**Table 2.**

*Nutraceuticals shown to reduce analgesic and NSAID use.*

*Pain Management - Practices, Novel Therapies and Bioactives*

[291]

**174**

**Proposed main active** 

**Treatment regime**

BCM-95® (curcumin, demethoxycurcumin,

bisdemethoxycurcumin, and volatile oils from

turmeric rhizome), 500-mg three times daily

versus diclofenac 50-mg tablet two times daily

Longvida®, 800 mg patented lipophilic matrix

delivering 160 mg curcumin versus Ibuprofen

(400 mg) orally and daily for 12 weeks

Herbal formulation of curcumin (300 mg),

gingerols (7.5 mg), and piperine (3.75 mg;

(~27 pg./mL)

Mixodin) versus Naproxen 250 mg capsules, both

twice a day for 4 weeks

Meriva tablets, a curcumin-phosphatidylcholine

↓ NSAIDs use (by ~80%) vs. control

↓ Gastrointestinal complaints (by ~40%) vs. control

↓ Pain (by ~44%), stiffness (by ~28%), physical function (by ~40%), WOMAC score

(by ~41%), compared to no improvements in controls

↑ Karnofsky Performance Scale (by ~22%), compared to no improvement in controls

↑ Treadmill walking distance (345% increase from baseline) compared to 89% in

↓ inflammatory markers sCD40L (by ~56%), IL-1β (by ~35%), IL-6(by ~27%),

sVCAM-1 (by ~30%), ESR (by ~25%), compared to no change in controls

↓ NSAID (celecoxib) dependence (p = 0.0252)

[294]

↓ Pain (by ~55%) vs. placebo

Curcumin

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)

for 8 weeks

C3 complex, 500 mg curcuminoid capsules

↓ Naproxen use (by ~73%) vs. controls

↓ Pain (by >38%), function (by ~41%) and WOMAC score (by ~41%) vs. placebo

[295]

including 5 mg Bioperine, 3 times daily for

6 weeks

Curcumin

controls

phytosome complex, 200 mg equivalent

curcumin daily with best available care (BCA)

compared to BCA only as control for 8 months

Curcumin

for 28days

Curcumin Curcumin

**Effect on OA Analgesia and NSAID**

↓ Pain similar in both groups (by ~78% for both), no difference between groups

↑ KOOS variables (n = 5) similar in both groups, no difference between groups

↑ Flatulence in diclofenac vs. curcumin (by ~79%)

↓ Requirement for H2 blockers in curcumin vs. diclofenac (by 100%, i.e. zero in

↓ Incidence of adverse effects in curcumin vs. diclofenac (by ~76%)

↓ Pain in both (by ~60%), no difference between groups

↓ prostaglandin E2 (PGE2) in booth groups with no difference between the two

[292]

[293]

curcumin)

**Reference**

[290]

**compound**

Curcumin *in vivo* therapeutic effects. Turmeric/curcumin extracts have been shown to reduce proinflammatory cytokines such as tumour necrosis factor alpha, interleukin (IL)-1 beta, IL-8, IL-6 and structural degradation protases such as matrix metalloproteinases, collagenase, induce positive cell behavioural characteristics (induces apoptosis and growth arrest) and anti-oxidative properties (through stimulation of nuclear factor-erythroid-2-related factor 2 (Nrf2) [292, 302–311]). Of particular interest to the present chapter, turmeric/curcumin extracts inhibit the NFkB pathway and other proinflammatory signalling pathways including COX-2, AP-1, Egr-1, STAT (signal transducers and activators of transcription) and mitogen-activated protein (MAP) kinases [309, 310, 312]. Considering these molecular targets, turmeric/ curcumin extracts appear to enact there *in vivo* effects via similar mechanisms of action as commonly used pharmaceutical agents (**Figure 1**). These data clearly point to the positive impact that turmeric/curcumin extracts, including propriety formulations, can have on NSAID and analgesia use in the short term (best effects from study durations generally ≤12 weeks). While the long-term benefits are still being investigated, the current data suggests that turmeric/curcumin extracts could be recommended as an early stage treatment adjunct.

Alternative terrestrial botanicals have shown some advantages for OA. Three studies have investigated avocado/soybean extracts and their potential in reducing NSAID and analgesics use. One large randomised control trial (n = 260) showed that after 30 days (and continued to day 90) of supplementation, the extracts (300 or 600 mg) reduced the daily intake of NSAID and analgesics compared to placebo. Furthermore, 71% (compared to 36% in placebo) of avocado/soybean extract participants reduced their daily intake by greater than 50%, [281]. Although it must be noted that the treatment was stopped in nine participants due to adverse events from the extract, however the authors did not statistically analyse incidence of adverse events of the remaining participants, but they were generally similar to placebo. These results were somewhat supported by a smaller (n = 31; part of a large cohort receiving a number of nutraceutical compounds) observational study showing that the proportion of OA patients using analgesics and NSAIDs dropped by 34% over 6 months consuming avocado/soybean extracts [282]. Although, in this large scale "real-world" (PEGASus) study cohort where analgesic and NSAID use was assessed by phone interview bi-monthly over 2 years, avocado/soybean extracts showed no effect on reducing medication use [313]. Recently, a 2-month supplementation of avocado/soybean unsaponifiables (n = 30; 300 mg daily) was compared to celecoxib (n = 30; 200 mg/day) for changes in a biomarker of cartilage breakdown (Cartilage oligomeric matrix protein; COMP). The results showed that both interventions reduced serum COMP levels with a tendency for greater improvements with avocado/soybean unsaponifiables (33.8% vs. 30.3%; p = 0.06; [283]). These data in addition to other mechanistic work show that avocado/soybean unsaponifiables can impact both inflammatory and structural protein biomarkers of OA pathology. Specifically they can inhibit IL-1, reduce production of stromelysin, IL-6, IL-8 and PGE-2, increase the expression of TGF-β and activate collagen synthesis [283, 314–316]. There is some debate over the efficacy of avocado/soybean extracts to alleviate analgesics and NSAID use but there is developing molecular evidence that they may elicit similar reductions on *in vivo* cartilage breakdown which requires further investigation.

Two studies investigated Ginger root extract formulations in OA NSAID use. Compared to 1% diclofenac gel, topical ginger extract (Plygersic gel) reduce KOOS variables (pain, symptoms etc.) equally after a six week intervention in mild radiographic KOA [296]. Further, oral consumption of a Ginger root extract formulation, compared (1) 50 mg of oral Diclofenac with Ginger 750, (2) Ginger 750 mg and (3) Diclofenac 50 mg for 12 weeks [297]. All interventions decreased pain and WOMAC

**177**

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis*

variables but there was a reduction in rescue medication in the ginger groups, although this was not statically significant [297]. While these results are interesting, significantly more research is needed with larger more well controlled studies but there is molecular evidence to support these reported effects. Ginger root species can block the formation of inflammatory mediators such as thromboxane, leukotrienes and prostaglandins and inhibit COX and lipoxygenase in arachidonic acid metabolism [317–325] i.e. similar mechanisms to those presented in **Figure 1**. Finally, the trade marked Pycnogenol® (pine bark extract; 100 mg) has been shown to reduces NSAID use by 58%, compared to only 1% in the placebo group in early-KOA patients over 12 weeks [286]. This resulted in reduced hospital admissions and days spent in hospital by 50% compared to placebo (n = 156; [286]). As with the above, Pycnogenol inhibits activation of NFκB pathway mediators, particularly, COX and pain-producing prostaglandins and also activates metabolomic compounds with anti-inflammatory bio-efficacy [326–328]. Again, these data are interesting and demonstrate good potential but require further *in vivo* replication in

New Zealand Green Lipped Mussel (Perna canaliculus) lipid extracts have recently been investigated for their potentially benefits for OA symptoms. Moderate-to-severe hip and knee OA patients received 600 mg of Biolex®-GLM for 12 weeks or a placebo and were allowed to consume paracetamol for additional pain relief [285]. Participants consuming the placebo took more paracetamol each week of the 12 weeks resulting in a statically significant change at the final week (p = 0.001), however did not differ in NSAID equivalence score. This suggests that there may be some potential for Green Lipped Mussel to reduce analgesic medication, although less so than others mentioned herein. Again, Green Lipped Mussel appears to inhibit COX enzymes, competitive inhibition of arachidonic acid

A fish oil and Urtica dioica preparation has also been shown to reduce medication use in OA. A proprietary combination of omega-3 and omega-6 fatty acids, Urtica dioica (the common nettle), zinc and vitamin E (Phytalgic®) progressively reduced NSAID and analgesia use over a tree month period (n = 81; 6.5 Paracetamol 500 mg-Equivalent per week, compared to 16.5 in the placebo group; [284]). The authors ascribed this adaptation to the anti-inflammatory potential of the mineral composition, mainly from Urtica dioica within the formulation rather than the fish oil component [284]. This was most likely the case as a previous study showed no effect of cod liver oil an OA [330] and the articles referenced to show a mechanistic potential for fish oil components (n-3 and n-6 polyunsaturated fatty acids) have

The marine red Algae species Lithothamnion corallioide, rich in sea water derived minerals including Calcium and Magnesium (AquaminF®), have recently been investigated for a potential impact on NSAID usage. In a randomised control trial of moderate-to-severe KOA patients that were regularly consuming NSAIDs, AquaminF (534 mg daily) was an effective agent for improving physical performance (six minuet walking distance), when NSAID use was intentionally reduced to 50% of previous consumption, but not when NSAID consumption was reduced to zero [298]. Furthermore, Lithothamnion (2668 mg) combined with seawaterderived Mg(OH)2 (268 mg) and pine bark extract (120 mg) reduced analgesic and

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

relation to NSAID and analgesic.

recently been retracted [331, 332].

**3.3 Marine botanicals**

metabolism and reduce chronic inflammation [329].

**3.2 Marine Fauna**

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

variables but there was a reduction in rescue medication in the ginger groups, although this was not statically significant [297]. While these results are interesting, significantly more research is needed with larger more well controlled studies but there is molecular evidence to support these reported effects. Ginger root species can block the formation of inflammatory mediators such as thromboxane, leukotrienes and prostaglandins and inhibit COX and lipoxygenase in arachidonic acid metabolism [317–325] i.e. similar mechanisms to those presented in **Figure 1**.

Finally, the trade marked Pycnogenol® (pine bark extract; 100 mg) has been shown to reduces NSAID use by 58%, compared to only 1% in the placebo group in early-KOA patients over 12 weeks [286]. This resulted in reduced hospital admissions and days spent in hospital by 50% compared to placebo (n = 156; [286]). As with the above, Pycnogenol inhibits activation of NFκB pathway mediators, particularly, COX and pain-producing prostaglandins and also activates metabolomic compounds with anti-inflammatory bio-efficacy [326–328]. Again, these data are interesting and demonstrate good potential but require further *in vivo* replication in relation to NSAID and analgesic.

#### **3.2 Marine Fauna**

*Pain Management - Practices, Novel Therapies and Bioactives*

be recommended as an early stage treatment adjunct.

*in vivo* therapeutic effects. Turmeric/curcumin extracts have been shown to reduce proinflammatory cytokines such as tumour necrosis factor alpha, interleukin (IL)-1 beta, IL-8, IL-6 and structural degradation protases such as matrix metalloproteinases, collagenase, induce positive cell behavioural characteristics (induces apoptosis and growth arrest) and anti-oxidative properties (through stimulation of nuclear factor-erythroid-2-related factor 2 (Nrf2) [292, 302–311]). Of particular interest to the present chapter, turmeric/curcumin extracts inhibit the NFkB pathway and other proinflammatory signalling pathways including COX-2, AP-1, Egr-1, STAT (signal transducers and activators of transcription) and mitogen-activated protein (MAP) kinases [309, 310, 312]. Considering these molecular targets, turmeric/ curcumin extracts appear to enact there *in vivo* effects via similar mechanisms of action as commonly used pharmaceutical agents (**Figure 1**). These data clearly point to the positive impact that turmeric/curcumin extracts, including propriety formulations, can have on NSAID and analgesia use in the short term (best effects from study durations generally ≤12 weeks). While the long-term benefits are still being investigated, the current data suggests that turmeric/curcumin extracts could

Alternative terrestrial botanicals have shown some advantages for OA. Three studies have investigated avocado/soybean extracts and their potential in reducing NSAID and analgesics use. One large randomised control trial (n = 260) showed that after 30 days (and continued to day 90) of supplementation, the extracts (300 or 600 mg) reduced the daily intake of NSAID and analgesics compared to placebo. Furthermore, 71% (compared to 36% in placebo) of avocado/soybean extract participants reduced their daily intake by greater than 50%, [281]. Although it must be noted that the treatment was stopped in nine participants due to adverse events from the extract, however the authors did not statistically analyse incidence of adverse events of the remaining participants, but they were generally similar to placebo. These results were somewhat supported by a smaller (n = 31; part of a large cohort receiving a number of nutraceutical compounds) observational study showing that the proportion of OA patients using analgesics and NSAIDs dropped by 34% over 6 months consuming avocado/soybean extracts [282]. Although, in this large scale "real-world" (PEGASus) study cohort where analgesic and NSAID use was assessed by phone interview bi-monthly over 2 years, avocado/soybean extracts showed no effect on reducing medication use [313]. Recently, a 2-month supplementation of avocado/soybean unsaponifiables (n = 30; 300 mg daily) was compared to celecoxib (n = 30; 200 mg/day) for changes in a biomarker of cartilage breakdown (Cartilage oligomeric matrix protein; COMP). The results showed that both interventions reduced serum COMP levels with a tendency for greater improvements with avocado/soybean unsaponifiables (33.8% vs. 30.3%; p = 0.06; [283]). These data in addition to other mechanistic work show that avocado/soybean unsaponifiables can impact both inflammatory and structural protein biomarkers of OA pathology. Specifically they can inhibit IL-1, reduce production of stromelysin, IL-6, IL-8 and PGE-2, increase the expression of TGF-β and activate collagen synthesis [283, 314–316]. There is some debate over the efficacy of avocado/soybean extracts to alleviate analgesics and NSAID use but there is developing molecular evidence that they may elicit similar reductions on *in vivo* cartilage breakdown

Two studies investigated Ginger root extract formulations in OA NSAID use. Compared to 1% diclofenac gel, topical ginger extract (Plygersic gel) reduce KOOS variables (pain, symptoms etc.) equally after a six week intervention in mild radiographic KOA [296]. Further, oral consumption of a Ginger root extract formulation, compared (1) 50 mg of oral Diclofenac with Ginger 750, (2) Ginger 750 mg and (3) Diclofenac 50 mg for 12 weeks [297]. All interventions decreased pain and WOMAC

**176**

which requires further investigation.

New Zealand Green Lipped Mussel (Perna canaliculus) lipid extracts have recently been investigated for their potentially benefits for OA symptoms. Moderate-to-severe hip and knee OA patients received 600 mg of Biolex®-GLM for 12 weeks or a placebo and were allowed to consume paracetamol for additional pain relief [285]. Participants consuming the placebo took more paracetamol each week of the 12 weeks resulting in a statically significant change at the final week (p = 0.001), however did not differ in NSAID equivalence score. This suggests that there may be some potential for Green Lipped Mussel to reduce analgesic medication, although less so than others mentioned herein. Again, Green Lipped Mussel appears to inhibit COX enzymes, competitive inhibition of arachidonic acid metabolism and reduce chronic inflammation [329].

A fish oil and Urtica dioica preparation has also been shown to reduce medication use in OA. A proprietary combination of omega-3 and omega-6 fatty acids, Urtica dioica (the common nettle), zinc and vitamin E (Phytalgic®) progressively reduced NSAID and analgesia use over a tree month period (n = 81; 6.5 Paracetamol 500 mg-Equivalent per week, compared to 16.5 in the placebo group; [284]). The authors ascribed this adaptation to the anti-inflammatory potential of the mineral composition, mainly from Urtica dioica within the formulation rather than the fish oil component [284]. This was most likely the case as a previous study showed no effect of cod liver oil an OA [330] and the articles referenced to show a mechanistic potential for fish oil components (n-3 and n-6 polyunsaturated fatty acids) have recently been retracted [331, 332].

#### **3.3 Marine botanicals**

The marine red Algae species Lithothamnion corallioide, rich in sea water derived minerals including Calcium and Magnesium (AquaminF®), have recently been investigated for a potential impact on NSAID usage. In a randomised control trial of moderate-to-severe KOA patients that were regularly consuming NSAIDs, AquaminF (534 mg daily) was an effective agent for improving physical performance (six minuet walking distance), when NSAID use was intentionally reduced to 50% of previous consumption, but not when NSAID consumption was reduced to zero [298]. Furthermore, Lithothamnion (2668 mg) combined with seawaterderived Mg(OH)2 (268 mg) and pine bark extract (120 mg) reduced analgesic and NSAID use by 72% compared to Glucosamine Sulphate (2000 mg Daily dose) [299]. Mechanistically, Lithothamnion corallioide species appear to have the ability to inhibit the NFκB pathway, reduce inflammatory cytokines such as tumour necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and COX2, along with reduced serum TNF-α [333–336]. This suggested there is potential for Lithothamnion species to reduce the KOA-related drug dependency *in vivo* with mechanistic rationale similar to that of pharmaceuticals (**Figure 1**). It appears as though Lithothamnion species have the ability to improve physical function and analgesia with reduced NSAID use, and induce a further reduction in drug use when combined with other nutraceuticals previously shown to reduce NSAID use. With larger scale replication and confirmation, Lithothamnion species could develop into a recommended early stage treatment adjunct.

### **4. Discussion and conclusions**

These data are of considerable interest to those suffering from OA and medical practitioners concerned with the broader health impacts of pharmaceuticals use in OA patients. There appears to be a growing body of evidence suggesting that a variety of nutraceutical compounds, many in preparatory formulations, could provide some relief from the burden of NSAID and analgesic dependence, thus their associated side-effects. Currently the data are limited with respect to replication, sample size and duration, making conclusions about long term effectiveness difficult. The one potential exception is turmeric/curcumin extracts that in a recent meta-analysis it was shown that typically 1000mg/day of curcumin was effective for improve OA symptoms (potentially better that NSAID) over 8-12 weeks - but the authors still call for significantly more research, specifically with increased sample size and better design quality [300].

While the precise molecular mechanisms of OA progression remain unclear, it appears to be exacerbated by the activation of NFκB signalling pathway, initiated by a host of mechanical and chemical stress stimuli, including excessive mechanical stress brought about by surplus body mass, proinflammatory cytokines and extracellular matrix degradation products [337, 338]. These actions reduce the amount of articular cartilage in the joints and degrade subchondral bone, thus induce pain and difficulty in movement. As a result, OA treatments focus on relieving pain and swelling, improving joint mobility, increasing musculoskeletal strength and minimising the disabling effects of the disease [339]. The NFκB signalling pathway and inflammatory mechanisms appear to be the molecular actions of the majority of the above nutraceuticals in combination with the inhibition of COX enzymes. These imply that their mechanism of action for pain relief (and therefore potential reduction in analgesic use) are via peripheral nociceptive action with little interaction through neuropathic mechanisms (unless through local inflammatory assault of nerve fibres).

As discussed throughout, there appears to be even further benefit through combinations of nutraceuticals that may have an additive effects to reduce NSAID/ analgesic use and are recommended [263]. However, additional work needs to be carried out to understand the individual effects of these combinations in addition to the synergistic impact. This requirement is evident through the work by Jacquet et al. [284] where it appears that the proposed benefit of the combination was not attributable to the ingredient that is mentioned and discussed firstly (fish oil), rather the benefit lies with Urtica dioica and mineral composition. These combinations are often proprietary formulations where the precise combinations are not publicly available. However, where this is not the case better understanding can be

**179**

**Author details**

Shane M. Heffernan1

University, Swansea, Wales, UK

provided the original work is properly cited.

\* and Gillian E. Conway2

\*Address all correspondence to: s.m.heffernan@swansea.ac.uk

1 Applied Sport Technology Exercise and Medicine Research Centre (A-STEM), Faculty of Science and Engineering, Swansea University, Swansea, Wales, UK

2 In vitro Toxicology Group, Institute of Life Science, College of Medicine, Swansea

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis*

achieved through *in vitro* experimentation to elucidate the mechanisms of action

osteoarthritis, and presented evidence that specific nutraceuticals and combinations may have potential to either elicit the same pain reliving effect of NSAIDs and analgesics or reduce the dependency on these drugs. Specifically, the greatest evidence exists for the inclusion of turmeric/curcumin extracts as an mild-OA treatment adjunct to reduce NSAID consumption. Any reduction in the use of harmful pharmaceutical drugs should be a welcome inclusion to any treatment plan particularly when some nutraceuticals, that appear to interact with similar molecular pathways as the discussed analgesics, may be capable of offering such benefit. However, it must be noted that significantly more experimental evidence is required for a number of these bioactives and their propitiatory formulations before specific

In conclusion, this chapter has described and discussed chronic pain, specifically

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

both individually and combined.

recommendations can be made.

The authors have no acknowledgements to make.

The authors declare no conflict of interest.

**Acknowledgements**

**Conflict of interests**

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

achieved through *in vitro* experimentation to elucidate the mechanisms of action both individually and combined.

In conclusion, this chapter has described and discussed chronic pain, specifically osteoarthritis, and presented evidence that specific nutraceuticals and combinations may have potential to either elicit the same pain reliving effect of NSAIDs and analgesics or reduce the dependency on these drugs. Specifically, the greatest evidence exists for the inclusion of turmeric/curcumin extracts as an mild-OA treatment adjunct to reduce NSAID consumption. Any reduction in the use of harmful pharmaceutical drugs should be a welcome inclusion to any treatment plan particularly when some nutraceuticals, that appear to interact with similar molecular pathways as the discussed analgesics, may be capable of offering such benefit. However, it must be noted that significantly more experimental evidence is required for a number of these bioactives and their propitiatory formulations before specific recommendations can be made.
