CLINICAL STUDIES - INDEPENDENT INGREDIENT REVIEW

There are a vast number of clinical studies over the last few decades that have shown the effectiveness of the ingredients found in PodiVite. Our clinical research team has compiled several of these studies with the results so that you can find out for yourself that the ingredients in PodiVite can help reduce foot and ankle pain*.

Boswellia (Boswellia Serrata) Gum Resin Extract CLINICAL STUDIES

Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis.

Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis

Umar S, et al. Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis. Phytomedicine. 2014 May 15;21(6):847-56. doi: 10.1016/j.phymed.2014.02.001. Epub 2014 Mar 22. PubMed PMID: 24667331.

Rheumatoid arthritis (RA) is a chronic inflammatory disease which leads to destruction of joints. Current treatment modalities for RA either produce symptomatic relief (NSAIDs) or modify the disease process (DMARDs). Though effective, their use is also limited by their side effects. As a result, the interest in alternative, well tolerated anti-inflammatory remedies has re-emerged. Our aim was to evaluate the antioxidant and antiarthritic activity of Boswellia serrata gum resin extract (BSE) in collagen induced arthritis. Arthritis was induced in male Wistar rats by collagen induced arthritis (CIA) method. BSE was administered at doses of 100 and 200mg/kg body weight once daily for 21 days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1β, IL-6, TNF-α, IL-10, IFN-γ and PGE2), and histological studies in joints. BSE was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of BSE resulted in significantly reduced levels of inflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ and PGE2), and increased level of IL-10. The protective effects of BSE against RA were also evident from the decrease in arthritis scoring and bone histology. The abilities to inhibit proinflammatory cytokines and modulation of antioxidant status suggest that the protective effect of Boswellia serrata extract on arthritis in rats might be mediated via the modulation of immune system.

Five Herbs Plus Thiamine Reduce Pain and Improve Functional Mobility in Patients With Pain: A Pilot Study.

Five Herbs Plus Thiamine Reduce Pain and Improve Functional Mobility in Patients With Pain: A Pilot Study

Hedaya R. Five Herbs Plus Thiamine Reduce Pain and Improve Functional Mobility in Patients With Pain: A Pilot Study. Altern Ther Health Med. 2017 Jan;23(1):14-19. PubMed PMID: 28160759.

A clinically significant reduction in perceived pain and improvement in functional mobility had occurred for the intervention group as related to their chronic joint, back, and muscle pain. The complex of 5 herbs, plus vitamin B1, was well tolerated, and the results suggest that the blend should be considered to be a valuable alternative treatment in the management of chronic musculoskeletal pain.

Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview

Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview

Siddiqui MZ. Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview. Indian Journal of Pharmaceutical Sciences. 2011;73(3):255-261. doi:10.4103/0250-474X.93507.

The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.

Natural anti-inflammatory agents for pain relief

Natural anti-inflammatory agents for pain relief

Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surgical Neurology International. 2010;1:80. doi:10.4103/2152-7806.73804.

The Boswellia species are trees located in India, Ethiopia, Somalia, and the Arabian Peninsula, and they produce a gum resin called olibanum, better known in the western world as frankincense. This resin possesses anti-inflammatory, anti-arthritic, and analgesic properties. Boswellia can inhibit the leukotriene biosynthesis in neutrophilic granulocytes by inhibiting 5-LOX, thus affecting various inflammatory diseases that are perpetuated by leukotrienes.[95] Clinically, the substance is used in the treatment of degenerative and inflammatory joint disorders. It reduces the total white blood cell count in joint fluid, and it also inhibits leukocyte elastase, which is released in rheumatoid arthritis. In one recent study, a statistically significant improvement in arthritis of the knee was shown after 8 weeks of treatment with 333 mg B. serrata extract taken three times a day. The treatment improved function, but radiographically there was no change in the affected joints.[62]

Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives

Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives

Beg S, Swain S, Hasan H, Barkat MA, Hussain MS. Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives. Pharmacognosy Reviews. 2011;5(10):120-137. doi:10.4103/0973-7847.91102.

A combination of Boswellia and curcumin showed superior efficacy and tolerability compared with nonsteroidal diclofenac for treating active osteoarthritis. Boswellia typically is given as an extract standardized to contain 30-40% boswellic acids (300-500 mg two or three times/day). Boswellia has been well tolerated in most studies, although some people may experience stomach discomfort, including nausea, acid reflux, or diarrhea.

Devils Claw CLINICAL STUDIES

Analgesic effect of Harpagophytum procumbens on postoperative and neuropathic pain in rats.

Analgesic effect of Harpagophytum procumbens on postoperative and neuropathic pain in rats

Lim DW, Kim JG, Han D, Kim YT. Analgesic effect of Harpagophytum procumbens on postoperative and neuropathic pain in rats. Molecules. 2014 Jan 16;19(1):1060-8. doi: 10.3390/molecules19011060. PubMed PMID: 24441655.

Harpagophytum procumbens, also known as Devil's Claw, has historically been used to treat a wide range of conditions, including pain and arthritis. The study was designed to investigate whether H. procumbens extracts exhibit analgesic effects in plantar incision and spared nerve injury (SNI) rats. The whole procedure was performed on male SD rats. To evaluate pain-related behavior, we performed the mechanical withdrawal threshold (MWT) test measured by von Frey filaments. Pain-related behavior was also determined through analysis of ultrasonic vocalization (USVs). The results of experiments showed MWT values of the group that was treated with 300 mg/kg H. procumbens extract increased significantly; on the contrary, the number of 22-27 kHz USVs of the treated group was reduced at 6 h and 24 h after plantar incision operation. After 21 days of continuous treatment with H. procumbens extracts at 300 mg/kg, the treated group showed significantly alleviated SNI-induced hypersensitivity responses by MWT, compared with the control group. These results suggest that H. procumbens extracts have potential analgesic effects in the case of acute postoperative pain and chronic neuropathic pain in rats.

A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis.

A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis

Denner SS. A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis. Holist Nurs Pract. 2007 Jul-Aug;21(4):203-7. Review. PubMed PMID: 17627199.

Harpagophytum procumbens, known as devil's claw, has been used traditionally for the treatment of pain, fevers, and dyspepsia. Recently, it has become popular for the treatment of rheumatoid and osteoarthritis. Studies have yet to establish a clear mechanism of action; however, current research is focusing on pro-inflammatory mediators as well as on potential antioxidant characteristics.

Analgesic, antiinflammatory and antidiabetic properties of Harpagophytum procumbens DC (Pedaliaceae) secondary root aqueous extract.

Analgesic, antiinflammatory and antidiabetic properties of Harpagophytum procumbens DC (Pedaliaceae) secondary root aqueous extract

Mahomed IM, Ojewole JA. Analgesic, antiinflammatory and antidiabetic properties of Harpagophytum procumbens DC (Pedaliaceae) secondary root aqueous extract. Phytother Res. 2004 Dec;18(12):982-9. PubMed PMID: 15742343.

South Africa is blessed with a rich floral biodiversity of medicinally useful plants. One such plant is Harpagophytum procumbens DC (Family: Pedaliaceae). H. procumbens is widely used in South African traditional medicine for the treatment, management and/or control of a variety of human ailments. In the present study, the analgesic effect of H. procumbens secondary root aqueous extract was evaluated in mice, using the 'hot-plate' and 'acetic acid' test methods; while the antiinflammatory and antidiabetic effects of the plant's secondary root extract were investigated in rats. Fresh egg albumin-induced pedal oedema and streptozotocin (STZ)-induced diabetes mellitus were used as experimental test models of inflammation and diabetes Diclofenac (DIC, 100 mg/kg i.p.) was used as a reference analgesic and antiinflammatory agent for comparison. Chlorpropamide (250 mg/kg p.o.) was used as a reference hypoglycaemic agent for comparison. H. procumbens root aqueous extract (HPE, 50-800 mg/kg i.p.) produced significant (p < 0.05-0.001) analgesic effects against thermally and chemically induced nociceptive pain stimuli in mice. H. procumbens root extract (HPE, 50-800 mg/kg i.p.) also produced dose-related, significant reductions (p < 0.05-0.001) of the fresh egg albumin-induced acute inflammation of the rat hind paw oedema. Furthermore, the plant extract (HPE, 50-800 mg/kg i.p.) produced dose-dependent, significant reductions (p < 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. The results of this experimental animal study indicate that H. procumbens root aqueous extract possesses analgesic, antiinflammatory and hypoglycaemic properties, and lend pharmacological support to the suggested folklore uses of Harpagophytum procumbens root in the management and/or control of painful, arthritic and other inflammatory conditions, as well as for adult-onset, type-2 diabetes mellitus in some communities of South Africa.

[Devil's claw extract as an example of the effectiveness of herbal analgesics].

Devil's claw extract as an example of the effectiveness of herbal analgesics.

Chrubasik S. [Devil's claw extract as an example of the effectiveness of herbal analgesics]. Orthopade. 2004 Jul;33(7):804-8. Review. German. PubMed PMID: 15150687.

Preparations from devil's claw differ in their content of active ingredients as assessed by the quantity of harpagoside present. The harpagoside content in the daily dose of Doloteffin (extraction solvent water) is double that of preparations extracted with 60% ethanol. Only preparations with proven effectiveness for painful lower back or arthrotic pain are an attractive alternative to synthetic analgesics, and are of substantial benefit in the treatment of chronic pain. From an evidence based view, extract with at least 50 mg harpagoside in the daily dose should be recommended for the treatment of pain. Treatment with devil's claw extract is associated with a lower risk of adverse events than treatment with synthetic analgesics, and may contribute in the majority of patients to the relief of pain.

Treatment of patients with arthrosis of hip or knee with an aqueous extract of devil's claw (Harpagophytum procumbens DC.).

Treatment of patients with arthrosis of hip or knee with an aqueous extract of devil's claw (Harpagophytum procumbens DC.).

Wegener T, Lüpke NP. Treatment of patients with arthrosis of hip or knee with an aqueous extract of devil's claw (Harpagophytum procumbens DC.). Phytother Res. 2003 Dec;17(10):1165-72. PubMed PMID: 14669250.

Preparations made from the secondary tubers of Devil's claw (Harpagophytum procumbens) are successfully used in patients with rheumatic diseases (arthrosis and low back pain). In order to add data on the efficacy and long-term safety of an aqueous extract (Doloteffin; 2400 mg extract daily, corresponding to 50 mg harpagoside), which has been tested successfully in patients with low back pain, an uncontrolled multicentre drug surveillance study for about 12 weeks was conducted in 75 patients with arthrosis of the hip or knee. To standardize the assessment of treatment effects, the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index (10 point scale) as well as the 10 cm VAS pain scale were used. The results of the study revealed a strong reduction of pain and the symptoms of osteoarthritis. There was a relevant improvement of each WOMAC subscale as well as of the total WOMAC index: 23.8% for the pain subscale, 22.2% for the stiffness subscale and 23.1% for the physical function subscale. The WOMAC total score was reduced by 22.9%. VAS pain scores were decreased by 25.8% for actual pain, 25.2% for average pain, 22.6% for worst pain and 24.5% for the total pain score. The physicians reported a continuous improvement in typical clinical findings such as 45.5% for pain on palpation, 35% for limitation of mobility and 25.4% for joint crepitus. Only two cases of possible adverse drug reactions were reported (dyspeptic complaints and a sensation of fullness). Although this was an open clinical study, the results suggest that this Devil's claw extract has a clinically beneficial effect in the treatment of arthrosis of the hip or knee.

Current nutraceuticals in the management of osteoarthritis: a review

Current nutraceuticals in the management of osteoarthritis: a review

Akhtar N, Haqqi TM. Current nutraceuticals in the management of osteoarthritis: a review. Therapeutic Advances in Musculoskeletal Disease. 2012;4(3):181-207. doi:10.1177/1759720X11436238.

Osteoarthritis (OA) is a progressive degenerative joint disease that has a major impact on joint function and quality of life. Nutraceuticals and dietary supplements derived from herbs have long been used in traditional medicine and there is considerable evidence that nutraceuticals may play an important role in inflammation and joint destruction in OA. We review the biological effects of some medicinal fruits and herbs – pomegranate, green tea, cat’s claw, devil’s claw, ginger, Indian olibaum, turmeric and ananas – in an attempt to understand the pivotal molecular targets involved in inflammation and the joint destruction process and to summarize their toxicities and efficacy for OA management. So far there is insufficient reliable evidence on the effectiveness of ginger, turmeric and ananas. Pomegranate and green tea only have preclinical evidence of efficacy due to the lack of clinical data. In vivo and clinical studies are required to understand their targets and efficacy in OA. Limited in vitro and in vivo evidence is available for cat’s claw and Indian olibaum. More extensive studies are required before long-term controlled trials of whole cat’s claw and Indian olibaum extracts, or isolated active compounds, are carried out in patients with OA to determine their long-term efficacy and safety. Devil’s claw has not been rigorously tested to determine its antiarthritic potential in in vitro and in vivo models. There is strong clinical evidence of the effectiveness of devil’s claw in pain reduction. However, high-quality clinical trials are needed to determine its effectiveness. No serious side effects have been reported for any fruits and herbs. Overall, these studies identify and support the use of nutraceuticals to provide symptomatic relief to patients with OA and to be used as adjunct therapy for OA management. More high-quality trials are needed to provide definitive answers to questions related to their efficacy and safety for OA prevention and/or treatment.

White Willow Bark Extract CLINICAL STUDIES

Medicinal potential of willow: A chemical perspective of aspirin discovery

Medicinal potential of willow: A chemical perspective of aspirin discovery

Mahdi JG. Medicinal potential of willow: A chemical perspective of aspirin discovery. Saudi Chem. Soc., 14, 317 – 322 (2010).

The willow tree is a symbolic medicinal plant that has been associated with the discovery of aspirin, chemically known as acetylsalicylic acid, or salicylate, which still offers surprises as a revival drug. The philosophical perspective of the significance of the willow tree has been elaborated since the Assyrians (4000 BC) and Sumerians (3500 BC), who were aware of its medicinal merits. In 1838, the main pharmacologically active ingredient of willow, the salicin structure was elucidated by hydrolysis to comprise D-glucose and salicyl alcohol. These uncovered new perspectives, which eventually lead to the discovery of aspirin.

Herbal medicine for low-back pain

Herbal medicine for low-back pain

Oltean H, et al. Herbal medicine for low-back pain. Cochrane Database Syst Rev. 2014 Dec 23;(12):CD004504. doi: 10.1002/14651858.CD004504.pub4. Review. PubMed PMID: 25536022.

BACKGROUND:
Low-back pain (LBP) is a common condition and imposes a substantial economic burden upon people living in industrialized societies. A large proportion of people with chronic LBP use complementary and alternative medicine (CAM), visit CAM practitioners, or both. Several herbal medicines have been purported for use in treating people with LBP. This is an update of a Cochrane Review first published in 2006.
OBJECTIVES:
To determine the effectiveness of herbal medicine for non-specific LBP.
SEARCH METHODS:
We searched the following electronic databases up to September 2014: MEDLINE, EMBASE, CENTRAL, CINAHL, Clinical Trials.gov, World Health Organization International Clinical Trials Registry Portal and PubMed; checked reference lists in review articles, guidelines and retrieved trials; and personally contacted individuals with expertise in this area.
SELECTION CRITERIA:
We included randomized controlled trials (RCTs) examining adults (over 18 years of age) suffering from acute, sub-acute, or chronic non-specific LBP. The interventions were herbal medicines which we defined as plants used for medicinal purposes in any form. Primary outcome measures were pain and function.
DATA COLLECTION AND ANALYSIS:
A library scientist with the Cochrane Back Review Group conducted the database searches. One review author contacted content experts and acquired relevant citations. We downloaded full references and abstracts of the identified studies and retrieved a hard copy of each study for final inclusion decisions. Two review authors assessed risk of bias, GRADE criteria (GRADE 2004), and CONSORT compliance and a random subset were compared to assessments by a third individual. Two review authors assessed clinical relevance and resolved any disagreements by consensus.
MAIN RESULTS:
We included 14 RCTs (2050 participants) in this review. One trial on Solidago chilensis M. (Brazilian arnica) (20 participants) found very low quality evidence of reduction in perception of pain and improved flexibility with application of Brazilian arnica-containing gel twice daily as compared to placebo gel. Capsicum frutescens cream or plaster probably produces more favourable results than placebo in people with chronic LBP (three trials, 755 participants, moderate quality evidence). Based on current evidence, it is not clear whether topical capsicum cream is more beneficial for treating people with acute LBP compared to placebo (one trial, 40 participants, low quality evidence). Another trial found equivalence of C. frutescens cream to a homeopathic ointment (one trial, 161 participants, very low quality evidence). Daily doses of Harpagophytum procumbens (devil's claw), standardized to 50 mg or 100 mg harpagoside, may be better than placebo for short-term improvements in pain and may reduce use of rescue medication (two trials, 315 participants, low quality evidence). Another H. procumbens trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (Vioxx®) but was of very low quality (one trial, 88 participants, very low quality). Daily doses of Salix alba (white willow bark), standardized to 120 mg or 240 mg salicin, are probably better than placebo for short-term improvements in pain and rescue medication (two trials, 261 participants, moderate quality evidence). An additional trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (one trial, 228 participants) but was graded as very low quality evidence. S. alba minimally affected platelet thrombosis versus a cardioprotective dose of acetylsalicylate (one trial, 51 participants). One trial (120 participants) examining Symphytum officinale L. (comfrey root extract) found low quality evidence that a Kytta-Salbe comfrey extract ointment is better than placebo ointment for short-term improvements in pain as assessed by VAS. Aromatic lavender essential oil applied by acupressure may reduce subjective pain intensity and improve lateral spine flexion and walking time compared to untreated participants (one trial, 61 participants,very low quality evidence). No significant adverse events were noted within the included trials.
AUTHORS' CONCLUSIONS:
C. frutescens (Cayenne) reduces pain more than placebo. Although H. procumbens, S. alba, S. officinale L., S. chilensis, and lavender essential oil also seem to reduce pain more than placebo, evidence for these substances was of moderate quality at best. Additional well-designed large trials are needed to test these herbal medicines against standard treatments. In general, the completeness of reporting in these trials was poor. Trialists should refer to the CONSORT statement extension for reporting trials of herbal medicine interventions.

Efficacy and Safety of White Willow Bark (Salix alba) Extracts

Efficacy and Safety of White Willow Bark (Salix alba) Extracts

Shara M, Stohs SJ. Efficacy and Safety of White Willow Bark (Salix alba) Extracts. Phytother Res. 2015 Aug;29(8):1112-6. doi: 10.1002/ptr.5377. Epub 2015 May 22. Review. PubMed PMID: 25997859.

Willow bark extract has been used for thousands of years as an anti-inflammatory, antipyretic, and analgesic. In spite of its long history of use, relatively few human and animal studies have been published that confirm anecdotal observations. A small number of clinical studies have been conducted that support the use of willow bark extracts in chronic lower back and joint pain and osteoarthritis. Willow bark extracts also are widely used in sports performance and weight loss products presumably because of anti-inflammatory and analgesic activities, although no human studies have been published that specifically and directly document beneficial effects. In recent years, various in vitro and animal studies have demonstrated that the anti-inflammatory activity of willow bark extract is associated with down regulation of the inflammatory mediators tumor necrosis factor-α and nuclear factor-kappa B. Although willow bark extracts are generally standardized to salicin, other ingredients in the extracts including other salicylates as well as polyphenols, and flavonoids may also play prominent roles in the therapeutic actions. Adverse effects appear to be minimal as compared to non-steroidal anti-inflammatory drugs including aspirin. The primary cause for concern may relate to allergic reactions in salicylate-sensitive individuals.

Natural anti-inflammatory agents for pain relief

Natural anti-inflammatory agents for pain relief

Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surgical Neurology International. 2010;1:80. doi:10.4103/2152-7806.73804.

The use of both over-the-counter and prescription nonsteroidal medications is frequently recommended in a typical neurosurgical practice. But persistent long-term use safety concerns must be considered when prescribing these medications for chronic and degenerative pain conditions. This article is a literature review of the biochemical pathways of inflammatory pain, the potentially serious side effects of nonsteroidal drugs and commonly used and clinically studied natural alternative anti-inflammatory supplements. Although nonsteroidal medications can be effective, herbs and dietary supplements may offer a safer, and often an effective, alternative treatment for pain relief, especially for long-term use.

Curcumin CLINICAL STUDIES

Effects of turmeric curcuminoids and metformin against central sensitivity to pain in mice

Effects of turmeric curcuminoids and metformin against central sensitivity to pain in mice

Vermaa S, Mundkinajeddub D, Agarwalb A, Chatterjeecd SS, Kumar V. Effects of turmeric curcuminoids and metformin against central sensitivity to pain in mice. Journal of Trad and Compl Med. 2017 Apr. 7(2); 145-51.

The reported experimental study was conducted to compare the effects of repeated daily oral doses of curcuminoids (CLE) with metformin as potential antidepressants and analgesics. Effects of a single and ten daily oral doses of CLE (5, 20, 80 mg/kg/day) and of 50 mg/kg/day metformin (MET) were compared in mice hot plate test (HPT) for analgesics. On the 11th treatment day, all animals were subjected to foot shock stress triggered hyperthermia test, and on the 12th treatment day to tail suspension test (TST) for antidepressants. Immediately thereafter, their blood levels of glucose, insulin and cortisol were quantified. Dose dependent analgesic activity of CLE was observed in HPT, whereas the metformin dose tested suppressed only pain hypersensitivity in the test. But statistically significant effects of both of them were observed in TST, and both of them also afforded protections against body weight loss and slight elevation in core temperatures induced by daily handling and repeated testing. CLE or metformin had no significant effects in foot shock stress triggered transient hyperthermic responses or on blood glucose, insulin and cortisol levels. Reported results reveal that curcuminoids as well as metformin are stress response modifiers with antidepressants like activities, but only low dose curcuminoids possess centrally acting analgesics like activities. They suggest that the bio-assay system used in this study is well suited for identifying curcuminoids like plant metabolites with analgesic and anti-stress activities, and that low dose curcuminoids are more effective as analgesics than low dose metformin.

The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis

The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis

Chin K-Y. The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis. Drug Design, Development and Therapy. 2016;10:3029-3042. doi:10.2147/DDDT.S117432.

Osteoarthritis is a degenerative disease of the joint affecting aging populations worldwide. It has an underlying inflammatory cause, which contributes to the loss of chondrocytes, leading to diminished cartilage layer at the affected joints. Compounds with anti-inflammatory properties are potential treatment agents for osteoarthritis. Curcumin derived from Curcuma species is an anti-inflammatory compound as such. This review aims to summarize the antiosteoarthritic effects of curcumin derived from clinical and preclinical studies. Many clinical trials have been conducted to determine the effectiveness of curcumin in osteoarthritic patients. Extracts of Curcuma species, curcuminoids and enhanced curcumin, were used in these studies. Patients with osteoarthritis showed improvement in pain, physical function, and quality of life after taking curcumin. They also reported reduced concomitant usage of analgesics and side effects during treatment. In vitro studies demonstrated that curcumin could prevent the apoptosis of chondrocytes, suppress the release of proteoglycans and metal metalloproteases and expression of cyclooxygenase, prostaglandin E-2, and inflammatory cytokines in chondrocytes. These were achieved by blocking the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) system in the chondrocytes, by preventing the activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha, phosphorylation, and translocation of the p65 subunit of NF-κB complexes into the nucleus. In conclusion, curcumin is a potential candidate for the treatment of osteoarthritis. More well-planned randomized control trials and enhanced curcumin formulation are required to justify the use of curcumin in treating osteoarthritis.

Antinociceptive effects of curcumin in a rat model of postoperative pain

Antinociceptive effects of curcumin in a rat model of postoperative pain

Zhu Q, Sun Y, Yun X, Ou Y, Zhang W, Li J-X. Antinociceptive effects of curcumin in a rat model of postoperative pain. Scientific Reports. 2014;4:4932. doi:10.1038/srep04932.

Curcumin is a principal ingredient of traditional Chinese medicine, Curcuma Longa, which possesses a variety of pharmacological activities including pain relief. Preclinical studies have demonstrated that curcumin has antinociceptive effects for inflammatory and neuropathic pain. This study examined the effects of curcumin in a rat model of postoperative pain. A surgical incision on the right hind paw induced a sustained mechanical hyperalgesia that lasted for 5 days. Acute curcumin treatment (10–40 mg/kg, p.o) significantly and dose dependently reversed mechanical hyperalgesia. In addition, repeated curcumin treatment significantly facilitated the recovery from surgery. In contrast, repeated treatment with curcumin before surgery did not impact the postoperative pain threshold and recovery rate. All the doses of curcumin did not significantly alter the spontaneous locomotor activity. Combined, these results suggested that curcumin could alleviate postoperative pain and promote recovery from the surgery, although there was no significant preventive value. This study extends previous findings and supports the application of curcumin alone or as an adjunct therapy for the management of peri-operative pain.

Natural anti-inflammatory agents for pain relief

Natural anti-inflammatory agents for pain relief

Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surgical Neurology International. 2010;1:80. doi:10.4103/2152-7806.73804.

The use of both over-the-counter and prescription nonsteroidal medications is frequently recommended in a typical neurosurgical practice. But persistent long-term use safety concerns must be considered when prescribing these medications for chronic and degenerative pain conditions. This article is a literature review of the biochemical pathways of inflammatory pain, the potentially serious side effects of nonsteroidal drugs and commonly used and clinically studied natural alternative anti-inflammatory supplements. Although nonsteroidal medications can be effective, herbs and dietary supplements may offer a safer, and often an effective, alternative treatment for pain relief, especially for long-term use.

Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study

Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study

Belcaro G, et al. Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study. Eur Rev Med Pharmacol Sci. 2014;18(24):3959-63. PubMed PMID: 25555891.

OBJECTIVE:
Osteoarthritis (OA) is a major cause of physical disability and impaired quality of life. Non-steroidal anti-inflammatory drugs are the most used treatment for OA, but they are frequently associated to adverse events. Alternative therapies are under investigation for the treatment of OA. Meriva® is a lecithin delivery form of curcumin, a powerful promoter of anti-oxidant response studied in a number of conditions related to chronic inflammation and pain.
PATIENTS AND METHODS:
This 4-month observational study, conducted in a 'real-life' scenario, compares the association of Meriva and glucosamine (n=63) with chondroitin sulphate+glucosamine (n=61) in 124 patients with grade 1-2 OA of the knee.
RESULTS:
Patients treated with Meriva+glucosamine had significantly higher Karnofsky Index and WOMAC score (both in the physical and emotional domains), compared to those in the chondroitin+glucosamine group. Noteworthy, the walking distance at the treadmill test after 1 month was also significantly higher in the meriva+glucosamine group; this advantage was sustained until the end of the study. Although the need for concomitant drugs and medical attention decreased in both groups, this reduction was more evident for patients treated with Meriva+glucosamine.
CONCLUSIONS:
Taken together, the results of this study shows that the 4-month administration of the association of Meriva and glucosamine can result in a faster onset of action and improved outcomes than the administration of an association of chondroitin sulphate and glucosamine in patients with OA.

Bromelain CLINICAL STUDIES

Therapeutic uses of pineapple-extracted bromelain in surgical care - A review.

Therapeutic uses of pineapple-extracted bromelain in surgical care - A review

Muhammad ZA, Ahmad T. Therapeutic uses of pineapple-extracted bromelain in surgical care - A review. J Pak Med Assoc. 2017 Jan;67(1):121-125. PubMed PMID: 28065968.

Bromelain is an extract obtained from the pineapple plant and is used as a traditional folk remedy for several ailments. In this review, a comprehensive electronic database search was carried out to compile available literature on therapeutic implications of bromelain. Pharmaceutical value of bromelain has been demonstrated in different surgical sub-specialties. Diverse biological processes like anti-inflammatory, anti-oedematous, analgesic, anti-thrombotic, exfoliation etc. are involved in bromelain's therapeutic actions, mediated through the kallikrein-kinin and arachidonic acid pathways as well as through effects on cell mediated immunity. Bromelain equals non-steroidal anti-inflammatory drugs as an anti-inflammatory agent, but has been shown to have fewer side effects. In Europe it is approved for oral and topical use, mainly for surgical wounds, inflammation due to trauma and surgery, and debridement of deep burns. Literature suggests a promising role of bromelain in surgical care. More clinical trials to establish its utility as an anti-inflammatory agent in surgical care are recommended.

Properties and Therapeutic Application of Bromelain: A Review

Properties and Therapeutic Application of Bromelain: A Review

Pavan R, Jain S, Shraddha, Kumar A. Properties and Therapeutic Application of Bromelain: A Review. Biotechnology Research International. 2012;2012:976203. doi:10.1155/2012/976203.

Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple. Fruit bromelain and stem bromelainare prepared differently and they contain different enzymatic composition. “Bromelain” refers usually to the “stem bromelain.” Bromelain is a mixture of different thiol endopeptidases and other components like phosphatase, glucosidase, peroxidase, cellulase, escharase, and several protease inhibitors. In vitro and in vivo studies demonstrate that bromelain exhibits various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities. Bromelain is considerably absorbable in the body without losing its proteolytic activity and without producing any major side effects. Bromelain accounts for many therapeutic benefits like the treatment of angina pectoris, bronchitis, sinusitis, surgical trauma, and thrombophlebitis, debridement of wounds, and enhanced absorption of drugs, particularly antibiotics. It also relieves osteoarthritis, diarrhea, and various cardiovascular disorders. Bromelain also possesses some anticancerous activities and promotes apoptotic cell death. This paper reviews the important properties and therapeutic applications of bromelain, along with the possible mode of action.

Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies

Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies

Brien S, Lewith G, Walker A, Hicks SM, Middleton D. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies. Evidence-based Complementary and Alternative Medicine. 2004;1(3):251-257. doi:10.1093/ecam/neh035.

Bromelain, an extract from the pineapple plant, has been demonstrated to show anti-inflammatory and analgesic properties and may provide a safer alternative or adjunctive treatment for osteoarthritis. All previous trials, which have been uncontrolled or comparative studies, indicate its potential use for the treatment of osteoarthritis. This paper reviews the mechanism of its putative therapeutic actions, those clinical trials that have assessed its use in osteoarthritis to date, as well as considering the safety implications of this supplement for osteoarthritis and reviewing the evidence to date regarding the dosage for treating this condition. The data available at present indicate the need for trials to establish the efficacy and optimum dosage for bromelain and the need for adequate prospective adverse event monitoring in such chronic conditions as osteoarthritis.

A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain.

A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain.

Conrozier T, Mathieu P, Bonjean M, Marc JF, Renevier JL, Balblanc JC. A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain. Altern Ther Health Med. 2014 Winter;20 Suppl 1:32-7. PubMed PMID: 24473984.

Devil's claw (Harpagophytum procumbens), turmeric (Curcuma longa), and bromelain are nutraceuticals that have demonstrated anti-inflammatory and analgesic properties and may be potential solutions in the treatment of acute or chronic joint pain. Their analgesic effect, however, is generally considered mild to moderate, and the relevance of their clinical use remains subject to discussion. The aim of the study was to evaluate the clinical relevance of the efficacy of a marketed complex of 3 plant extracts-H procumbens, C longa, and bromelain (AINAT, 650 mg)-in the treatment of degenerative joint pain The improvement of joint pain was clinically relevant in patients treated with AINAT for both acute and chronic OA pain. Considering its excellent tolerance profile, the tested complex of 3 plant extracts with antiinflammatory properties may be a valuable and safe alternative to NSAIDs in patients suffering from degenerative joint diseases.

Vitamin C (Ascorbic Acid) CLINICAL STUDIES

Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery.

Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery

Besse JL, Gadeyne S, Galand-Desmé S, Lerat JL, Moyen B. Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery. Foot Ankle Surg. 2009;15(4):179-82. doi: 10.1016/j.fas.2009.02.002. Epub 2009 Apr 5. PubMed PMID: 19840748.

BACKGROUND:
The public health cost impact of complex regional pain syndrome type I (CRPS I) is considerable in both emergency and scheduled orthopaedic surgery. We proposed to assess the effectiveness of vitamin C in prevention of CRPS I in foot and ankle surgery.
METHODS:
We carried out a "before-after" quasi-experimental study comparing two chronologically successive groups without (Group I: July 2002-June 2003) and with (Group II: July 2003-June 2004) preventive 1g daily vitamin C treatment. All patients having surgery on the foot or ankle were enrolled, with the exception of diabetic foot cases. Several factors were analysed: sex, age, type of pathology, history of CRPS I, psychological context, tourniquet time, and cast immobilisation time.
RESULTS:
420 feet (392 patients) were included in the study: 185 in Group I, 235 in Group II. CRPS I occurred in 18 cases in Group I (9.6%) and 4 cases in Group II (1.7%) (p<10(-4)), with history of CRPS I as a significantly correlated factor (relative risk=10.4). The psychological context (anxio-depressive state) showed a (sub-significant) tendency to increase the risk of CRPS I (relative risk=2.6).
CONCLUSION:
Vitamin C has been shown to be effective in preventing CRPS I secondary to wrist fracture, but few data are available with respect to foot and ankle cases. The present study demonstrates the effectiveness of vitamin C in preventing CRPS I of the foot and ankle-a frequent complication in our control group (9.6%). The authors recommend preventive management by vitamin C.

Plantar Fasciitis: A Case Review

Plantar Fasciitis: A Case Review

Ross C, Prousky J. Plantar Fasciitis: A Case Review. 2016. Journal of Ortho Med. 16 (1).

Supporting the integrity of the fascia by supplying copper and vitamin C may re-regulate disordered fibroblastic activity by promoting healthy connective tissue formation. Improving fibroblastic activity may be a factor in alleviating fibrosis formation and/or the pain associated with plantar fasciitis.

The role of vitamin C in the treatment of pain: new insights.

The role of vitamin C in the treatment of pain: new insights

Carr AC, McCall C. The role of vitamin C in the treatment of pain: new insights. J Transl Med. 2017 Apr 14;15(1):77. doi: 10.1186/s12967-017-1179-7. Review. PubMed PMID: 28410599; PubMed Central PMCID: PMC5391567.

The vitamin C deficiency disease scurvy is characterised by musculoskeletal pain and recent epidemiological evidence has indicated an association between suboptimal vitamin C status and spinal pain. Furthermore, accumulating evidence indicates that vitamin C administration can exhibit analgesic properties in some clinical conditions. The prevalence of hypovitaminosis C and vitamin C deficiency is high in various patient groups, such as surgical/trauma, infectious diseases and cancer patients. A number of recent clinical studies have shown that vitamin C administration to patients with chronic regional pain syndrome decreases their symptoms. Acute herpetic and post-herpetic neuralgia is also diminished with high dose vitamin C administration. Furthermore, cancer-related pain is decreased with high dose vitamin C, contributing to enhanced patient quality of life. A number of mechanisms have been proposed for vitamin C's analgesic properties. Herein we propose a novel analgesic mechanism for vitamin C; as a cofactor for the biosynthesis of amidated opioid peptides. It is well established that vitamin C participates in the amidation of peptides, through acting as a cofactor for peptidyl-glycine α-amidating monooxygenase, the only enzyme known to amidate the carboxy terminal residue of neuropeptides and peptide hormones. Support for our proposed mechanism comes from studies which show a decreased requirement for opioid analgesics in surgical and cancer patients administered high dose vitamin C. Overall, vitamin C appears to be a safe and effective adjunctive therapy for acute and chronic pain relief in specific patient groups.

Vitamin D (Cholecalciferol) CLINICAL STUDIES

Vitamin D supplementation for patients with chronic pain

Vitamin D supplementation for patients with chronic pain

Kragstrup TW. Vitamin D supplementation for patients with chronic pain. Scandinavian Journal of Primary Health Care. 2011;29(1):4-5. doi:10.3109/02813432.2010.530738.

A study in a previous issue of the Scandinavian Journal of Primary Health Care (SJPHC) adds to the growing list of publications on vitamin D as a possible treatment for chronic pain. It describes a high prevalence of hypovitaminosis D in patients with non-specific musculoskeletal pain, headache, and fatigue. The conclusion is that general practitioners should maintain awareness of hypovitaminosis D in these patients. The authors are, however, aware that firm conclusions regarding cause and effect cannot be based on a cross-sectional study, which leaves plenty of room for confounding. Vitamin D supply is defined by sun exposure and dietary intake, which may be affected by work, economy, culture, diseases etc. Similarly, chronic pain may be affected by work, economy, culture, diseases etc. It seems reasonable to use vitamin D supplementation (with or without previous measurement of the vitamin D status) with up to 50 μg (2.000 IU) daily for patients with chronic pain. The supplement may not be a cure for the pain, but the study in the SJPHC demonstrates that low levels of vitamin D are common in this group of patients. The treatment is cheap, relatively safe, and there is emerging evidence that vitamin D supplementation has positive effects on public health. Underlying conditions causing the chronic pain should be diagnosed irrespective of vitamin D status.

Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States

Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States

Shipton EE, Shipton EA. Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States. Pain and Therapy. 2015;4(1):67-87. doi:10.1007/s40122-015-0036-8.

A number of studies suggest a link between low levels of 25-hydroxy vitamin D and incidence of acute and chronic pain. Clinical studies of vitamin D supplementation in patients with known vitamin D deficiency have shown mixed results in improving pain scores. There remains a growing body of both clinical and laboratory evidence pointing to a potential relationship between low levels of 25-hydroxy vitamin D and a variety of chronic pain states. More focused research involving large RCTs is necessary.

Vitamin D Deficiency, Prevention and Treatment

Vitamin D Deficiency, Prevention and Treatment

Iraj B, Ebneshahidi A, Askari G. Vitamin D Deficiency, Prevention and Treatment. International Journal of Preventive Medicine. 2012;3(10):733-736.

Case Study Result: The serum of 25 (OH) D was 42 ng/ml and the PTH was 70 Pg/ml. As it is known, the secondary hyperparathyroidism due to vitamin D deficiency improves after 6-12 months of treatment with vitamin D. Therefore, the serum PTH level in this patient is not worrisome. Therefore, the maintenance therapy in this patient continued and after 3 months of the treatment the patient reported sense of wellbeing and the low back pain and the throbbing bone pain totally resolved.

Unrecognised severe vitamin D deficiency

Unrecognised severe vitamin D deficiency

Sievenpiper JL, McIntyre EA, Verrill M, Quinton R, Pearce SHS. Unrecognised severe vitamin D deficiency. BMJ : British Medical Journal. 2008;336(7657):1371-1374. doi:10.1136/bmj.39555.820394.BE.

Although persistent, non-specific musculoskeletal pains and weakness may represent a unifying set of features, this overlap with other rheumatological conditions, as well as depression, necessitates a high index of suspicion in the diagnosis of hypovitaminosis D. 

Vitamin D Deficiency Promotes Skeletal Muscle Hypersensitivity and Sensory Hyperinnervation

Vitamin D Deficiency Promotes Skeletal Muscle Hypersensitivity and Sensory Hyperinnervation

Tague SE, et al. Vitamin D Deficiency Promotes Skeletal Muscle Hypersensitivity and Sensory Hyperinnervation. The Journal of Neuroscience. 2011;31(39):13728-13738. doi:10.1523/JNEUROSCI.3637-11.2011.

Musculoskeletal pain affects nearly half of all adults, most of whom are vitamin D deficient. Previous findings demonstrated that putative nociceptors (“pain-sensing” nerves) express vitamin D receptors (VDRs), suggesting responsiveness to 1,25-dihydroxyvitamin D. In the present study, rats receiving vitamin D-deficient diets for 2– 4 weeks showed mechanical deep muscle hypersensitivity, but not cutaneous hypersensitivity. Muscle hypersensitivity was accompanied by balance deficits and occurred before onset of overt muscle or bone pathology. Hypersensitivity was not due to hypocalcemia and was actually accelerated by increased dietary calcium. Morphometry of skeletal muscle innervation showed increased numbers of presumptive nociceptor axons (peripherin-positive axons containing calcitonin gene-related peptide), without changes in sympathetic or skeletal muscle motor innervation. Similarly, there was no change in epidermal innervation. In culture, sensory neurons displayed enriched VDR expression in growth cones, and sprouting was regulated by VDR-mediated rapid response signaling pathways, while sympathetic outgrowth was not affected by different concentrations of 1,25-dihydroxyvitamin D. These findings indicate that vitamin D deficiency can lead to selective alterations in target innervation, resulting in presumptive nociceptor hyperinnervation of skeletal muscle, which in turn is likely to contribute to muscular hypersensitivity and pain.

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study

Kanzaki N, Ono Y, Shibata H, Moritani T. Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. Clin Interv Aging. 2015 Oct 28;10:1743-53. doi: 10.2147/CIA.S93077. eCollection 2015. PubMed PMID: 26604721; PubMed Central PMCID: PMC4631410.

BACKGROUND:
The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain.
METHODS:
A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions.
RESULTS:
In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment.
CONCLUSION:
In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions.

Vitamin B12 (Methylcobalamin) CLINICAL STUDIES

Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience

Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience

Dongre YU, Swami OC. Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience. International Journal of General Medicine. 2013;6:413-417. doi:10.2147/IJGM.S45271.

Introduction
Neuropathic pain is intense in nature and difficult to manage. Thus, the primary goal is maximum relief from pain. The aim of this study was to assess the efficacy and safety of a fixed-dose combination of sustained-release pregabalin and methylcobalamin in reducing neuropathic pain in Indian patients, in the real-life situation.
Methods
This was a multicenter, prospective, open-labeled, single-arm, observational, 14-day study. Patients received fixed dose combination of 75 or 150 mg sustained-release pregabalin combined with 1500 mcg immediate release methylcobalamin, depending on the clinical requirement. Data was collected for pain reduction and other positive and negative symptoms associated with neuropathy, including hyperesthesia, paresthesia, numbness/tingling, burning sensation, muscle weakness, sleep disturbances, and impairment of movement. Pain intensity was measured on a ten-point visual analog scale (VAS) (0 represented “no pain,” and 10 represented “worst pain ever”). The safety of the drug was also evaluated throughout the study duration. Data was analyzed using appropriate statistical methods.
Results
The overall reduction in mean VAS score over 14 days was 72.3%. The reduction in mean VAS score was significant as early as the first week. Both positive and negative symptoms of peripheral neuropathy were significantly improved in >50% patients within the 2 weeks. Giddiness (4.7%), followed by sedation (3.6%), dizziness (2.9%), drowsiness (2.3%), and nausea (2.3%) were the most commonly observed adverse effects. The overall efficacy and tolerability was rated as good to excellent by >95% of the investigators and patients.
Conclusion
Fixed dose combination of sustained-release pregabalin and methylcobalamin significantly reduced neuropathic pain, with significant improvement in both the positive and negative symptoms associated with neuropathy, in Indian patients and was well tolerated.

Methylcobalamin: A Potential Vitamin of Pain Killer

Methylcobalamin: A Potential Vitamin of Pain Killer

Zhang M, Han W, Hu S, Xu H. Methylcobalamin: A Potential Vitamin of Pain Killer. Neural Plasticity. 2013;2013:424651. doi:10.1155/2013/424651.

Methylcobalamin (MeCbl), the activated form of vitamin B12, has been used to treat some nutritional diseases and other diseases in clinic, such as Alzheimer's disease and rheumatoid arthritis. As an auxiliary agent, it exerts neuronal protection by promoting regeneration of injured nerves and antagonizing glutamate-induced neurotoxicity. Recently several lines of evidence demonstrated that MeCbl may have potential analgesic effects in experimental and clinical studies. For example, MeCbl alleviated pain behaviors in diabetic neuropathy, low back pain and neuralgia. MeCbl improved nerve conduction, promoted the regeneration of injured nerves, and inhibited ectopic spontaneous discharges of injured primary sensory neurons. This review aims to summarize the analgesic effect and mechanisms of MeCbl at the present.

B complex vitamins for analgesic therapy

B complex vitamins for analgesic therapy

Gazoni FM, Malezan WR, Santos FC. B complex vitamins for analgesic therapy. 2016. Revista Dor, 17(1), 52-56. https://dx.doi.org/10.5935/1806-0013.20160013

The B complex vitamins have been used as single therapy or combined to other drugs, such as anti-inflammatory drugs, in different clinical situations, such as degenerative spinal diseases, rheumatologic diseases, polyneuropathies and in different postoperative situations. This study aimed at identifying in the scientific literature most recent evidences of the use of B complex vitamins as analgesic therapy and at describing clinical situations where their analgesic action could be observed. Existing studies, although scarce and heterogeneous, have shown that B complex vitamins have analgesic effect. They are considered safe and have low cost and have shown to be a good option as adjuvant analgesic therapy.

Magnesium Bisglycinate Chelate CLINICAL STUDIES

Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps.

Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps

Roffe C, Sills S, Crome P, Jones P. Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit. 2002 May;8(5):CR326-30. PubMed PMID: 12011773.

BACKGROUND:
Nocturnal leg cramps are common and distressing. The only treatment of proven effectiveness is quinine, but this has a number of side effects. Magnesium salts have been shown to reduce leg cramp distress in pregnancy. This study tests whether magnesium citrate is effective in the treatment of leg cramps in non-pregnant individuals by conducting in a randomised, double-blind, cross-over placebo-controlled trial.
MATERIAL/METHODS:
Volunteers suffering regular leg cramps were recruited. Magnesium citrate equivalent to 300 mg magnesium and matching placebo were given for 6 weeks each. The number of cramps recorded in the cramp diary during the final 4 weeks of magnesium and placebo treatment, severity and duration of cramps and the participants' subjective assessment of effectiveness were analysed.
RESULTS:
In subjects who started with placebo (n=29) the median (95% CI) number of cramps was 9 (6-17) on placebo and 5 (4-8) on magnesium. For the group starting with magnesium (n=17) the median no of cramps was 9 (5-13) on magnesium and 8 (4-14) on placebo. There was no significant carry-over effect (p=0.88), but a highly significant period effect (p=0.008). There was a trend towards less cramps on magnesium (p=0.07). There was no difference in cramp severity and duration between the groups. Significantly more subjects thought that the treatment had helped after magnesium than after placebo 36 (78%) and 25 (54%) respectively, (p=0.03). Diarrhoea was recorded as a side effect of magnesium.
CONCLUSIONS:
The results suggest that magnesium may be effective in treatment of nocturnal leg cramps. Further evaluation is recommended.

Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain.

Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain.

Vormann J, Worlitschek M, Goedecke T, Silver B. Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain. J Trace Elem Med Biol. 2001;15(2-3):179-83. PubMed PMID: 11787986.

The cause of low back pain is heterogeneous, it has been hypothesised that a latent chronic acidosis might contribute to these symptoms. It was tested whether a supplementation with alkaline minerals would influence symptoms in patients with low back pain symptoms. In an open prospective study 82 patients with chronic low back pain received daily 30 g of a lactose based alkaline multimineral supplement (Basica) over a period of 4 weeks in addition to their usual medication. Pain symptoms were quantified with the "Arhus low back pain rating scale" (ARS). Mean ARS dropped highly significant by 49% from 41 to 21 points after 4 weeks supplemention. In 76 out of 82 patients a reduction in ARS was achieved by the supplementation. Total blood buffering capacity was significantly increased from 77.69 +/- 6.79 to 80.16 +/- 5.24 mmol/L (mean +/- SEM, n = 82, p < 0.001) and also blood pH rose from 7.456 +/- 0.007 to 7.470 +/- 0.007 (mean +/- SEM, n = 75, p < 0.05). Only intracellular magnesium increased by 11% while other intracellular minerals were not significantly changed in sublingual tissue as measured with the EXA-test. Plasma concentrations of potassium, calcium, iron, copper, and zinc were within the normal range and not significantly influenced by the supplementation. Plasma magnesium was slightly reduced after the supplemenation (-3%, p < 0.05). The results show that a disturbed acid-base balance may contribute to the symptoms of low back pain. The simple and safe addition of an alkaline multimineral preparate was able to reduce the pain symptoms in these patients with chronic low back pain.

MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol

MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol

Venturini MA, Zappa S, Minelli C, et al. MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol. BMJ Open. 2015;5(12):e009137. doi:10.1136/bmjopen-2015-009137.

Magnesium exerts analgaesic effects in several animal pain models, as well as in patients affected by acute postoperative pain and neuropathic chronic pain. There is no evidence that magnesium can modulate pain in patients with peripheral arterial occlusive disease (PAOD). We describe the protocol of a single-centre randomised double-blind clinical trial aimed at assessing the efficacy of oral magnesium supplementation in controlling severe pain in patients with advanced PAOD.

Manganese Bisglycinate Chelate (TRAACS) CLINICAL STUDIES

Retooling Manganese(III) Porphyrin-Based Peroxynitrite Decomposition Catalysts for Selectivity and Oral Activity: A Potential New Strategy for Treating Chronic Pain

Retooling Manganese(III) Porphyrin-Based Peroxynitrite Decomposition Catalysts for Selectivity and Oral Activity: A Potential New Strategy for Treating Chronic Pain

Rausaria S, Ghaffari MME, Kamadulski A, et al. Retooling Manganese(III) Porphyrin-Based Peroxynitrite Decomposition Catalysts for Selectivity and Oral Activity: A Potential New Strategy for Treating Chronic Pain. Journal of medicinal chemistry. 2011;54(24):8658-8669. doi:10.1021/jm201233r.

Redox-active metalloporphyrins represent the most well characterized class of catalysts capable of attenuating oxidative stress in vivo through the direct interception and decomposition of superoxide and peroxynitrite. While many interesting pharmacological probes have emerged from these studies, few catalysts have been developed with pharmaceutical properties in mind. Herein we describe our efforts to identify new Mn(III)-porphyrin systems with enhanced membrane solubilizing properties. To this end seven new Mn(III)-tetracyclohexenylporphyin (TCHP) analogues 7, 10, 12, 15, 16a–c have been prepared in which the beta-fused cyclohexenyl rings provide a means to shield the charged metal center from the membrane during passive transport. Compounds 7, 15, and 16a–c have been shown to be orally active and potent analgesics in a model of carrageenan-induced thermal hyperalgesia. In addition oral administration of compound 7 (10–100 mg/kg, n = 5) has been shown to dose dependently reverse mechano-allodynia in the CCI model of chronic neuropathic pain.

Zinc Glycinate Chelate (TRAACS) CLINICAL STUDIES

Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit

Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit

Nozaki C, Vergnano AM, Filliol D, et al. Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit. Nature neuroscience. 2011;14(8):1017-1022. doi:10.1038/nn.2844.

Zinc is abundant in the central nervous system and regulates pain, but the underlying mechanisms are unknown. In vitro studies have shown that extracellular zinc modulates a plethora of signaling membrane proteins, including NMDA receptors containing the NR2A subunit, which display exquisite zinc sensitivity. We created NR2A-H128S knock-in mice to investigate whether Zn2+–NR2A interaction influences pain control. In these mice, high-affinity (nanomolar) zinc inhibition of NMDA currents was lost in the hippocampus and spinal cord. Knock-in mice showed hypersensitivity to radiant heat and capsaicin, and developed enhanced allodynia in inflammatory and neuropathic pain models. Furthermore, zinc-induced analgesia was completely abolished under both acute and chronic pain conditions. Our data establish that zinc is an endogenous modulator of excitatory neurotransmission in vivo and identify a new mechanism in pain processing that relies on NR2A NMDA receptors. The study also potentially provides a molecular basis for the pain-relieving effects of dietary zinc supplementation.

Hyaluronic acid (from Sodium Hyaluronate) CLINICAL STUDIES

The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses

The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses

Nelson FR, et al. The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatol Int. 2015 Jan;35(1):43-52. doi: 10.1007/s00296-014-3047-6. Epub 2014 Jun 5. Erratum in: Rheumatol Int. 2015 Jan;35(1):53. PubMed PMID: 24899570.

The purpose of this study was to determine the effects of an oral preparation containing hyaluronic acid on osteoarthritic knee joint pain and function as well as changes in inflammatory cytokines, bradykinin, and leptin. We also used heavy water to determine the turnover rates of glycosaminoglycans in synovial fluid. This was a double-blind, randomized, placebo-controlled study of 40 subjects over a period of 3 months. Visual analog scale, Western Ontario McMaster pain, and WOMAC function scores were recorded. Serum and synovial fluid were measured by enzyme-linked immunosorbent assays for inflammatory cytokines, bradykinin, and leptin. In 20 subjects, terminal heavy water ingestion was used for spectral analyses of serum and joint fluid samples. There were statistically significant improvements in pain and function. Both serum and synovial fluid samples showed significant decreases for a majority of inflammatory cytokines, leptin, and bradykinin in the oral hyaluronic acid preparation group. Heavy water analyses revealed a significant decrease in hyaluronic acid turnover in the synovial fluid of the treatment group. A preparation containing hyaluronic acid and other glycosaminoglycans holds promise for a safe and effective agent for the treatment for patients with knee osteoarthritis and who are overweight. Further studies will be required to see whether this is a disease-modifying agent.

The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritic knee pain

The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritic knee pain

Trigkilidas D, Anand A. The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritic knee pain. Ann R Coll Surg Engl. 2013 Nov;95(8):545-51. doi: 10.1308/003588413X13629960049432. Review. PubMed PMID: 24165334; PubMed Central PMCID: PMC4311527.

INTRODUCTION:
Knee osteoarthritis (OA) is a common and progressive joint disease. Treatment options for knee OA vary from simple analgesia in mild cases to knee replacement for advanced disease. Knee pain due to moderate OA can be targeted with intra-articular injections. Steroid injections have been used widely in managing acute flare-ups of the disease. In recent years, viscosupplementation has been used as a therapeutic modality for the management of knee OA. The principle of viscosupplementation is based on the physiological properties of the hyaluronic acid (HA) in the synovial joint. Despite a sound principle and promising in vitro studies, clinical studies have been less conclusive on the effectiveness of HA in managing osteoarthritic knee pain. The aim of this systematic review was to assess the effectiveness of HA intra-articular injections in the management of osteoarthritic knee pain.
METHODS:
A systematic review of the literature was performed using MEDLINE®, Embase™ and CINAHL® (Cumulative Index to Nursing and Allied Health Literature). The databases were searched for randomised controlled trials available on the effectiveness of HA intra-articular injections in managing osteoarthritic knee pain.
RESULTS:
The search yielded 188 studies. Of these, 14 met the eligibility criteria and were reviewed in chronological order.
CONCLUSIONS:
HA intra-articular injections have a modest effect on early to moderate knee OA. The effect peaks at around 6-8 weeks following administration, with a doubtful effect at 6 months.

MSM (Methyl Sulfonyl Methane) CLINICAL STUDIES

Effects of MSM on exercise-induced muscle and joint pain: a pilot study

Effects of MSM on exercise-induced muscle and joint pain: a pilot study

Withee ED, Tippens KM, Dehen R, Hanes D. Effects of MSM on exercise-induced muscle and joint pain: a pilot study. Journal of the International Society of Sports Nutrition. 2015;12(Suppl 1):P8. doi:10.1186/1550-2783-12-S1-P8.

Exercise-induced muscle pain and joint pain increase within 15 minutes of completing a half-marathon, continue through the following day, and diminish approximately two days post-race. Three weeks of MSM supplementation at 3g/day attenuated post-exercise muscle and joint pain at clinically significant levels compared to placebo. However, the pain reductions did not reach statistical significance, warranting further research on MSM and post-exercise pain among larger samples.

Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial12

Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial

Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis and Cartilage. 2006 Mar. 14(3); 286-94.

MSM (3 g twice a day) improved symptoms of pain and physical function during the short intervention without major adverse events. The benefits and safety of MSM in managing OA and long-term use cannot be confirmed from this pilot trial, but its potential clinical application is examined. Underlying mechanisms of action and need for further investigation of MSM are discussed.

Evaluation of the Effect of Mega MSM on Improving Joint Function in Populations Experiencing Joint Degeneration

Evaluation of the Effect of Mega MSM on Improving Joint Function in Populations Experiencing Joint Degeneration

Xu G, et al. Evaluation of the Effect of Mega MSM on Improving Joint Function in Populations Experiencing Joint Degeneration. Int J Biomed Sci. 2015 Jun;11(2):54-60. PubMed PMID: 26199577; PubMed Central PMCID: PMC4502733.

Joint degeneration has become a commonplace problem in aging populations. The main clinical manifestations include joint pain, joint stiffness and joint swelling with functional disorder. Mega MSM is a nutritional supplement that may provide potential relief for joint problems associated with joint degeneration. The current experiment performed was a 12-week, randomized, double-blind, controlled study conducted on populations in China experiencing joint degeneration. The objective of the study was to determine whether the daily use of Mega MSMcapsules could improve joint function, relieve symptoms of joint degeneration and improve the quality of life in aging populations. A total of 100 male and female participants over 50 years old who had at least one of the related symptoms of joint degeneration (joint pain, joint stiffness, joint swelling, difficulty walking, difficulty getting up from bed and difficulty going down stairs) were recruited and their symptoms of joint degeneration before and after the intervention were recorded. In this study, Mega MSM shows positive effects in improving joint function, relieving symptoms associated with joint degeneration and improving the quality of life in aging populations.

Hydrolyzed Collagen CLINICAL STUDIES

Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis.

Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis

Dar QA, et al. Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis. PLoS One. 2017 Apr 6;12(4):e0174705. doi: 10.1371/journal.pone.0174705. eCollection 2017. PubMed PMID: 28384173; PubMed Central PMCID: PMC5383229.

Osteoarthritis (OA) is a degenerative joint disease for which there are no disease modifying therapies. Thus, strategies that offer chondroprotective or regenerative capability represent a critical unmet need. Recently, oral consumption of a hydrolyzed type 1 collagen (hCol1) preparation has been reported to reduce pain in human OA and support a positive influence on chondrocyte function. To evaluate the tissue and cellular basis for these effects, we examined the impact of orally administered hCol1 in a model of posttraumatic OA (PTOA). In addition to standard chow, male C57BL/6J mice were provided a daily oral dietary supplement of hCol1 and a meniscal-ligamentous injury was induced on the right knee. At various time points post-injury, hydroxyproline (hProline) assays were performed on blood samples to confirm hCol1 delivery, and joints were harvested for tissue and molecular analyses were performed, including histomorphometry, OARSI and synovial scoring, immunohistochemistry and mRNA expression studies. Confirming ingestion of the supplements, serum hProline levels were elevated in experimental mice administered hCol1. In the hCol1 supplemented mice, chondroprotective effects were observed in injured knee joints, with dose-dependent increases in cartilage area, chondrocyte number and proteoglycan matrix at 3 and 12 weeks post-injury. Preservation of cartilage and increased chondrocyte numbers correlated with reductions in MMP13 protein levels and apoptosis, respectively. Supplemented mice also displayed reduced synovial hyperplasia that paralleled a reduction in Tnf mRNA, suggesting an anti-inflammatory effect. These findings establish that in the context of murine knee PTOA, daily oral consumption of hCol1 is chondroprotective, anti-apoptotic in articular chondrocytes, and anti-inflammatory. While the underlying mechanism driving these effects is yet to be determined, these findings provide the first tissue and cellular level information explaining the already published evidence of symptom relief supported by hCol1 in human knee OA. These results suggest that oral consumption of hCol1 is disease modifying in the context of PTOA.

Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial.

Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial

Bakilan F, et al. Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial. Eurasian J Med. 2016 Jun;48(2):95-101. doi: 10.5152/eurasianjmed.2015.15030. PubMed PMID: 27551171; PubMed Central PMCID: PMC4970562.

OBJECTIVE:
The aim of this randomized controlled study was to evaluate the efficacy of oral native type II collagen treatment on the symptoms and biological markers of cartilage degradation, when given concomitantly with acetaminophen in patients with knee osteoarthritis.
MATERIALS AND METHODS:
Thirty-nine patients diagnosed with knee osteoarthritis were included and randomly distributed into two groups: one treated with 1500 mg/day of acetaminophen (group AC; n=19) and the other treated with 1500 mg/day of acetaminophen plus 10 mg/day of native type II collagen (group AC+CII; n=20) for 3 months. Visual Analogue Scale (VAS) at rest and during walking, Western Ontario McMaster (WOMAC) pain, WOMAC function, and Short Form-36 (SF-36) scores, were recorded. Coll2-1, Coll2-1NO2 and Fibulin-3 levels were quantified in urine as biomarkers of disease progression. ClinicalTrials.gov: NCT02237989.
RESULTS:
After 3 months of treatment, significant improvements compared to baseline were reported in joint pain (VAS walking), function (WOMAC) and quality of life (SF-36) in the AC+CII group, while only improvements in some subscales of the SF-36 survey and VAS walking were detected in the AC group. Comparisons between the groups revealed a significant difference in VAS walking score in favour of the AC+CII group as compared to AC group. Biochemical markers of cartilage degradation in urine did not significantly improve in any of the groups.
CONCLUSION:
All in all, these results suggest that native type II collagen treatment combined with acetaminophen is superior to only acetaminophen for symptomatic treatment of patients with knee osteoarthritis.

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study

Kanzaki N, Ono Y, Shibata H, Moritani T. Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. Clin Interv Aging. 2015 Oct 28;10:1743-53. doi: 10.2147/CIA.S93077. eCollection 2015. PubMed PMID: 26604721; PubMed Central PMCID: PMC4631410.

BACKGROUND:
The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain.
METHODS:
A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions.
RESULTS:
In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment.
CONCLUSION:
In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions.

Glucosamine (Glucosamine Sulfate Complex) CLINICAL STUDIES

Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee

Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee

Zeng C, et al. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015 Nov 18;5:16827. doi: 10.1038/srep16827. PubMed PMID: 26576862; PubMed Central PMCID: PMC4649492.

This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects (withdrawal due to adverse events, serious adverse events and the number of patients with adverse events), the additional classical meta-analysis showed that celecoxib exhibited a higher rate of gastrointestinal adverse effect comparing with the placebo group. The present study provided evidence for the symptomatic efficacy of glucosamine plus chondroitin in the treatment of knee OA.

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study

Kanzaki N, Ono Y, Shibata H, Moritani T. Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. Clin Interv Aging. 2015 Oct 28;10:1743-53. doi: 10.2147/CIA.S93077. eCollection 2015. PubMed PMID: 26604721; PubMed Central PMCID: PMC4631410.

BACKGROUND:
The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain.
METHODS:
A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions.
RESULTS:
In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment.
CONCLUSION:
In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions.

Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study

Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study

Belcaro G, et al. Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study. Eur Rev Med Pharmacol Sci. 2014;18(24):3959-63. PubMed PMID: 25555891.

OBJECTIVE:
Osteoarthritis (OA) is a major cause of physical disability and impaired quality of life. Non-steroidal anti-inflammatory drugs are the most used treatment for OA, but they are frequently associated to adverse events. Alternative therapies are under investigation for the treatment of OA. Meriva® is a lecithin delivery form of curcumin, a powerful promoter of anti-oxidant response studied in a number of conditions related to chronic inflammation and pain.
PATIENTS AND METHODS:
This 4-month observational study, conducted in a 'real-life' scenario, compares the association of Meriva and glucosamine (n=63) with chondroitin sulphate+glucosamine (n=61) in 124 patients with grade 1-2 OA of the knee.
RESULTS:
Patients treated with Meriva+glucosamine had significantly higher Karnofsky Index and WOMAC score (both in the physical and emotional domains), compared to those in the chondroitin+glucosamine group. Noteworthy, the walking distance at the treadmill test after 1 month was also significantly higher in the meriva+glucosamine group; this advantage was sustained until the end of the study. Although the need for concomitant drugs and medical attention decreased in both groups, this reduction was more evident for patients treated with Meriva+glucosamine.
CONCLUSIONS:
Taken together, the results of this study shows that the 4-month administration of the association of Meriva and glucosamine can result in a faster onset of action and improved outcomes than the administration of an association of chondroitin sulphate and glucosamine in patients with OA.

Role of glucosamine in the treatment for osteoarthritis

Role of glucosamine in the treatment for osteoarthritis

Reginster JY, Neuprez A, Lecart MP, Sarlet N, Bruyere O. Role of glucosamine in the treatment for osteoarthritis. Rheumatol Int. 2012 Oct;32(10):2959-67. Epub 2012 Mar 30. Review. PubMed PMID: 22461188; PubMed Central PMCID: PMC3456914.

Over the last 20 years, several studies have investigated the ability of glucosamine sulfate to improve the symptoms (pain and function) and to delay the structural progression of osteoarthritis. There is now a large, convergent body of evidence that glucosamine sulfate, given at a daily oral dose of 1,500 mg, is able to significantly reduce the symptoms of osteoarthritis in the lower limbs. This dose of glucosamine sulfate has also been shown, in two independent studies, to prevent the joint space narrowing observed at the femorotibial compartment in patients with mild-to-moderate knee osteoarthritis. This effect also translated into a 50 % reduction in the incidence of osteoarthritis-related surgery of the lower limbs during a 5-year period following the withdrawal of the treatment. Some discrepancies have been described between the results of studies performed with a patent-protected formulation of glucosamine sulfate distributed as a drug and those having used glucosamine preparations purchased from global suppliers, packaged, and sold over-the-counter as nutritional supplements.

Chondroitin Sulfate CLINICAL STUDIES

Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial

Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT)

Reginster JY, Dudler J, Blicharski T, Pavelka K. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT). Ann Rheum Dis. 2017 Sep;76(9):1537-1543. doi: 10.1136/annrheumdis-2016-210860. Epub 2017 May 22. PubMed PMID: 28533290; PubMed Central PMCID: PMC5561371.

OBJECTIVES:
Chondroitin sulfate 800 mg/day (CS) pharmaceutical-grade in the management of symptomatic knee osteoarthritis consistent with the European Medicines Agency guideline.
METHODS:
A prospective, randomised, 6-month, 3-arm, double-blind, double-dummy, placebo and celecoxib (200 mg/day)-controlled trial assessing changes in pain on a Visual Analogue Scale (VAS) and in the Lequesne Index (LI) as coprimary endpoints. Minimal-Clinically Important Improvement (MCII), Patient-Acceptable Symptoms State (PASS) were used as secondary endpoints.
RESULTS:
604 patients (knee osteoarthritis) diagnosed according to American College of Rheumalogy (ACR) criteria, recruited in five European countries and followed for 182 days. CS and celecoxib showed a greater significant reduction in pain and LI than placebo. In the intention-to-treat (ITT) population, pain reduction in VAS at day 182 in the CS group (-42.6 mm) and in celecoxib group (-39.5 mm) was significantly greater than the placebo group (-33.3 mm) (p=0.001 for CS and p=0.009 for celecoxib), while no difference observed between CS and celecoxib. Similar trend for the LI, as reduction in this metric in the CS group (-4.7) and celecoxib group (-4.6) was significantly greater than the placebo group (-3.7) (p=0.023 for CS and p=0.015 for celecoxib), no difference was observed between CS and celecoxib. Both secondary endpoints (MCII and PASS) at day 182 improved significantly in the CS and celecoxib groups. All treatments demonstrated excellent safety profiles.
CONCLUSION:
A 800 mg/day pharmaceutical-grade CS is superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee osteoarthritis (OA) patients. This formulation of CS should be considered a first-line treatment in the medical management of knee OA.

Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee

Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee

Zeng C, et al. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015 Nov 18;5:16827. doi: 10.1038/srep16827. PubMed PMID: 26576862; PubMed Central PMCID: PMC4649492.

This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects (withdrawal due to adverse events, serious adverse events and the number of patients with adverse events), the additional classical meta-analysis showed that celecoxib exhibited a higher rate of gastrointestinal adverse effect comparing with the placebo group. The present study provided evidence for the symptomatic efficacy of glucosamine plus chondroitin in the treatment of knee OA.

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study

Kanzaki N, Ono Y, Shibata H, Moritani T. Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. Clin Interv Aging. 2015 Oct 28;10:1743-53. doi: 10.2147/CIA.S93077. eCollection 2015. PubMed PMID: 26604721; PubMed Central PMCID: PMC4631410.

BACKGROUND:
The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain.
METHODS:
A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions.
RESULTS:
In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment.
CONCLUSION:
In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions.

L-proline CLINICAL STUDIES

Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health.

Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health.

Li Y, Xiao W, Luo W, Zeng C, Deng Z, Ren W, Wu G, Lei G. Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Amino Acids. 2016 Apr;48(4):907-14. doi: 10.1007/s00726-015-2168-x. Epub 2016 Jan 14. Review. PubMed PMID: 26767374.

Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA.

Design and synthesis of proline-derived α2δ ligands

Design and synthesis of proline-derived α2δ ligands

Rawson DJ, et al. Part 3: Design and synthesis of proline-derived α2δ ligands. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3771-3. doi: 10.1016/j.bmcl.2011.04.058. Epub 2011 Apr 20. PubMed PMID: 21550802.

A potent series of substituted (2S,4S)-benzylproline α(2)δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.

L-glutamine CLINICAL STUDIES

Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health.

Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health.

Li Y, Xiao W, Luo W, Zeng C, Deng Z, Ren W, Wu G, Lei G. Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Amino Acids. 2016 Apr;48(4):907-14. doi: 10.1007/s00726-015-2168-x. Epub 2016 Jan 14. Review. PubMed PMID: 26767374.

Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA.

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity

Zunhammer M, et al. Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity. Journal of Int Assn for Study of Pain. 2016 Oct. 157(10); 2248-56.

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher–Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.