**Acknowledgements**

*Pain Management - Practices, Novel Therapies and Bioactives*

stage treatment adjunct.

better design quality [300].

**4. Discussion and conclusions**

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

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

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

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

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of nerve fibres).

The authors have no acknowledgements to make.
