to include such symptoms as fatigue, high blood pressure, proteinurea, and high triglycerides.  In some patients a reduced dose of medicine was more tolerable.⁵

Thirteen studies, including three prospective studies and ten randomized controlled trials, compared PRP to HA intra-articular injections in patients with knee osteoarthritis.  Both treatments were equal after three months post-treatment.  PRP was shown to be slightly more effective than HA after six months follow up but was not obviously superior. More high-quality studies suggested the benefits of these two treatments.⁶

A meta-analysis of fifteen randomized controlled trials with 1,314 patients showed the plasma rich platelet therapy was better than hyaluronic acid in pain reduction.  Plasma rich platelets is an autologous highly concentrated solution made from the patient’s own blood that contains a variety of growth factors that promotes healing in ligaments, tendons, and cartilage.  Some of these growth factors include platelet derived growth factor, fibroblast growth factor, transforming factor B, vascular endothelial growth factor and bioactive proteins that increase cartilage repair and production.  There was a lack of clarity in terms of the number and frequency of injections to achieve maximum results and the ideal treatment regime for different areas.⁷

A randomized controlled trial of 120 patients compared intra-articular injections of cortisone, hyaluronic acid and PRP.  After three months post injection treatment all patients showed basically the same improvement rate.  However, after six, nine and twelve months the PRP-treated group was slightly superior to either the cortisone or hyaluronic acid groups.⁸

A systematic review and meta-analysis of three randomized controlled trials with 258 patients showed positive and beneficial effects of prolotherapy with a dextrose solution.  Positive benefits included decreased pain and improved range of motion.⁹ In one study twenty-four women with knee osteoarthritis received monthly injections of a 20% dextrose solution. Patients were monitored at four, eight, and 24 weeks.  A significant improvement in pain reduction, range of motion and stiffness was noted.  Two patients left the study because of pain from the injections.¹⁰  In another study seventy-six patients with knee osteoarthritis received four intra-articular injections at 0, 4, 8 and 16 weeks consisting of 1.0 milliliter of 1.0% Xylocaine and 5.0 milliliters of a 25% dextrose solution.  Patients were instructed that it was ok to take acetaminophen if needed for post-injection pain but were advised not to take non-steroidal anti-inflammatory drugs (NSAIDS).  Significant reduction in pain and inflammation in the treated joint was observed.¹¹

In a double blinded study of 54 patients, intra-articular glucosamine was compared to 0.9% sodium chloride injections into degenerative joints at a frequency of once per week for five weeks.  The glucosamine-treated group showed a marked increase in recovery, decrease in pain, increased range of motion and decrease in swelling.  No side effects were noted and the improvement lasted for about one month post treatment.  The glucosamine seemed to partially restore articular function.¹²

In one study intra-articular dimethyl sulfoxide (DMSO) injections by itself showed no positive benefits in terms of joint repair or connective tissue production.¹³  In another study a 40% DMSO solution mixed with Ringer’s lactate injected in to the carpal bones of horse showed a marked increase in endogenous hyaluronic acid production.¹⁴ 

Intra-articular hyaluronic acid has demonstrated to be superior to intra-articular ozone treatments for knee osteoarthritis in terms of pain relief and improved range of motion.  A six-month randomized controlled trial of 174 patients who either received either hyaluronic acid injections or 10 milliliters of 30 microgram/milliliter of ozone. Both ozone and hyaluronic acid treatments showed benefits.¹⁵ An analysis of four randomized controlled studies of 289 patients showed that hyaluronic acid was superior to ozone treatments after six months post therapy.¹⁶

Intra-articular injection of corticosteroids appears to be more effective on pain relief in the short term, less than one month, than intra-articular injections of HA.  HA showed to be more effective in the long, for up to six months.  Both medications appeared to be relatively safe and well tolerated; HA injections showed slightly more adverse effects than the corticosteroids.¹⁷  In another study 40 milligrams of methylpredisonolone and 0.5 milliliters of 2.0% xylocaine was compared to 0.5 milliliters of a 20% dextrose solution plus 0.5% xylocaine.  Intra-articular shots were repeated once per month for three months in 60 patients with hand osteoarthritis.  Follow up after six months showed that the dextrose injections were slightly more effective in decreasing pain and improving range of motion than the cortisone injections.¹⁸

Intra-articular injections of local anesthetics can relieve joint pain. In one study the intra-articular injection of 5.0 milliliters of 0.25% bupivacaine significantly reduced the pain in the affected joint.¹⁹ However, the use of intra-articular local anesthetics should be used with much caution. Bupivacaine, lidocaine and ropivacaine are chondro-toxic to human articular cartilage.  The toxicity increases proportionally to the time exposed to the anesthetic.  Even a single injection of an anesthetic can damage the cartilage matrix and promote chondrocyte cell death.²⁰

Intra-articular injections of the most common anesthetics, including bupivacaine and lidocaine, are toxic to cartilage. Data from 289 studies was evaluated. Continuous intra-articular infusions of anesthetics following joint surgery are much more toxic than a single injection.  The addition of norepinephrine to decrease post-surgical bleeding was also shown to be toxic to chondrocytes.  Anesthetics were shown to cause chondrolysis and decrease cell density up to 50% for up to six months months after injection.  Lidocaine was further shown to cause mitochondrial damage in chondrocytes leading to cartilage cell apoptosis. Some studies showed that the addition of magnesium sulphate and normal saline with the anesthetic did not significantly reduce cell viability.²¹ Procaine appears to be less toxic to articular cartilage.  Twenty rats were injected with intra-articular procaine anesthetic or saline and then evaluated histologically.  No difference was noted between the procaine and saline groups.  Further studies to evaluate the safety of procaine were suggested.²²

I have experimented with different substances and prefer to use gentler, non-irritating solutions such as dextrose, hyaluronic acid, and PRP.  Sometimes I use only one proliferant mixed with a small amount of local anesthetic such as lidocaine or procaine.  Other times I mix all three of these substances with a small amount of local anesthetic.  For knee osteoarthritis I typically inject one or two 3.0 cc syringes with a 25-gauge needle from the medial and lateral sides of the infra-patellar tendon that gives access to the intra-articular joint space.  All substances appear to be about equally effective for pain relief and improvement in joint range of motion.  One patient may prefer hyaluronic acid while another patient may prefer dextrose or PRP injections.  The combination of these ingredients seems to be moderately better than an individual single ingredient.  The addition of a small amount of local anesthetic helps to reduce pain almost immediately and make the patient feel better.  I prefer to use ester anesthetic procaine in small doses as it appears to be safer to cartilage tissue than amide anesthetics.  With chronic cases I usually repeat the treatment in three- or four-week intervals with time for healing in between.  Other patients I see when they feel they need another treatment, which can last as long as six months to a year.  A few patients find no relief or benefit. Most patients find some relief and benefit. Some patients find tremendous relief and improvement.

Side effects of hyaluronic acid injections include pain and joint swelling at the site of injection, redness, and inflammation. Some local pain after an injection may be normal and is best managed with conservative therapies such as topical ice and oral acetaminophen.  Non-steroidal anti-inflammatory medication are not recommended because they can interfere with chondrocyte and fibroblast function and the healing process.  In rare cases, bacterial or fungal infection has occurred.  Improper aseptic technique and/or cross contamination of injectable products are to blame.  Intra-articular infection is usually difficult to treat and may also require surgical intervention. I can’t over emphasize that need for proper, safe and clean technique, especially when doing joint injections. Appropriate training courses are available for health professionals.

Hyaluronic acid injections are not recommended for pregnant and nursing patients, pediatric patients and patients with active infection, especially around the joint to be injected.  Also some animal studies show that production of hyaluronic acid is over-expressed in many types of cancer cells.  The clinical significance of this is not fully understood yet.²³   

My dad was a strong, powerful man who was a skilled mechanic and master craftsman. He would often be working on a car or an engine in the middle of winter in a poorly heated garage.  Later in life he was riddled with degenerative arthritis and was in chronic pain. I remember receiving a letter from him one time while I was away at school.  He ended the letter with a prophetic piece of advice to me whose meaning I would only understand in later years.  He said, “Son, whatever you do remember to take care of your knees.”  I am now heeding his warning with a combination of common sense, nutritional supplementation, and injection therapy.  Gentle prolotherapy with hyaluronic acid can be a great adjunct to help prevent arthritic degeneration. With time we will see how this episode plays out.

References

1. Gupta RC et al. Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory. Front. Vet. Sci., 2019 June 25;6(192):1-80.
2. Bowman S et al. Recent advances in hyaluronic acid based therapy for osteoarthritis. Clin Transl Med. 2018 Feb;7(1):6.
3. Altman R et al. Efficacy and Safety of Repeated Courses of Hyaluronic Acid Injections for Knee Osteoarthritis: A Systematic Review. Semin Arthritis Rheum. 2018 Oct. 48(2);168-175.
4. Gigis I et al. Comparison of two different molecular weight intra-articular injections of hyaluronic acid for the treatment of knee osteoarthritis. Hippokratia. 2016;20(1):26–31.
5. Yu W et al. Clinical therapy of hyaluronic acid combined with platelet-rich plasma for the treatment of knee osteoarthritis. Exp Ther Med. 2018;16(3):2119–2125.
6. Zhang HF et al. Intra-articular Platelet-Rich Plasma Versus Hyaluronic Acid in the Treatment of Knee Osteoarthritis: A Meta-Analysis. Drug Des Devel Ther. 2018 Mar; 12:445-453.
7. Han Y et al. Meta-analysis Comparing Platelet-Rich Plasma vs Hyaluronic Acid Injection in Patients with Knee Osteoarthritis Pain Medicine. July 2019 Volume 20, Issue 7:1418–1429.
8. Huang Y et al. Intra-articular Injections of Platelet-Rich Plasma, Hyaluronic Acid or Corticosteroids for Knee Osteoarthritis : A Prospective Randomized Controlled Study. 2019 Mar; 48(3):239-247.
9. Sit RWS et al. Hypertonic dextrose injections (prolotherapy) in the treatment of symptomatic knee osteoarthritis: A systematic review and meta-analysis. Scientific Reports. 2016 May 6. Volume 6; article number 25247.
10. Eslamian F and Amousandeh B. Therapeutic effects of prolotherapy with intra-articular dextrose injection in patients with moderate knee osteoarthritis: a single-arm study with 6 months follow up. Ther Adv Musculoskelet Dis. 2015;7(2):35–44.
11. Sit RWS et al. Efficacy of intra-articular hypertonic dextrose prolotherapy versus normal saline for knee osteoarthritis: a protocol for a triple-blinded randomized controlled trial. BMC Complement Altern Med. 2018;18(1):157.
12. Vajaradul Y. Double-blind Clinical Evaluation of Intra-Articular Glucosamine in Outpatients With Gonarthrosis. Clin Ther. 1981; 3 (5):336-43.
13. Bennett RM et al. Dimethyl sulfoxide does not suppress an experimental model of arthritis in rabbits.The Journal of Rheumatology, 31 Jul 1983; 10(4):533-538.
14. Welch RD et al. Effects of Intra-Articular Administration of Dimethylsulfoxide on Chemically Induced Synovitis in Immature Horses. Am J Vet Res. Jun 1991; 52 (6), 934-9.
15. 15.  Raeissadat SA et al. Intra-articular ozone or hyaluronic acid injection: Which one is superior in patients with knee osteoarthritis? A 6-month randomized clinical trial. J Pain Res. 2018 Jan 4;11:111–117.
16. Li Q et al. Intra-articular Oxygen-Ozone Versus Hyaluronic Acid in Knee Osteoarthritis: A Meta-Analysis of Randomized Controlled Trials. Int J Surg. 2018 Oct; 58:3-10.
17. He WW et al. Efficacy and Safety of Intraarticular Hyaluronic Acid and Corticosteroid for Knee Osteoarthritis: A Meta-Analysis. Int J Surg. 2017 Mar;39:95-103.
18. Jahangiri A et al. Hypertonic dextrose versus corticosteroid local injectionfor the treatment of osteoarthritis in the first carpometacarpal joint: a double-blind randomized clinical trial. J Orthoped Sci. 2014; 19:737-743.
19. Creamer P et al. Pain mechanisms in osteoarthritis of the knee: effect of intraarticular anesthetic. The Journal of Rheumatology, 1996 May 31; 23(6):1031-1036.
20. Piper SL et al. Effects of Local Anesthetics on Articular Cartilage. The Am J of Sports Med. 2011 Oct; 39 (10): 2245-53.
21. Gulihar A et al. Articular cartilage and local anaesthetic: A systematic review of the current literature.J Orthop. 2015 Oct ;12(Suppl 2):S200–S210.
22. Yilbas AA et al. Procaine and Saline Have Similar Effects on Articular Cartilage and Synovium in Rat Knee. 2018 May. 18(1); 51.
23. Cheng J and Abdi S. Complications of Joint, Tendon, and Muscle Injections. Tech Reg Anesth Pain Manag. 2007;11(3):141–147.