Lipoxygenase Inhibition: A Missed opportunity for controlling pain and inflammation
Are we only "half treating" our back and joint pains?
Back and joint pains are among the top reasons for visits to the doctor. Yet complete resolution of the complaint is often slow in coming or never completely resolved. Why?
There are 2 major physiologic pathways leading to inflammatory and pain responses: the cyclooxygenase (COX) mediated and the lipoxygenase (5-LO) dependent one. While the former is widely known, and inhibited by the well popularized NSAID's (like Celebrex, Vioxx(!)), etc, the second one is virtually ignored in the current management of pain syndromes. Principal cause for this is the failure of major drug companies to develop synthetic drugs that can inhibit the 5-LO and its downstream metabolites, the all important leukotrienes. To make up for the failure to deal with the 5-LO, pharmaceutical solutions like corticosteroids are usually put in place - with their well known side effects.
The bottom line is that when only one of two pathways to pain is addressed the patient is only "half treated" and half satisfied.
Lipoxygenase and pain
The 5-LO enzyme works to produce the "misery" of the leukotrienes.1 They are abundantly involved in over 35 chronic conditions including: asthma, allergies, colitis, arthritis, gastric disorders (promote ulcer formation, stimulate acid secretion, etc), scleroderma, neurological diseases, and so on. 2
More recently the involvement of the leukotrienes in pain syndromes has become clear from a multitude of studies. 1
5-LO and leukotriene B4 are involved in orofacial pain perception and mechanical and thermal sensitivity.3-7
Postoperative incision pain in animal models could be considerably reduced using experimental 5-LO inhibitors.8
The beneficial effects of 5-LO inhibition were demonstrated in the reduction of inflammatory events accompanying experimental spinal cord injury. 9
Several studies have identified inflammatory mediators in disk herniation, such as leukotrienes. Cytokines occurring in degenerated facets have been shown to contribute to the pain of degenerative lumbar disorders. 10, 11
5-LO has been shown to be involved in both pain modulation and induction of opioid tolerance at the spinal level. 12 5-LO metabolites are found in clinical cases of herniated nucleus pulposus and experimental data gathered in the study of associated radicular pain in animals demonstrated that 5-LO inhibition may prove to be beneficial in such conditions.13
Pharmacological inhibition of the 5-LO
While the market availability of COX inhibitors is widespread the opposite seems to be the case with pharmaceuticals in the lipoxygenase class direction. Partially this is not due to lack of trying. Promising experimental drugs had to be abandoned due to unacceptable side effects - death of animal subjects! Even those that made it to market carry warnings of hepatotoxicity (Zileuton) or have been associated with an increase in abnormal mental behavior (Singulair). On the other hand there is a persistent lack of research on the part of the pharmaceutical industry secondary to a tragic underestimation of the potential market size.
Financial disincentives explain the lack of studies of extracts of "natural" substances which are not easily patentable.
Advances in nutritional therapy with high concentration boswellia (frankincense) extracts
The premier 5-LO inhibitor is the natural, herbal ingredient AKBA, acetyl-11-keto-beta-boswellia acid, the most active component of the frankincense, Boswellia serrata. Boswellia as such has been known for centuries to be a potent anti-inflammatory agent. Studies have proven its efficacy in arthritis, colitis, allergies and environmental sensitivities. 14-16
More recent studies have confirmed the analgesic properties of boswellia extracts, both as stand alone solutions as well as synergistic enhancers of pain relief when given in conjunction with COX inhibitors, opioids and other NSAID's. 17, 18
The success of boswellia extracts is all the more surprising since only poorly standardized products have been available on the general market. The component AKBA is recognized as the active anti- inflammatory principle in the boswellia and yet by far most of the formulas have only 1-3% AKBA concentration.
Fortunately high concentration boswellia extracts are now available with a concentration of over 90% AKBA! This leads to enhanced efficacy. There are a number of high quality boswellia products on the market. To get the best a careful reading of the supplement facts on the label is necessary.
If the label does not specifically state that the AKBA content is minimum 90% you are not getting the best quality possible.
With the right quality and dosage, however, either taken alone or together with other therapies symptom relief could be seen from this nutritional modality. Improvement in previously therapy resistant back or joint pain, prolonged "holding" of chiropractic adjustments and faster pain relief after injury has been routinely noted.
Safety and toxicology;
High concentration boswellia extracts are considered GRAS - generally regarded as safe. There are practically no side effects except for an occasional report of headache. There have not been any reports of the intestinal distress seen with other boswellia preparations.
Conclusion
High concentration boswellia extracts with 90% or more AKBA is highly beneficial for the treatment of pain syndromes ranging from back to joints and other damaged soft tissues. They can help in other organ and neurological pain conditions due to their anti- inflammatory properties. It can be given as a stand alone solution or in conjunction with other COX inhibitors. They are considered nutritional supplements and should be part of a general health maintenance.
(These statements have not been evaluated by the FDA. These ingredients are not intended to diagnose, treat, cure, or prevent any disease. Never start a new program without consulting a qualified heath care professional.)
References
1. Whitehouse MW, Rainsford KD. Lipoxygenase inhibition: The neglected frontier for regulating chronic inflammation and pain. Inflammopharmacology. 2006;14( 3-4):99-102. 2. Werz O, Steinhilber D. Pharmacological intervention with 5-lipoxygenase: New insights and novel compounds. Expert Opinion on Therapeutic Patents. 2005;15( 5):505-519. 3. Aley KO, Levine JD. Contribution of 5- and 12-lipoxygenase products to mechanical hyperalgesia induced by prostaglandin E2 and epinephrine in the rat. Experimental Brain Research. 2003;148( 4):482-487. 4. Amann R, Schuligoi R, Lanz I, Peskar BA. Effect of a 5-lipoxygenase inhibitor on nerve growth factor-induced thermal hyperalgesia in the rat. European Journal of Pharmacology. 1996;306( 1-3):89-91. 5. Bisgaard H, Kristensen JK. Leukotriene B4 produces hyperalgesia in humans. Prostaglandins. 1985;30( 5):791-797. 6. Chichorro JG, Lorenzetti BB, Zampronio AR. Involvement of bradykinin, cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial nociception in rats. British Journal of Pharmacology. 2004;141( 7):1175-1184. 7. Martin HA. Leukotriene B4 induced decrease in mechanical and thermal thresholds of C-fiber mechanonociceptors in rat hairy skin. Brain Research. 1990;509( 2):273-279. 8. Gaspar AF, Prado WA. Comparison of pre- versus post-incision administration of intraplantar indomethacin and MK886 in a rat model of postoperative pain. Brazilian Journal of Medical and Biological Research. 2007;40( 8):1141-1147. 9. Genovese T, Rossi A, Mazzon E, et al. Effects of zileuton and montelukast in mouse experimental spinal cord injury. British Journal of Pharmacology. 2008;153( 3):568-582. 10. Goupille P, Jayson MIV, Valat J-, Freemont AJ. The role of inflammation in disk herniation-associated radiculopathy. Seminars in Arthritis and Rheumatism. 1998;28( 1):60-71. 11. Igarashi A, Kikuchi S, Konno S, Olmarker K. Inflammatory cytokines released from the facet joint tissue in degenerative lumbar spinal disorders. Spine. 2004;29( 19):2091-2095. 12. Trang T, McNaull B, Quirion R, Jhamandas K. Involvement of spinal lipoxygenase metabolites in hyperalgesia and opioid tolerance. European Journal of Pharmacology. 2004;491( 1):21-30. 13. Singh VP, Patil CS, Kulkarni SK. Effect of licofelone against mechanical hyperalgesia and cold allodynia in the rat model of incisional pain. Pharmacological Reports. 2005;57( 3):380-384. 14. Ammon HPT. Boswellic acids in chronic inflammatory diseases. Planta Medica. 2006;72( 12):1100-1116. 15. Ammon HPT. Boswellic acids for the treatment of chronic inflammatory diseases. Medizinische Monatsschrift fur Pharmazeuten. 2003;26( 9):309-315. 16. Poeckel D, Werz O. Boswellic acids: Biological actions and molecular targets. Current Medicinal Chemistry. 2006;13( 28):3359-3369. 17. Bishnoi M, Patil CS, Kumar A, Kulkarni SK. Analgesic activity of acetyl-11-keto-beta-boswellic acid, a 5-lipoxygenase-enzyme inhibitor. Indian Journal of Pharmacology. 2005;37( 4):255-256. 18. Bishnoi M, Patil CS, Kumar A, Kulkarni SK. Protective effects of nimesulide (COX inhibitor), AKBA (5-LOX inhibitor), and their combination in aging-associated abnormalities in mice. Methods and Findings in Experimental and Clinical Pharmacology. 2005;27( 7):465-470.
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