Inflagesic™ Technical Data

Inflagesic™ Technical Data

Herbs that May Assist

Curcumin
Turmeric longa, root
BosPure® Boswellia
Boswellia serrata, dry gum oleoresin
Rhuleave-K™

Actions

  • Anti-inflammatory
  • Analgesic and antinociceptive

Clinical Applications

  • ·Acute pain

Curcumin and Boswellia (Rhuleave-K™) for Rapid Pain Relief

Inflammatory pain is a prominent health burden. To help manage acute pain, Rhuleave-K™ is a clinically proven blend of curcumin derived from Curcuma longa and Boswellia serrata (boswellia) within black sesame oil that offers effective analgesia. In human studies, this combination reduces muscular pain within 63 minutes,[1] offering a similar time-to-effect as paracetamol.[2] Rhuleave-K™ features innovative SPEEDTECH™ technology with particle micronisation and a phospholipid-rich sesame oil delivery system[3] to enhance ingredient absorption,[4] providing a fast-acting solution for inflammatory pain.

Background Information

Inflammation is an adaptive response caused by tissue damage mediated in four stages[5]:

  1. Cell receptors activation that induce intracellular signalling (e.g. toll-like receptors [TLRs], NOD-like receptor pyrin domain containing 3 [NLRP3]).
  2. Messenger proteins that relay signals into nuclei (e.g. peroxisome proliferator-activated receptor gamma [PPAR-γ] and IkappaB kinase [IKK]).
  3. Inflammatory transcription factors that enter nuclei and interact with DNA, such as nuclear factor kappa B (NFκB), to stimulate the transcription of:
  4. Effector mediators released into tissue, including interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α); and, pro-inflammatory enzymes (e.g. cyclooxygenases [COX]) which promote arachidonic acid inflammatory pathways (e.g. prostaglandin activity).

This process promotes the cardinal signs of inflammation: heat, swelling, redness and pain.[6]

To alleviate acute inflammatory pain, paracetamol and non-steroidal anti-inflammatories (NSAIDs) are commonly used. However, complete relief may be difficult to achieve with these alone.[7] Additionally, single doses above >400 mg of ibuprofen [NSAID] and >1,000 mg of paracetamol may result in higher risks of adverse effects.[7] Curcumin and boswellia within Rhuleave-K™ have been shown to achieve comparable outcomes to paracetamol[2] and NSAIDs[8,9] offering individuals an effective alternative to OTC pain treatments.

Unique to the manufacture of Rhuleave-K™, proprietary SPEEDTECH™ technology with micronised botanical particles within a phospholipid-rich base[3] to create a highly bioavailable dispersion. For this reason, anti-inflammatory benefits of Rhuleave-K™ can support effective management.[4,10-12]

Actions

Anti-inflammatory

Boswellia and curcumin target several stages of inflammation. Boswellia inhibits intermediate messenger molecule IKK in vitro, limiting its effect on promoting NFκB activation.[13] Subsequently, boswellia downregulates pro-inflammatory cytokines, including TNF-α, IL-1 and IL-6, which may help to mitigate acute inflammatory pain.[11] Boswellia also blocks the activity of the enzyme, 5-LOX,[11,14] which plays a key role in attracting pro-inflammatory cells into tissues (e.g. neutrophils and eosinophils).[15]

Curcumin also moderates the inflammatory response.[5] By binding to TLRs and PPAR-γ, curcumin inhibits NFκB and transcriptional signalling molecules that promote inflammation (e.g. Janus kinase [JAK] and signal transducer and activator of transcription [STAT]).[5] Through these mechanisms, curcumin has been observed to lower cytokine levels, such as TNF-α, IL-1, IL-1β, IL-6 and IL-8.[5,16]

Through downregulating transcriptional mediators, curcumin reduces the expression of COX-2 and 5-LOX, which promote the release pro-inflammatory prostaglandins and leukotrienes.[17,18] Interestingly, human studies have shown curcumin-containing extracts to reduce COX-2 levels as effectively as to NSAIDs,[19] further supporting the benefits of curcumin compared to OTC pain relief.

Analgesic and Antinociceptive

Through targeting sensory pain receptors (nociceptors), analgesic agents can help to reduce pain perception. This in turn can help minimise pain sensitivity.[20,21]

Curcumin has been shown to reduce nociception via transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), which are linked to heightened pain sensitivity.[22,23] In addition, curcumin also stimulates adenosine triphosphate (ATP)-sensitive potassium channels that block nociceptor activation, which further dampens pain transmission.[24] Evidence indicates that curcumin can activate alpha 7 nicotinic acetylcholine receptors (α7-nACh) to reduce nociceptive pain[25] and limit pain sensitivity following injury in animals.[26]


Clinical Applications

Acute Pain

Rhuleave-K™ is comparable to a single dose of acetaminophen (paracetamol) in open-label study (n= 88 healthy subjects; mean age 42 ± 12 years) in individuals with grade 1 musculoskeletal strain.[2] 1,000 mg/d Rhuleave K (equivalent to 266 mg/d curcumin and 1,000 mg/d boswellia extract; n=44) with breakfast was compared to 1,000 mg of acetaminophen (n=44). Outcomes revealed Rhuleave-K™ offered equal benefit to acetaminophen (p<0.001), within 2.5 hours (Figure 2). After six hours, Rhuleave-K™ reduced total pain by 53.1% versus 55.4%, and lowered pain intensity by 37.7% comparable to acetaminophen (38.6%). Rhuleave-K™ treatment improved pain quality and intensity after seven days by 71.8%, akin to OTC drug treatment (73.6%).[2]

Figure 2: Pain reduction with Rhuleave-K™ treatment was comparable to acetaminophen (p<0.001). [2]

The fast-acting benefits of Rhuleave-K™ were documented in 232 healthy individuals (mean age 36.4 years) with exercise-induced muscle pain. These patients received either Rhuleave-K™ (n=116) or placebo (n=116) and were monitored over six hours.[1] Results revealed a reduction of severe pain from greater than 74% to less than 3% in the head, neck, upper and lower limbs, torso and back (p<0.001).

This demonstrated a relative >95% improvement in pain with Rhuleave-K™, while no significant relief occurred in the placebo group. Researchers also observed that perceived pain relief occurred around 63 minutes with active treatment. Further, complete pain relief in the head, neck, upper and lower limb, torso, and back was achieved in 3.1 hours.[1]

In a systematic review and meta-analysis of randomised-controlled clinical trials, researchers analysed data from 159 participants (aged 19.5 to 35.5) with muscle soreness.[16] Pooled statistics revealed that 150 mg/d to 180 mg/d of curcumin achieved a near-significant effect in reducing muscle soreness (p<0.051). Further evaluation revealed this effect was significant in reducing pain in untrained individuals (p<0.001) following resistance exercise (p<0.001) after 72 and 96 hours (p<0.034; p<0.001).[16]

Curcumin has also been observed to reduce inflammatory arthritic pain.[8,19] In a randomised double-blind, placebo-controlled trial, 24 rheumatoid arthritis patients (mean age 36) received 250 mg of curcumin twice daily or placebo for 90 days. Results revealed a 78.1% improvement in joint tenderness and a 80.4% reduction swelling versus 4.4% and 3.7% improvement in the placebo group respectively.[27] This research indicates that ingredients within Rhuleave-K™ can deliver fast-acting pain relief.

Summary of Ingredients

Population

Study details

Outcomes

Healthy subjects (mean age 42 ± 12 years) with grade 1 musculoskeletal strain (<5% loss of function[28]) experiencing acute pain rated 60% to 65% (n=88).

Randomised open-label study.

Single dose 1,000 mg/d Rhuleave-K™ (equivalent to 266 mg/d curcumin + 1,000 mg/d boswellia) with breakfast

vs.

1,000 mg acetaminophen (paracetamol)7 days;

Pain reduction from baseline with Rhuleave-K™ treatment was comparable to acetaminophen (p<0.001). Both treatments achieved noticeable pain relief within 2.5 hours. Within 6 hours, Rhuleave-K™ achieved a 53.1% reduction in total pain comparable to 55.4% with acetaminophen, as well as 37.7% improvement in pain intensity vs. 38.6% with acetaminophen. After 7 days, Rhuleave-K™ improved pain quality and intensity by 71.8% compared to 73.6% in the acetaminophen group.[2]

Healthy subjects (mean age 36.4 years) with exercise-induced acute muscle pain (grade 1) rated at 80% (n=232).

6 hours; Randomised double-blind placebo-controlled study.

Single dose 1,000 mg/d Rhuleave-K™ (equivalent to 266 mg/d curcumin + 1,000 mg/d boswellia)

vs.

placebo

Pain rated between 74% to 86% in the head, neck, upper and lower limbs, torso, and back was reduced down to 0% to 3% after six hours with Rhuleave-K™ (p<0.001), improving relative pain scores by >95%. No significant pain relief was observed in the placebo group. Perceived pain relief occurred around 63 minutes with Rhuleave-K™. Complete pain relief with Rhuleave K in the head, neck, upper and lower limb, torso, and back occurred around 3.1 hours. [1]

Curcumin

159 participants (aged 19.5 to 35.5) with exercise-induced muscle damage and delayed-onset muscle soreness (DOMS).

24 hours to 56 days; Systematic review and meta-analysis of randomised-controlled clinical trials.

150 mg/d – 6,000 mg/d curcumin featuring enhanced bioavailability delivery systems

Pooled data analysis revealed that <180 mg/d of curcumin across 4 clinical trials achieved a near significant effect in reducing muscle soreness in adults (p<0.051). Further analysis found curcumin to effectively reduce muscle soreness in untrained individuals (p<0.001), in response to resistance exercise (p<0.001) after 72 and 96 hours (p<0.034; p<0.001).[16]

Key: BD: twice daily; TDS: thrice daily

Safety Information

Disclaimer: In the interest of supporting Healthcare Practitioners, all safety information provided at the time of publishing is in accordance with Natural Medicine Database (NATMED PRO), renowned for its professional monographs which include a thorough assessment of safety, warnings, and adverse effects.

For further information on specific interactions with medications, please contact Clinical Support on 1800 777 648, or via email, anz_clinicalsupport@metagenics.com

Pregnancy and Lactation

  • Insufficient reliable information available when used in medicinal amounts; avoid using.[29]

Contraindications

  • None listed.[29]

References

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  2. Rudrappa GH, Chakravarthi PT, Benny IR. Efficacy of high-dissolution turmeric-sesame formulation for pain relief in adult subjects with acute musculoskeletal pain compared to acetaminophen. Medicine. 2020;99(28):e20373. doi: 10.1097/md.0000000000020373
  3. Bali S, Prasad S, Saini V. Ayurvedic lipid based rasayans - A perspective on the preparation and pharmacological significance of lipids on the bioavailability of phytoconstituents. J Ayurveda Integr Med. 2021;13(2):100526. doi: 10.1016/j.jaim.2021.09.004
  4. Jain S, Jain V, Mahajan SC. Lipid based vesicular drug delivery systems. Adv Pharma. 2014;1(1):1-12. doi: 10.1155/2014/574673
  5. Peng Y, Ao M, Dong B, Jiang Y, Yu L, Chen Z, et al. Anti-inflammatory effects of curcumin in the inflammatory diseases: status, limitations and countermeasures. Drug Des Devel Ther. 2021;15:4503-25. doi: 10.2147/DDDT.S327378
  6. Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier JP. Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis. 2003;62(6):501-9. doi: 10.1136/ard.62.6.501
  7. Kellstein D, Leyva R. Evaluation of fixed-dose combinations of ibuprofen and acetaminophen in the treatment of postsurgical dental pain: A pilot, dose-ranging, randomized study. Drugs in R&D. 2020;20(3):237-47.
  8. Daily JW, Yang M, Park S. Efficacy of Turmeric extracts and curcumin for alleviating the symptoms of joint arthritis: a systematic review and meta-analysis of randomized clinical trials. J Med Food. 2016;19(8):717–29. doi: 10.1089/jmf.2016.3705
  9. Bannuru RR, Osani MC, Al-Eid F, Wang C. Efficacy of curcumin and Boswellia for knee osteoarthritis: Systematic review and meta-analysis. Semin Arthritis Rheum. 2018;48(3):416-29. doi: 10.1016/j.semarthrit.2018.03.001
  10. Mirzaei H, Shakeri A, Rashidi B, Jalili A, Banikazemi Z, Sahebkar A. Phytosomal curcumin: A review of pharmacokinetic, experimental and clinical studies. Biomed Pharmacother. 2017;85:102-112. doi: 10.1016/j.biopha.2016.11.098
  11. Meins J, Behnam D, Abdel-Tawab M. Enhanced absorption of boswellic acids by a micellar solubilized delivery form of Boswellia extract. NFS Journal. 2018;11:12-16.
  12. Prasad S, Tyagi AK, Aggarwal BB. Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice. Cancer Res Treat. 2014;46(1):2-18. doi: 10.4143/crt.2014.46.1.2
  13. Takada Y, Ichikawa H, Badmaev V, Aggarwal BB. Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression. J Immunol. 2006;176(5):3127-40. doi: 10.4049/jimmunol.176.5.3127
  14. Siddiqui MZ. Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci. 2011;73(3):255-61. doi: 10.4103/0250-474X.93507
  15. O’Donnell SR. Leukotrienes - biosynthesis and mechanisms of action. Aust Prescr. 1999;22:55-7. doi:10.18773/austprescr.1999.053
  16. Fang W, Nasir Y. The effect of curcumin supplementation on recovery following exercise-induced muscle damage and delayed-onset muscle soreness: A systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2021;35(4):1768-1781. doi: 10.1002/ptr.6912.
  17. Rao CV. Regulation of COX and LOX by curcumin. Adv Exp Med Biol. 2007;595:213-26. doi: 10.1007/978-0-387-46401-5_9
  18. Razavi BM, Ghasemzadeh Rahbardar M, Hosseinzadeh H. A review of therapeutic potentials of turmeric (Curcuma longa) and its active constituent, curcumin, on inflammatory disorders, pain, and their related patents. Phytother Res. 2021;35(12):6489-513. doi: 10.1002/ptr.7224
  19. Kertia N, Asdie AH, Rochmah W, Marsetyawan. Ability of curcuminoid compared to diclofenac sodium in reducing the secretion of cycloxygenase-2 enzyme by synovial fluid’s monocytes of patients with osteoarthritis. Acta Med Indones. 2012;44(2):105-13. PMID: 22745140
  20. Fernandes ES, Fernandes MA, Keeble JE. The functions of TRPA1 and TRPV1: moving away from sensory nerves. Br J Pharmacol. 2012;166(2):510-21. doi: 10.1111/j.1476-5381.2012.01851.x.
  21. Gouin O, L’Herondelle K, Lebonvallet N, Le Gall-Ianotto C, Sakka M, Buhé V, et al. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell. 2017;8(9):644-61. doi: 10.1007/s13238-017
  22. Yang M, Wang J, Yang C, Han H, Rong W, Zhang G. Oral administration of curcumin attenuates visceral hyperalgesia through inhibiting phosphorylation of TRPV1 in rat model of ulcerative colitis. Mol Pain. 2017;13:1744806917726416. doi: 10.1177/1744806917726416
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  25. Nebrisi EGE, Bagdas D, Toma W, et al. Curcumin acts as a positive allosteric modulator of α7-nicotinic acetylcholine receptors and reverses nociception in mouse models of inflammatory pain. J Pharmacol Exp Ther. 2018;365(1):jpet.117.245068. doi: 10.1124/jpet.117.245068
  26. Sahbaie P, Sun Y, Liang DY, Shi XY, Clark JD. Curcumin treatment attenuates pain and enhances functional recovery after incision. Anesth Analg. 2014;118(6):1336-44. doi: 10.1213/ANE.0000000000000189
  27. Amalraj A, Varma K, Jacob J, et al. A novel highly bioavailable curcumin formulation improves symptoms and diagnostic indicators in rheumatoid arthritis patients: a randomized, double-blind, placebo-controlled, two-dose, three-arm, and parallel-group study. J Med Food. 2017;20(10):1022-30. doi: 10.1089/jmf.2017.3930
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  29. Natural Medicines Database. AusDi; 2024. Accessed September 20, 2024. https://ausdi.hcn.com.au/

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