June 1, 2015

Curcumin Reduces Degenerative Disc Disease Pain

Curcuma longa relieves back pain caused by degenerative disc disease
Curcumin, extracted from turmeric, is a popular remedy for combating many inflammatory musculoskeletal-based and nonmusculoskeletal-based health concerns. While attention has been given to the effects of curcumin in relation to the pain and disability associated with arthritis of the peripheral joints, little has been written about its potential to help spinal pain, especially that of degenerative intervertebral disc disease. This brief review redresses this gap in information and offers some support and rationale for the use of curcumin preparations in this common and disabling disease.

Abstract

Curcumin, extracted from the culinary spice turmeric, has become a popular natural agent in the battle against many inflammatory musculoskeletal-based and nonmusculoskeletal-based health concerns. Current evidence suggests that its anti-inflammatory properties are most likely associated with inhibition of the chemokines cyclooxygenase and lipoxygenase as well as other key proinflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α. While attention has been given to the effects of curcumin in relation to the pain and disability associated with arthritis of the peripheral joints, little has been written about its potential to help spinal pain, especially that of degenerative intervertebral disc disease. This brief review redresses this gap in information and offers some support and rationale for the use of curcumin preparations in this common and disabling disease.

Introduction

Estimating the true incidence of back pain is not an easy task, but figures from the World Health Organization suggest the lifetime prevalence of nonspecific back pain to be in the region of 60% to 70% in industrialized countries.1 The term nonspecific reflects the fact that only 5% to 15% of cases of back pain can actually be attributed to a specific pathological cause, leaving the 85% to 95% of back pain undiagnosed and unclassified.1-4 Current research indicates that significant inflammatory changes occur within the intervertebral disc (ID), forming highly vascularized zones of granulation tissue that are associated with a network of pain-sensitive nerve fibers.5 These changes have been shown to run from the outer part of the annulus through the body of the annulus and into the nucleus pulposus. The pathological changes associated with the generation of such highly vascularized infiltration of granulation tissue suggest a repeated cycle of injury and repair, the typical clinical presentation of someone with relapsing and remitting phases of back pain.
 
From a clinical perspective gathered through observations in an active osteopathic and naturopathic practice, it is clear that key protocols should revolve around reducing the degree of inflammation while improving the nutritional status of the tissue in question. This may involve diet, supplementation, osteopathic manipulation, and exercise-based regimens. Yet, in ID cases, a frequent limiting factor in treatment has been the ID’s anatomically poor blood supply and subsequent difficulties delivering nutrients into the disc itself. Pathophysiological observations have concluded that ID disease is avascular in nature. Conventional anatomical texts describe how an ID receives nutrition via diffusion across the cartilage endplate.6 In light of new data, we need to rethink how to approach this often neglected tissue. 
 
Work on ID pathology is now revealing how a degenerated ID loses its highly concentrated proteoglycan matrix, which normally inhibits vascular ingrowth and, as a result, triggers the ingrowth of blood vessels and nerve fibers from the outer borders of the annulus into the disc substance.4,7,8 Armed with this knowledge, we may have a newly identified conduit for delivering a therapeutic anti-inflammatory agent, such as curcumin, to the inner compartment of the ID where active deep-seated inflammation has been verified. The emerging knowledge about the ID in pathology makes it plausible that the combination of increased vascularity in close proximity with pain-sensitive nerve fibers and chronic inflammatory changes is a potentially significant contributory factor to chronic back pain and one that may respond to targeted natural anti-inflammatory therapy.

A Brief Overview of Curcumin and Its Bioavailability

Curcumin, not to be confused with the spice cumin, makes up just 2% to 5% of the spice turmeric (Curcuma longa). Curcumin is considered to be the most biologically active curcuminoid contained within the spice, which includes 2 other curcuminoids, demethoxycurcumin and bisdemethoxycurcumin.9 Insoluble in water, curcumin compounds are commonly extracted using ethanol or dimethyl sulfoxide (DMSO), resulting in a purified curcumin that is orange-yellow in color.10 Its chemical structure (C21H20O6) was first described in 1815, but its use as a medicinal agent considerably predates this discovery.10 Turmeric root was used to ease pain and inflammation long before modern science discovered and isolated curcumin. Ancient Hindi texts report on the use of powdered turmeric blended with slaked lime (calcium hydroxide) applied topically on strains and sprains.10
 
The anti-inflammatory actions of curcumin appear to be well established.11,12 Reviewing all of the medicinal and potential clinical effects of curcumin is beyond the scope of this article, but a Medline search yields more than 1,000 articles published about curcumin in 2014 alone. Despite this abundance of publications, one key factor that has limited the effective application of curcumin preparations is its poor gastric and intestinal absorption. Being naturally hydrophobic, curcumin is rapidly eliminated before enough of it can be absorbed to exert its anti-inflammatory actions.13 However, improved delivery forms of curcumin have been combined with hydrophilic carriers and clinically studied. One combination is curcumin blended with turmeric oil. This combination has been shown to increase absorption 10-fold compared to standard 95%-curcumin extracts.13
The use of natural anti-inflammatory agents such as curcumin in intervertebral disc (ID) pathology has been hampered historically by the notion that the ID was a rather impenetrable tissue, but new data indicate this not to be the case. 
Blending curcumin with turmeric oil has also been associated with longer blood retention time.14,15 As a strong anti-inflammatory, this more highly absorptive curcumin delivery system might be suggested for a patient complaining of chronic pain. In one study, the efficacy of curcumin with turmeric oil, or high absorption curcumin (HAC), was evaluated in 45 individuals with rheumatoid arthritis (RA) who were randomized into 3 groups. Group 1 received 50 mg of the nonsteroidal anti-inflammatory (NSAID) diclofenac sodium twice daily; the second group received 500 mg HAC twice daily; and the third group received both diclofenac sodium and HAC. HAC was found to be more effective than diclofenac sodium at reducing joint pain and swelling, while diclofenac sodium was no more effective than curcumin alone. Administration of diclofenac sodium was shown to be less effective than taking curcumin.16 In the HAC group, no dropouts occurred, whereas in the diclofenac sodium group, 14% withdrew reportedly due to adverse events.16 Considering the minefield of potential side effects associated with the use of NSAIDs, the results of this study provide preliminary yet encouraging experimental evidence in support of the biologically active form of curcumin. 
 
Whether curcumin might reduce pain associated with osteoarthritis (OA) is worth considering. A clinical study found HAC to be superior to celecoxib, a generic NSAID used to treat arthritis. Subjects who participated in this 12-week study were randomized into 2 groups. One group received 100 mg celecoxib twice daily, and the second group twice daily received a 500 mg blend of HAC combined with Boswellia serrata extract (standardized for 10% to 15% acetyl-keto 11 beta-boswellic acid and less than 5% beta boswellic acid). Regarding pain, 64% of those taking the herbal ingredients vs 29% in the celecoxib group improved to such a degree that they self-identified as moving from the “moderate to severe arthritis” category to the “mild to moderate arthritis” category.15 The study also showed that participants experienced an increase in their ability to walk for a distance of 1,000 m while also improving knee range of motion. At the end of the study, 93% of the herbal-treated subjects could walk more than 1,000 m vs 86% in the celecoxib group. In the herbal group, 93% reported an improvement in or elimination of pain vs 79% of the drug group. While both groups experienced a significant improvement in range of motion, no statistically significant differences between herbal vs drug group were observed for this outcome.15
 
Carried out on patients with RA and OA and not specifically on patients with low-back pain or in discogenic pain, these studies also do illustrate the enhanced ability of HAC to target pain associated with inflammation. The above cited clinical studies offer experimental evidence performed in humans that suggests there may be a role for administration of curcumin as a supplement in cases of chronic back pain of discogenic origin.

Discussion

We know that a degenerative ID disease is characterized by a loss of its proteoglycan matrix structure. This may be the result of ongoing work-related spinal stress and strain or simply a result of the aging process, but we are now aware of the potential for this proteoglycan shift to induce a related inflammatory change and ingrowth of blood vessels and nerve fibers. With this comes a classic inflammatory biochemical profile characterized by proinflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α. In addition to the classic inflammatory cytokines, ID disease also appears to be influenced by factors associated more specifically with cartilage pathology, namely transcription factor nuclear factor-KB which, in turn, is closely related to the activity of toll-like receptors. Interest is also growing in effects of mitogen-activated protein kinases (MAPK; eg, p38, ERK, JNK) that mediate the MAPK pathway in discogenic pain.17 
 
In a recent study, problems associated with the low bioavailability of curcumin were avoided by proposing that curcumin be injected directly into the ID. The in vitro study involved using curcumin on pre‒IL 1β‒stimulated ID tissue samples compared to IL 1β‒stimulated samples (without curcumin exposure) and controls of non‒IL 1β‒stimulated or curcumin-exposed samples. The results clearly showed that curcumin exposure to the IL 1β‒stimulated tissue samples reduced the gene expression for IL-6 and a number of other inflammatory cytokines after 6 hours of treatment. The authors of the study use this result as justification to consider intradiscal injection of curcumin as a potential mode of application in cases of discogenic back pain.17 This study goes some way to support the use of curcumin as a potentially effective anti-inflammatory agent that may directly influence the inflammatory cascade and cytokine profile within ID tissue. However, this was an in vitro study, and making the jump to suggesting that curcumin should be introduced directly into the ID may be a little premature. Also, we can’t ignore the fact that the use of DMSO as the solvent in this study may have influenced the results, given the inherent anti-inflammatory actions of DMSO itself. We also need to remember that, as with chemonucleolysis, the successful introduction of a therapeutic agent into the disc itself is dependent on careful clinical and radiological patient selection.18 Because curcumin is indicated in cases of inflammation rather than in cases of physical changes, there may not be apparent radiological features to support its intradiscal use, whereas the use of chemonucleolysis in cases of a physical disc bulge is more clear cut.
 
If we restrict ourselves to using oral curcumin preparations, we have to overcome the issue of its low bioavailability. Historically, curcumin's success as an anti-inflammatory agent may be due to the traditional use of turmeric combined with oils and fats in cooking long before we knew that the curcumin component played a key role. By isolating curcumin from the whole spice and using it as a standalone ingredient in botanical supplements, we may now consider using blends to address the bioavailability issue. Opting to use a curcumin extract that has been blended with hydrophilic carriers or ground down into an ultrafine powder with proven high bioavailability may be the answer.14-16 Once we have an absorbable form of oral curcumin available, the range of therapeutic options opens up. 
 
Calling on previously established and well-documented work, we know that inflammatory cytokines such as TNF, IL-1, IL-6, and chemokines cyclooxygenase-2 and 5- lipoxygenase all play pivotal roles in generating the pain and inflammation19 that are associated with the type of intradiscal granulation that has been previously identified in chronic ID disease. The use of curcumin has been shown to diminish many of these inflammatory compounds, a finding that has been supported by animal studies.20 In fact, curcumin has been shown to reduce TNF-α to such a degree that expression of chondrocyte matrix metalloproteinase-13 was inhibited, making curcumin a potential agent for reducing cartilage breakdown in arthritis.20,21 Since ID inflammation has been demonstrated to involve very similar inflammatory pathways to cartilage-related inflammation,21 it may be appropriate to consider curcumin as a potential therapeutic agent for combating ID inflammation using the increased vascular network also previously described5 as a conduit to entering the normally impenetrable inner matrix of the ID.

Safety Issues

Until recently, most of the research data on curcumin have involved in vitro studies, so we have had to rely on historical and traditional use of turmeric as a guide to the safety of the extract curcumin.22 However, a 2012 study looking at the safety profile of HAC compared to the conventional NSAID diclofenac sodium or a combination of the 2 showed curcumin therapy to be not only safe, but superior to conventional NSAID treatment in cases of RA. The study concluded curcumin had an anti‒TNF α‒like action without the serious side effects associated with drugs used for the same reason.16
 
While this paper has focused on the use of curcumin derived from the C longa species, it must be noted that other forms of curcumin have also been shown to be safe and effective. For example, Curcuma domestica extracts have been shown to be an effective alternative to ibuprofen in the management of knee OA. Doses of C domestica extracts can be provided at 2,000 mg per day for 6 weeks or an even higher dose of up to 8,000 mg per day for 3 months without any serious adverse effects.23 The overall safety of curcumin has been confirmed by numerous earlier studies, including a phase-1 human trial in which participants took doses up to 8,000 mg daily for 3 months with no discernible toxicity. Five further human trials using doses ranging from 1,125 mg per day to 2,500 mg per day curcumin have also found those dosages to be safe.24

Conclusion

Despite few human clinical trials, there is a fair amount of evidence supporting curcumin’s anti-inflammatory effects. This evidence, combined with the relatively new model of neovascularization of the ID, offers a plausible pathophysiological mechanism for inflammatory ID pain that may be relieved by the use of oral curcumin, since ID inflammation appears to mirror similar inflammatory pathways to cartilage inflammation. The use of natural anti-inflammatory agents such as curcumin in ID pathology has been hampered historically by the notion that the ID was a rather impenetrable tissue, but new data indicate this not to be the case. Evidence is emerging of a highly vascular capillary network that develops in response to inflammation. This vascular network has been shown to penetrate deep within the ID tissue. Using this vascular network as a conduit for natural anti-inflammatory agents such as curcumin may open up a raft of new, safe, and effective therapeutic options in naturopathic and osteopathic practice for treatment of this disabling disease. 

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References

  1. Duthey B. Priority Medicines for Europe and the World. “A Public Health Approach to Innovation.” Update on 2004 Background Paper. WHO Background Paper 6.24 Low Back Pain. March 15, 2013. Available at: http://www.who.int/medicines/areas/priority_medicines/BP6_24LBP.pdf. Accessed May 11, 2015.
  2. Deyo RA, Weinstein JN. Low back pain. N Engl J Med. 2001; 344(5):363-370.
  3. Andersson GB. Epidemiological features of chronic low-back pain. Lancet. 1999;354(9178):581-585. 
  4. Peng BG. Pathophysiology, diagnosis, and treatment of discogenic low back pain. World J Orthop. 2013;4(2):42-52. 
  5. Peng B, Wu W, Hou S, Li P, Zhang C, Yang Y. The pathogenesis of discogenic low back pain. J Bone Joint Surg Br. 2005;87(1):62-67.
  6. Urban JP, Smith S, Fairbank JC. Nutrition of the intervertebral disc. Spine (Phila Pa 1976). 2004;29(23):2700-2709.
  7. Urban JP, Robert S. Degeneration of the intervertebral disc. Arthritis Res Ther. 2003;5(3):120-130. 
  8. Haro H, Kato T, Komori H, Osada M, Shinoiniya K. Vascular endothelial growth factor (VEGF)-induced angiogenesis in herniated disc resorption. J Orthop Res. 2002;20(3):409-415. 
  9. Thaikert R, Paisooksantivatana Y. Variation of total curcuminoids content, antioxidant activity and genetic diversity in turmeric (Curcuma longa L.) collections. Kasetsart J (Nat Sci). 2009;43(3):507-518.
  10. Aggarwal BB, Kumar A, Aggarwal MS, Shishodia S. Curcumin derived from turmeric (Curcuma longa): a spice for all seasons. In:  Bagchi D, Ed. Phytopharmaceuticals in Cancer Chemoprevention (Modern Nutrition Science). Boca Raton, FL: CRC Press; 2004:349-389.
  11. Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev. 2009;14(2):141-153. 
  12. Menon VP, Sudheer AR. Antioxidant and anti-inflammatory properties of curcumin. Adv Exp Med Biol. 2007;595:105-125.
  13. Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutr J. 2014 Jan 14;13:11. 
  14. Benny B, Antony B. Bioavailability of BiocurcumaxTM (BCM-95TM). Spice India. September, 2006:11-15.
  15. Kizhakkedath R, Benny A, Benny M, Kuruvilla BT. Clinical evaluation of an herbal formulation in the management of knee osteoarthritis. Poster presented at: Osteoarthritis Research Symposium International Annual World Congress on Osteoarthritis; September 16, 2011; San Diego, CA.  
  16. Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012;26(11):1719-1725.
  17. Klawitter et al. Curcuma DMSO extracts and curcumin exhibit an anti-inflammatory and anti-catabolic effect on human intervertebral disc cells, possibly by influencing TLR2 expression and JNK activity. J Inflamm (London). 2012;9(1):29. 
  18. Poynton AR, O’Farrell DA, Mulcahy D, Corrigan NT, McManus F. Chymopapain chemonucleolysis: a review of 105 cases. J R Coll Surg Edinb. 1998;43(6):407-409. 
  19. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41(1):40-59.
  20. Banerjee M, Tripathi LM, Srivastava VM, Puri A, Shukla R. Modulation of inflammatory mediators by ibuprofen and curcumin treatment during chronic inflammation in rat. Immunopharmacol Immunotoxicol. 2003;25(2):213-224.
  21. Liacini A, Sylvester J, Li WQ, et al. Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF kappa B transcription factors in articular chondrocytes. Exp Cell Res. 2003;288(1):208-217. 
  22. Burgos-Morón E, Calderón-Montaño JM, Salvador J, Robles A, López-Lázaro M. The dark side of curcumin. Int J Cancer. 2010;126(7):1771-1775. 
  23. Kuptniratsaikul V, Dajpratham P, Taechaarpornkul W, et al. Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study. Clin Interv Aging. 2014 Mar 20;9:451-458.
  24. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa.) J Altern Complement Med. 2003;9(1):161-168.