**2.1 Pain and osteoarthritis**

*Pain Management - Practices, Novel Therapies and Bioactives*

potential substantial detrimental side effects of APAPs.

results on liver function tests than placebo [166].

mellitus [207–209] and habitual diet [187, 210].

**2. Osteoarthritis**

*illness" [172].*

receptors, PLC, DAGL and CB1 receptors, associated with the release of glutamate and GABA – through the endocannabinoid systems [155]. Though the molecular mechanisms that provide analgesia are beginning to come to light, there is also

APAPs are generally considered safe if administered at appropriate doses for short periods [156]. However, they remain one of the leading causes of liver disease in high-income countries [157, 158] which has led to legislative restrictions in many countries [159]. It is well accepted that APAPs cause liver injury, hepatotoxicity, mitochondrial toxicity [160, 161] and that this toxicity can be effected by interindividual variation [162]. Nonetheless, consuming APAP can increase the risks of hospitalisation for perforation, peptic ulceration and bleeding [163], relative rates of adverse cardiovascular events such as myocardial infarction, stroke, coronary heart disease and upper gastrointestinal disease such as gastroduodenal ulcers and haemorrhages [164], often in a dose response manor. However, observational studies show a favourable side effect profile for APAPs compared with NSAIDs when used in older people with chronic pain conditions [165]. Data from the most recent meta-analysis shows that APAPs are nearly four times more likely to have abnormal

Osteoarthritis (OA) is a complex musculoskeletal condition that effects people of all ages but particularly those over 55 years [167–171]. According to the Osteoarthritis Research Society International (OARSI) OA can be defined as;

*"…a disorder involving movable joints characterized by cell stress and extracellular matrix degradation initiated by micro- and macro-injury that activates maladaptive repair responses including pro-inflammatory pathways of innate immunity. The disease manifests first as a molecular derangement (abnormal joint tissue metabolism) followed by anatomic, and/or physiologic derangements (characterized by cartilage degradation, bone remodelling, osteophyte formation, joint inflammation and loss of normal joint function), that can culminate in* 

OA is a pro-inflammatory branch of rheumatic disease that effects synovial joints progressively and is caused by the failure of joint tissues to repair following damage. This damage may have been caused by stresses due to an abnormality in the articular cartilage, subchondral bone, ligaments, menisci, periarticular muscles, peripheral nerves or synovium [173, 174]. While cartilage degradation is the traditionally structural trademark of OA, it is generally considered a whole joint disease with many other morphological features [175–178]. For example, an osteoarthritic joint may exhibit sclerosis in the subchondral bone, osteophytes [179], local inflammation such as synovitis [177, 178, 180, 181] and bone marrow lesions [182]. Failure of normal biological repair processes that leads to breakdown of cartilage and bone [183] is characterised by symptoms of pain, stiffness, functional disability [184] that can lead to negative impacts on fatigue, mood, sleep, overall quality of life [185, 186]. OA confers a number of modifiable and non-modifiable risk factors [174, 187]. Non-modifiable risk factors include previous joint injury [188, 189], malalignment and other mechanical factors [175, 176, 190–193], age [189], sex [194], ethnicity [195] and genetic predisposition [196–198]. Modifiable risk factors include obesity [181, 189, 199–202], metabolic syndrome [181, 203–206], in particular diabetes

**168**

Chronic inflammatory-associated pain can have multiple mechanisms [219–223] and can stem from mechanical stress or central sensitization either concurrently and/or vary in their influences over time [224]. Pain derived from OA can generally be characterised into two common clinical forms of pain, intermittent but severe/ intense and persistent pain or aching [225]. These pain experiences can come from neuropathic and nociceptive process, as discussed above. The prevalence of neuropathic pain features at the knee in OA patients ranges from 19% to 29% [221, 226, 227]. However, recent studies of peripheral and central nerve sensitization [228], as well as nerve ending damage and regrowth [229, 230] have shown that neuropathic pain contributes substantially to the condition. This central sensitization is prominent in those that experience a high level of pain that is not proportional to radiographic evidence of structural damage [219] and contributes more to the pain experienced in women with symptomatic OA, compared to men [231]. Generally, a higher degree of central sensitization or neuropathic pain is associated with high pain intensity and a greater chance of developing chronic pain following joint replacement [232, 233]. The remaining 70-80% of knee OA pain appears to be nociceptive in nature, thus OA can be described as a chronic mild to moderate nociceptive dominant pain condition [24, 234] and should be considered as such with regards to initial treatment [24].

The diversity of pathophysiological maladaptation in OA effected joints and the low associations of these changes with pain, suggests doubt over the link between joint structural condition and the experience of pain. This is evident from the poor relationship between radiographic images and reported pain. A recent systematic review showed that the prevalence of knee pain in patients with radiographic knee OA ranged from 15% to 81% [235]. However, some studies reported associations between the structural damage of the joint (cartilage and bone) and pain [236] but at higher levels of X-ray derived pathology (Kellgren/Lawrence grade; [237]). Nonetheless, pain may still indicate a level of disease activity. In a number of studies looking more specifically at joint morphological characterises, OA pain has been associated with the rate of medial cartilage loss (also after adjustment for radiographic OA stage; [238]), osteophytes [239], more erosive OA compared to non-erosive OA [240] and changes of bone marrow lesions and synovitis [182]. These data show the complexity of the disease-pain nexus and suggests that the disease should, in the first instance (i.e. mild OA), be treated generally with lifestyle and nutritional intervention rather that pharmaceuticals that target specific pathological pathways (**Figure 1**) [241]. Regardless, pharmaceutical therapies remain the main treatment for such conditions [242].

#### **2.2 Pharmaceutical analgesics in osteoarthritis**

OA is a progressive condition with no cure where opioids, acetaminophen and non-steroidal anti-inflammatory drugs (NSAID) are the traditional, nonlifestyle, approach for early management. However, as eluded to earlier, these pharmaceutical treatments are often accompanied with significant side effects. For example, NSAIDs are the traditional approach for early clinical management of mild-to-moderate OA [241] and in the US 65% of all OA patients are prescribed NSAID for pain management - this is the current recommended strategy for OA clinical management by the leading authorities [243]. While some NSAIDs are effective at improving pain and physical function, they come with significant and potentially harmful side effects such as gastrointestinal complications, renal disturbances and severe cardiovascular events [244]. Although some of these risks may be reduced using topical administration such as Diclofenac gel/cream [245, 246]. Two recent large-scale studies have shown that, depending on the particular medication, the risk of hospital admissions (due to heart failure) can be nearly two times greater (Ketorolac; [247]) in OA/rheumatoid arthritis (n = 24,081), with ibuprofen (generally speaking, the most used NSAID) presenting with the highest rates of NSAID toxicity [248].

Approximately 34% of OA patients use Paracetamol [249], in isolation or in combination with NSAIDs. In fact, the effectiveness of Paracetamol to improve pain management has recently been called into question [124], as it has been shown to be ineffective for treating OA pain [125, 250] and may have similar side effects as ibuprofen [251], particularly when consumed at higher doses [164]. Specifically, in knee or hip OA, a recent Cochrane review concluded that Paracetamol provides no clinically important improvements in pain in the immediate and short term (up to 12 weeks; [16]). In addition, a recent network meta-analysis (56 randomised controlled trials, 22 128 participants) suggests that paracetamol was least effective for the treatment of knee and/or hip OA compared with celecoxib (NSAID) or the combination of glucosamine and chondroitin [117] – confirming other reports [252]. In contrast, some authors have concluded that paracetamol had similar efficacy to NSAIDs for the treatment of OA [253]. It is also important to remember that overuse of APAPs can cause liver injury, hepatotoxicity, mitochondrial toxicity [160, 161] which is relevant to a chronic condition with no known cure. These data led to confusion in earlier guidelines that consistently recommended the prescription of paracetamol (acetaminophen) as the first line analgesic for these conditions [90, 91, 241, 254, 255]. However, the data are now relatively clear that there is little clinically meaningful effect of Paracetamol for OA pain [153, 154].

The potential negative effects such as addiction and the physiological side effects of opioid use are well documented, as discussed above, however they remain highly prescribed for OA and are expected to triple in the coming years [256, 257]. More than half of those prescribed opioids in the first year of OA have been shown to be inappropriately dispensed [257]. The prevalence of opioid use for OA ranges from 8-26% and in Australia, with the use for knee/hip OA has being described as "alarmingly high" [257]. A number of systematic reviews and meta-analysis have been performed in recent years and have unanimously shown that the tolerability is low, efficacy for pain relief in OA is not clinically relevant and the potential harms are high [258–260]. Despite calls for guidelines to be changed on the use of opioids and the above-mentioned pharmaceuticals, their use is increasing (likely with the prevalence of the disease) and by proxy the negative consequences rising in tandem. Therefore, non-pharmaceutical food-based alternatives (termed bioactive nutraceuticals) have been developed and are beginning to be recommended as early treatment [261–263] to improve OA symptoms including pain [241, 264–266].

### **3. Nutraceutical alternatives and reduction in pharmacological analgesics in osteoarthritis**

Given the possible side-effects of pharmaceutical treatments, any reduction in their use is of particular importance to OA public health. As such, a number of

**171**

**Table 1.**

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis*

non-pharmaceutical alternatives have been developed that may reduce the use/ required dose of pharmaceuticals while maintaining or improving the impacts on OA pain and physical function. The majority of these alternatives are termed "nutraceuticals" (a portmanteau of the words "nutrition" and "pharmaceutical"), coined in 1989 by Dr. Stephen DeFelice [267], founder and chairman of the

While it is unlikely that Hippocrates (traditionally regarded as the father of modern medicine; died 375 BCE) actually said: "Let food be your medicine and medicine your food" [268], this is often cited in the context of nutraceuticals. A more apt and legitimate quote defines the position of nutraceuticals in health and disease as "beyond diet, before drug", coined by Ettore Novellino in 2012 [269]. There is currently no universally accepted definition of a nutraceutical [270],

*'a naturally derived biological substance, not synthetically created, that preserve its original active properties without chemical manipulation, can enhance health in dosages that exceed those that could be obtained from normal food digestion and has* 

Zeisel, [271] "……as those diet supplements that deliver a concentrated form of a presumed

"A nutraceutical is any substance that is a food or part of a food and provides medical

bioactive agent from a food, presented in a non-food matric, and used to enhance health in dosages that exceed those that could be obtained from normal food"

"a dietary supplement, food or medical food that has a benefit, which prevents or reduces the risk of a disease or health condition, including the management of a disease or health condition or the improvement of health; and is safe for human consumption in the quantity, and with the frequency required to realise such

"are nutritional products that provide health and medical benefits, including the prevention and treatment of disease. In contrast to pharmaceuticals however, these are not synthetic substances or chemical compounds formulated for specific indications. These are products that contain nutrients (partly in concentrated form) and mostly are assigned to the category of food. Dietary supplements are a typical example for nutraceuticals, but also dietetic and functional foods may be counted

"A nutraceutical is a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food. A nutraceutical is demonstrated to

denaturing processes to preserve their original properties without any chemical

have a physiological benefit or provide protection against chronic disease"

Corzo et al. [279] "Nutraceuticals are biological substances extracted from natural sources by non-

or health benefits, including the prevention and treatment of disease."

with the main confusion being the differences between nutraceuticals and functional foods, and the lack of regulatory definition between them (**Table 1**) [270–273]. In fact, current European regulations do not distinguish between nutraceuticals and food supplements (see the EC Regulation n. 1924/2006 of the European Parliament and Council, recently updated by the UE regulation 2015/2283), therefore neither does the European Food Safety Authority [274, 275]. However, a number of proposed definitions exist (**Table 1**) and from these definitions, for the purposes

*DOI: http://dx.doi.org/10.5772/intechopen.95919*

Foundation for Innovation in Medicine.

of this chapter, a nutraceutical will be defined as;

**Author(s) Definition**

DeFelice, [267]; coined in 1989

U.S. Nutraceutical Research and Education [276]

The European Nutraceutical Association [277]

Health Canada [278]

*peer-reviewed scientific evidenced to base health clams'.*

properties"

among these products."

manipulation."

*Currently used definitions to describe nutraceuticals.*

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.95919*

*Pain Management - Practices, Novel Therapies and Bioactives*

toxicity [248].

of mild-to-moderate OA [241] and in the US 65% of all OA patients are prescribed NSAID for pain management - this is the current recommended strategy for OA clinical management by the leading authorities [243]. While some NSAIDs are effective at improving pain and physical function, they come with significant and potentially harmful side effects such as gastrointestinal complications, renal disturbances and severe cardiovascular events [244]. Although some of these risks may be reduced using topical administration such as Diclofenac gel/cream [245, 246]. Two recent large-scale studies have shown that, depending on the particular medication, the risk of hospital admissions (due to heart failure) can be nearly two times greater (Ketorolac; [247]) in OA/rheumatoid arthritis (n = 24,081), with ibuprofen (generally speaking, the most used NSAID) presenting with the highest rates of NSAID

Approximately 34% of OA patients use Paracetamol [249], in isolation or in combination with NSAIDs. In fact, the effectiveness of Paracetamol to improve pain management has recently been called into question [124], as it has been shown to be ineffective for treating OA pain [125, 250] and may have similar side effects as ibuprofen [251], particularly when consumed at higher doses [164]. Specifically, in knee or hip OA, a recent Cochrane review concluded that Paracetamol provides no clinically important improvements in pain in the immediate and short term (up to 12 weeks; [16]). In addition, a recent network meta-analysis (56 randomised controlled trials, 22 128 participants) suggests that paracetamol was least effective for the treatment of knee and/or hip OA compared with celecoxib (NSAID) or the combination of glucosamine and chondroitin [117] – confirming other reports [252]. In contrast, some authors have concluded that paracetamol had similar efficacy to NSAIDs for the treatment of OA [253]. It is also important to remember that overuse of APAPs can cause liver injury, hepatotoxicity, mitochondrial toxicity [160, 161] which is relevant to a chronic condition with no known cure. These data led to confusion in earlier guidelines that consistently recommended the prescription of paracetamol (acetaminophen) as the first line analgesic for these conditions [90, 91, 241, 254, 255]. However, the data are now relatively clear that there is little

clinically meaningful effect of Paracetamol for OA pain [153, 154].

**3. Nutraceutical alternatives and reduction in pharmacological** 

Given the possible side-effects of pharmaceutical treatments, any reduction in their use is of particular importance to OA public health. As such, a number of

**analgesics in osteoarthritis**

The potential negative effects such as addiction and the physiological side effects of opioid use are well documented, as discussed above, however they remain highly prescribed for OA and are expected to triple in the coming years [256, 257]. More than half of those prescribed opioids in the first year of OA have been shown to be inappropriately dispensed [257]. The prevalence of opioid use for OA ranges from 8-26% and in Australia, with the use for knee/hip OA has being described as "alarmingly high" [257]. A number of systematic reviews and meta-analysis have been performed in recent years and have unanimously shown that the tolerability is low, efficacy for pain relief in OA is not clinically relevant and the potential harms are high [258–260]. Despite calls for guidelines to be changed on the use of opioids and the above-mentioned pharmaceuticals, their use is increasing (likely with the prevalence of the disease) and by proxy the negative consequences rising in tandem. Therefore, non-pharmaceutical food-based alternatives (termed bioactive nutraceuticals) have been developed and are beginning to be recommended as early treatment [261–263] to improve OA symptoms including pain [241, 264–266].

**170**

non-pharmaceutical alternatives have been developed that may reduce the use/ required dose of pharmaceuticals while maintaining or improving the impacts on OA pain and physical function. The majority of these alternatives are termed "nutraceuticals" (a portmanteau of the words "nutrition" and "pharmaceutical"), coined in 1989 by Dr. Stephen DeFelice [267], founder and chairman of the Foundation for Innovation in Medicine.

While it is unlikely that Hippocrates (traditionally regarded as the father of modern medicine; died 375 BCE) actually said: "Let food be your medicine and medicine your food" [268], this is often cited in the context of nutraceuticals. A more apt and legitimate quote defines the position of nutraceuticals in health and disease as "beyond diet, before drug", coined by Ettore Novellino in 2012 [269].

There is currently no universally accepted definition of a nutraceutical [270], with the main confusion being the differences between nutraceuticals and functional foods, and the lack of regulatory definition between them (**Table 1**) [270–273]. In fact, current European regulations do not distinguish between nutraceuticals and food supplements (see the EC Regulation n. 1924/2006 of the European Parliament and Council, recently updated by the UE regulation 2015/2283), therefore neither does the European Food Safety Authority [274, 275]. However, a number of proposed definitions exist (**Table 1**) and from these definitions, for the purposes of this chapter, a nutraceutical will be defined as;

*'a naturally derived biological substance, not synthetically created, that preserve its original active properties without chemical manipulation, can enhance health in dosages that exceed those that could be obtained from normal food digestion and has peer-reviewed scientific evidenced to base health clams'.*


#### **Table 1.**

*Currently used definitions to describe nutraceuticals.*

As such, the following sections will discuss those nutraceuticals that are currently not in mainstream use but may have the potential to aid in treatment of OA (i.e. the well discussed Glucosamine and Chondroitin will not feature in this chapter) but are in regular use worldwide [280]. The identified nutraceuticals that have been compared to/with NSAID/analgesics for OA can be divided into three categories, defined by their origin, and are presented in **Table 2**;


#### **3.1 Terrestrial botanicals**

Turmeric/curcumin extracts (spices used mainly in South Asian cooking) or nutraceuticals combinations where turmeric/curcumin extracts are the main active ingredient, have the greatest amount of evidence for improving OA symptoms, with some recent data on NSAID and analgesics use (**Table 2**) [300]. Two studies have directly compared raw turmeric/curcumin extracts to NSAIDs and their effectiveness for OA symptoms [287, 288]. These data show that turmeric extracts either improved or were shown to be non-inferior for knee osteoarthritis (KOA) pain, pain during stair walking and resulted in less side effects (particularly the rate of abdominal pain/distention) compared to oral ibuprofen [287–289]. Furthermore, patented/propriety formulations of turmeric/curcumin extracts have been developed around the world and show some promising effects on OA (**Table 2**). Interestingly, Chandran et al. demonstrated that curcumin formulated as BCM-95® or 'BCM-95® + diclofenac sodium' showed superior 'Disease Activity Scores', American College of Rheumatology score, pain, CRP levels and erythrocyte sedimentation rate, compared to diclofenac alone (Indian population; [289]). The same formulation showed similar improvements of KOOS variables, but BCM-95® resulted in less adverse events (including flatulence) and a lower requirements for H2 blockers (0% vs. 28%; a group of medicines that reduce the amount of acid produced by the cells in the lining of the stomach), compared to diclofenac [290]. In the longest of these studies (8 months in a European cohort), the addition of Meriva® (curcuminoids 20%, phosphatidylcholine 40%, and microcrystalline cellulose 40%) to the "best available treatment", reduced NSAID and analgesia use by 63% compared to the control group ("best available treatment" only). This reduction resulted in less side-effects between 45-67%, depending on the specific adverse advent, compared to side-effects in the control group (2-12%; [293]). Similarly, an alternative preparation (C3 complex®; Curcuminoids 500-mg capsules with 5-mg Bioperine®) reduced the use of naproxen by 84% (compared to 19% in placebo) in Iranian KOA patients and a further alternative (Theracurmin®; 10% of curcumin, 2% other curcuminoids such as demethoxycurcumin and isdemethoxycurcumin, 46% glycerin, 4% gum ghatti, and 38% of water; 180 mg of curcumin) reduced dependence on celecoxib in Japanese KOA patients (from ~70% to ~30% versus ~80 to ~60% in placebo; [294]). Recently, Heidari-Beni et al. [301] presented findings from a herbal formulation containing curcumin (300 mg), gingerols (7.5 mg) and piperine (3.75 mg), taken twice a day for 4 weeks. This formulation reduced PGE2 (see above text and **Figure 1**) of KOA patients to the same extent as Naproxen (250 mg capsules daily). There is significant mechanistic evidence to support these

**173**

**Proposed main active compound** Avocado/soybean unsaponifiables

Avocado/soybean unsaponifiables

Avocado/soybean unsaponifiables

Fish oil/*Urtica dioica*

Green lipped mussel

Pine bark extract

Turmeric Turmeric Curcumin

Turmeric extracts (2 g extracts/day) or ibuprofen

(800 mg) for 0, 2, 4 and 6 weeks

Turmeric extracts (1500 mg extracts/day) or

ibuprofen (1200 mg/day) for 4 weeks

BCM-95® Curcumin: 500 mg/capsule twice

daily, Curcumin 500 mg + diclofenac sodium

50 mg/capsule twice daily, diclofenac 50 mg/

capsule twice daily, all for 8 weeks

throughout)

600 mg of BioLex(R)-GLM extract daily or

placebo for 12 weeks

Pycnogenol (pine bark extract) 100 mg for

3 months

Avocado/soybean mixture, 300 mg daily orally

versus celecoxib,200 mg/day orally for 8 weeks

Phytalgic (fish-oil, vitamin E, Urtica dioica) 3

capsules daily for 12 weeks

Avocado/soybean unsaponifiables

300 mg or 600 mg ASU for 3 months

Piascledine/ASU (300 mg daily) for 6 months

walking (by ~60%)

↓ Mobility score (by ~50%)

↓ Cartilage oligomeric matrix protein (COMP) in both groups (by ~37%, Avocado/

soybean and ~ 27%, celecoxib), with no differences between groups

↓ NSAIDs use vs. the placebo (by ~60%)

↓ Analgesic use vs. the placebo (BY ~40%)

↓ Pain (by ~37%), stiffness (by ~43%) and function (by ~40\$) vs. placebo

↓ Paracetamol use (by ~30% post-trial) vs. placebo

↓ Stiffness (by ~19%) vs. placebo, no difference pain

↓ Use of drugs (by ~57%) vs. placebo

↓ Gastrointestinal complications (by ~60%) vs. placebo

↓ WOMAC score (by ~40%) vs. placebo

↑ Walking distance (by ~34%), compared to no improvement in placebo

↓ Pain on walking stairs vs. ibuprofen (however, ibuprofen was greater at baseline thus

[287]

No difference in pain on level walking, 100 m walking time or stair climb

↓ WOMAC score, pain and function compared to baseline scores at all time points,

[288]

[289]

and was non-inferior to ibuprofen.

↓ Rate of abdominal pain/distention vs. ibuprofen (by ~60%)

↓ Disease Activity Score (by ~45%), CRP (by ~52%), American College of

Rheumatology score, improved pain (by ~60%), erythrocyte sedimentation rate (by

~11%), greater in Curcumin and Curcumin+ diclofenac vs. diclofenac alone

**Treatment regime**

**Effect on OA Analgesia and NSAID**

↓ NSAIDs and analgesics use by 50% vs. placebo

↓ pain (~50%) in both 300 mg and 600 mg vs. placebo

↓ Participants using analgesics and NSAIDs (from 58.8% to 24.9%)

↓ Median pain (by ~50%) and pain intensity, pain at rest (by 100%) and pain during

**Reference**

[281]

[282]

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis*

[284]

[285]

[286]

*DOI: http://dx.doi.org/10.5772/intechopen.95919*

[283]


#### *Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.95919*

*Pain Management - Practices, Novel Therapies and Bioactives*

categories, defined by their origin, and are presented in **Table 2**;

soybean, pine bark extract and turmeric/curcumin).

thamnion species).

**3.1 Terrestrial botanicals**

As such, the following sections will discuss those nutraceuticals that are currently not in mainstream use but may have the potential to aid in treatment of OA (i.e. the well discussed Glucosamine and Chondroitin will not feature in this chapter) but are in regular use worldwide [280]. The identified nutraceuticals that have been compared to/with NSAID/analgesics for OA can be divided into three

1.Terrestrial Botanicals, compounds derived from 'land' plant sources (avocado/

2.Marine Botanicals, compounds derived from 'marine' plant sources (Litho-

3.Marine Fauna, derived from marine animals (fish oil and green lipped mussel).

Turmeric/curcumin extracts (spices used mainly in South Asian cooking) or nutraceuticals combinations where turmeric/curcumin extracts are the main active ingredient, have the greatest amount of evidence for improving OA symptoms, with some recent data on NSAID and analgesics use (**Table 2**) [300]. Two studies have directly compared raw turmeric/curcumin extracts to NSAIDs and their effectiveness for OA symptoms [287, 288]. These data show that turmeric extracts either improved or were shown to be non-inferior for knee osteoarthritis (KOA) pain, pain during stair walking and resulted in less side effects (particularly the rate of abdominal pain/distention) compared to oral ibuprofen [287–289]. Furthermore, patented/propriety formulations of turmeric/curcumin extracts have been developed around the world and show some promising effects on OA (**Table 2**). Interestingly, Chandran et al. demonstrated that curcumin formulated as BCM-95® or 'BCM-95® + diclofenac sodium' showed superior 'Disease Activity Scores', American College of Rheumatology score, pain, CRP levels and erythrocyte sedimentation rate, compared to diclofenac alone (Indian population; [289]). The same formulation showed similar improvements of KOOS variables, but BCM-95® resulted in less adverse events (including flatulence) and a lower requirements for H2 blockers (0% vs. 28%; a group of medicines that reduce the amount of acid produced by the cells in the lining of the stomach), compared to diclofenac [290]. In the longest of these studies (8 months in a European cohort), the addition of Meriva® (curcuminoids 20%, phosphatidylcholine 40%, and microcrystalline cellulose 40%) to the "best available treatment", reduced NSAID and analgesia use by 63% compared to the control group ("best available treatment" only). This reduction resulted in less side-effects between 45-67%, depending on the specific adverse advent, compared to side-effects in the control group (2-12%; [293]). Similarly, an alternative preparation (C3 complex®; Curcuminoids 500-mg capsules with 5-mg Bioperine®) reduced the use of naproxen by 84% (compared to 19% in placebo) in Iranian KOA patients and a further alternative (Theracurmin®; 10% of curcumin, 2% other curcuminoids such as demethoxycurcumin and isdemethoxycurcumin, 46% glycerin, 4% gum ghatti, and 38% of water; 180 mg of curcumin) reduced dependence on celecoxib in Japanese KOA patients (from ~70% to ~30% versus ~80 to ~60% in placebo; [294]). Recently, Heidari-Beni et al. [301] presented findings from a herbal formulation containing curcumin (300 mg), gingerols (7.5 mg) and piperine (3.75 mg), taken twice a day for 4 weeks. This formulation reduced PGE2 (see above text and **Figure 1**) of KOA patients to the same extent as Naproxen (250 mg capsules daily). There is significant mechanistic evidence to support these

**172**


**175**

**Proposed main active compound**

Ginger Ginger Lithothamnion species (Red

AquaminF, 267 mg Lithothamnion, 3 capsules

per day, 3 times a day for 12 weeks

Algae)

Lithothamnion species

Aquamin+, 2668 mg Lithothamnion, 268 mg

seawater-derived Mg(OH)2 and pine bark

extract 120 mg versus 2000 mg Glucosamine

Sulphate Daily dose for 12 weeks

combination

**Table 2.**

*Nutraceuticals shown to reduce analgesic and NSAID use.*

**Treatment regime**

Topical ginger extract gel (4% gel Plygersic) versus sodium diclofenac gel applied 1 mL of solution 4 times a day for 6 weeks

Diclofenac 50 mg orally or Ginger 750 or Ginger

750 mg and Diclofenac 50 mg orally for 12 weeks

**Effect on OA Analgesia and NSAID**

↓ Pain (by ~27%), symptoms (by ~27%)

No difference in the above between groups

↓ Pain and WOMAC score in all three groups, greatest improvement with Ginger

(60%; 75%) the addition of ginger to Diclofenac (67%; 79%), compared to Diclofenac

↓ Use of rescue medication (paracetamol) in Ginger (50%) and Ginger with

Diclofenac (87%) compared to Diclofenac alone (not statistically significant)

↑ ROM (by 5.2°) and 6MWD (By 136 ft) following 50% forced reduction from all

No difference in rescue medication (acetaminophen) consumption between groups

↑ Six meter walking distance (by~92%) following 50% forced reduction from all

NSAID in AquaminF vs. placebo

↓ Pain (by ~11%), symptoms (by ~7%), no change in Glucosamine

[299]

↑ Sport and recreation (by ~9%), no change in Glucosamine

↑ Timed up and go performance (by 7%), no change in Glucosamine

↓ Rescue analgesic use (by 72%) vs. Glucosamine

NSAID in AquaminF vs. placebo

alone (59%; 64%)

**Reference**

[296]

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis*

[298]

*DOI: http://dx.doi.org/10.5772/intechopen.95919*

[297]

