**2. Topical treatments**

#### **2.1 Thermotherapy**

Thermotherapy refers to the application of either heat or cold (cryotherapy) to affected joints in an attempt to improve pain, stiffness and swelling.

Ice massage and the application of ice packs have both been studied in knee osteoarthritis [5–10]. It is likely that most of the observed effects of cryotherapy are related to the induction of local vasoconstriction. This leads to a reduction in blood flow, lower levels of local inflammation and reduced swelling. In one review [7], cryotherapy was found to reduce pain, stiffness and oedema. Regular ice massage, given five times a week, led to clinically significant effects on all three symptoms as well as function, strength and range of movement over a 2-week period [8]. However, these improvements were not replicated with less frequent applications (three times per week) [9]. There are no data to indicate a sustained effect of cold therapy on osteoarthritis as these studies looked only at a limited duration of therapy.

Common methods of superficial heat administration include the use of electrical heating pads, heat packs, towels or wax. Immersion in warm water or wax baths has also been shown to provide some subjective benefit. In some early trials, heat application failed to improve function or symptoms [8, 9]. In recent years, however, various studies have investigated different modalities of local heat therapy [10–13]. These include the application of heat packs [12], ultrasound [11, 13] and diathermy. The application of local heat packs has been found to provide short-lived alleviation of pain [12, 14], and in particular, wet heat (involving liquids) has been found to be better than dry heat [15] for symptomatic improvement.

In one study [12] 18 patients were randomised into two groups that received differing therapy over a course of 12 weeks. One was treated with application of steam generating heat sheets for 6 hours each day, and the other performed a daily quadriceps strengthening exercise regime. At the end of the study, patients in the heattreated group reported statistically significant improvements in their symptoms and objective "Up and Go" times (a measure of function). The mechanism of heat therapy in osteoarthritis is unclear, although ex vivo studies of cartilage [15, 16] have indicated that elevating the temperature of chondrocytes may increase their metabolism and the production of proteoglycans that are major components of cartilage in combination with collagen. This, in part, may be secondary to increased blood flow to the chondrocytes.

On the whole, the available data suggest that thermotherapy may be useful as an adjunct in the treatment of osteoarthritis, although long-term benefits have not been established, and there are no robust clinical trials evaluating its efficacy.

#### **2.2 Local ultrasound therapy**

The role of ultrasound (US) in diagnosis of musculoskeletal problems is well established. Its popularity is in large part due to the low cost and non-invasive nature of the modality. In recent years, there has been growing interest in its application for therapeutic purposes [13, 17–19]. In theory, direct treatment with US leads to local heating of the tissue at depths not achieved by applying heat packs. There are two main techniques utilised: continuous US which leads to a rise in temperature of the treated tissues, enhancing fibrous tissue extensibility [20] and promoting capillary permeability [21] and pulsed wave treatment which harnesses nonthermal effects and is beneficial for cartilage health [18].

**109**

**Figure 1.**

*Non-Surgical Regional Therapy for Osteoarthritis: An Update and Review of the Literature*

In vitro and animal studies [17, 18] have suggested that pulsed wave US can increase collagen production and reduce expression of membrane metalloproteinase, suggesting a protective role. However, this has failed to translate to long-term clinical benefit: randomised controlled studies [13, 19] comparing continuous, pulsed and sham US on knee osteoarthritis symptoms have shown no significant difference in pain scores nor function. In general, the safety of US has been established, and anecdotal trends have been observed, but evidence is scarce for any

Laser beam therapy directs intense light to treated tissue. Two types of laser therapy have been trialled in osteoarthritis: low-level and high-intensity. Low-level laser therapy (LLLT) uses red and infrared light wavelengths, whilst high-intensity laser therapy confers higher wavelengths of radiation for deeper tissue penetration. LLLT produces a photochemical rather than thermal response and has been found to reduce pain by modulating the local inflammatory process at a cellular level [22]. This involves the increased production of reactive oxygen species (ROS) and enables transcription of cellular components such as nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) that help modulate cell proliferation

In one rat model of osteoarthritis, laser therapy caused a reduction in neutrophil

This suggests that LLLT could have disease-modifying effects as well as symptomatic benefits, although the results of early clinical trials have been mixed thus far [33].

*Mechanisms of low-level light therapy (reproduced from Ref. [23]). Abbreviations: ATP, adenosine triphosphate; ROS, reactive oxygen species; NO, nitric oxide; Jun/Fos, Jun and Fos protein subunits; IκB, inhibitor of kappa B; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; AP-1, activator protein-1.*

migration, oxidative stress, altered levels of cyclooxygenase-2 and other proinflammatory mediators [24]. Another demonstrated that LLLT stimulates tissue repair and reduces the rate of extracellular matrix degradation [25]. There is also some evidence that LLLT promotes fibroblast proliferation, collagen synthesis and bone regeneration [26–31]. In a rabbit model of osteoarthritis, 6 weeks of treatment with laser therapy not only resulted in less pain but also histological evidence of

*DOI: http://dx.doi.org/10.5772/intechopen.91458*

significant therapeutic advantage [13, 19].

reduced inflammation and cartilage damage [32].

**2.3 Laser therapy**

and growth (**Figure 1**).

*Non-Surgical Regional Therapy for Osteoarthritis: An Update and Review of the Literature DOI: http://dx.doi.org/10.5772/intechopen.91458*

In vitro and animal studies [17, 18] have suggested that pulsed wave US can increase collagen production and reduce expression of membrane metalloproteinase, suggesting a protective role. However, this has failed to translate to long-term clinical benefit: randomised controlled studies [13, 19] comparing continuous, pulsed and sham US on knee osteoarthritis symptoms have shown no significant difference in pain scores nor function. In general, the safety of US has been established, and anecdotal trends have been observed, but evidence is scarce for any significant therapeutic advantage [13, 19].

#### **2.3 Laser therapy**

*Recent Advances in Bone Tumours and Osteoarthritis*

Thermotherapy refers to the application of either heat or cold (cryotherapy) to

Ice massage and the application of ice packs have both been studied in knee osteoarthritis [5–10]. It is likely that most of the observed effects of cryotherapy are related to the induction of local vasoconstriction. This leads to a reduction in blood flow, lower levels of local inflammation and reduced swelling. In one review [7], cryotherapy was found to reduce pain, stiffness and oedema. Regular ice massage, given five times a week, led to clinically significant effects on all three symptoms as well as function, strength and range of movement over a 2-week period [8]. However, these improvements were not replicated with less frequent applications (three times per week) [9]. There are no data to indicate a sustained effect of cold therapy on osteoarthritis as these studies looked only at a limited

Common methods of superficial heat administration include the use of electrical heating pads, heat packs, towels or wax. Immersion in warm water or wax baths has also been shown to provide some subjective benefit. In some early trials, heat application failed to improve function or symptoms [8, 9]. In recent years, however, various studies have investigated different modalities of local heat therapy [10–13]. These include the application of heat packs [12], ultrasound [11, 13] and diathermy. The application of local heat packs has been found to provide short-lived alleviation of pain [12, 14], and in particular, wet heat (involving liquids) has been found to be better than dry heat [15] for symptomatic

In one study [12] 18 patients were randomised into two groups that received differing therapy over a course of 12 weeks. One was treated with application of steam generating heat sheets for 6 hours each day, and the other performed a daily quadriceps strengthening exercise regime. At the end of the study, patients in the heattreated group reported statistically significant improvements in their symptoms and objective "Up and Go" times (a measure of function). The mechanism of heat therapy in osteoarthritis is unclear, although ex vivo studies of cartilage [15, 16] have indicated that elevating the temperature of chondrocytes may increase their metabolism and the production of proteoglycans that are major components of cartilage in combination with collagen. This, in part, may be secondary to increased

On the whole, the available data suggest that thermotherapy may be useful as an adjunct in the treatment of osteoarthritis, although long-term benefits have not been established, and there are no robust clinical trials evaluating its efficacy.

The role of ultrasound (US) in diagnosis of musculoskeletal problems is well established. Its popularity is in large part due to the low cost and non-invasive nature of the modality. In recent years, there has been growing interest in its application for therapeutic purposes [13, 17–19]. In theory, direct treatment with US leads to local heating of the tissue at depths not achieved by applying heat packs. There are two main techniques utilised: continuous US which leads to a rise in temperature of the treated tissues, enhancing fibrous tissue extensibility [20] and promoting capillary permeability [21] and pulsed wave treatment which harnesses

nonthermal effects and is beneficial for cartilage health [18].

affected joints in an attempt to improve pain, stiffness and swelling.

**2. Topical treatments**

**2.1 Thermotherapy**

duration of therapy.

improvement.

blood flow to the chondrocytes.

**2.2 Local ultrasound therapy**

**108**

Laser beam therapy directs intense light to treated tissue. Two types of laser therapy have been trialled in osteoarthritis: low-level and high-intensity. Low-level laser therapy (LLLT) uses red and infrared light wavelengths, whilst high-intensity laser therapy confers higher wavelengths of radiation for deeper tissue penetration. LLLT produces a photochemical rather than thermal response and has been found to reduce pain by modulating the local inflammatory process at a cellular level [22]. This involves the increased production of reactive oxygen species (ROS) and enables transcription of cellular components such as nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) that help modulate cell proliferation and growth (**Figure 1**).

In one rat model of osteoarthritis, laser therapy caused a reduction in neutrophil migration, oxidative stress, altered levels of cyclooxygenase-2 and other proinflammatory mediators [24]. Another demonstrated that LLLT stimulates tissue repair and reduces the rate of extracellular matrix degradation [25]. There is also some evidence that LLLT promotes fibroblast proliferation, collagen synthesis and bone regeneration [26–31]. In a rabbit model of osteoarthritis, 6 weeks of treatment with laser therapy not only resulted in less pain but also histological evidence of reduced inflammation and cartilage damage [32].

This suggests that LLLT could have disease-modifying effects as well as symptomatic benefits, although the results of early clinical trials have been mixed thus far [33].

#### **Figure 1.**

*Mechanisms of low-level light therapy (reproduced from Ref. [23]). Abbreviations: ATP, adenosine triphosphate; ROS, reactive oxygen species; NO, nitric oxide; Jun/Fos, Jun and Fos protein subunits; IκB, inhibitor of kappa B; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; AP-1, activator protein-1.*

Recent studies have tended to be more positive with those treated with laser therapy and exercise faring better than those treated with exercise alone in terms of pain measurements as well as function [34, 35]. These studies suggest that LLLT in combination with standard physiotherapy could provide advantages over standard therapy, and it shows potential as a non-invasive, safe and cost-efficient treatment modality [36]. Once again, however, evidence is lacking regarding long-term effects and whether the cellular effects seen modify disease progression.

#### **2.4 Topical non-steroidal anti-inflammatory drugs**

The mechanism of action of non-steroidal anti-inflammatory drugs is wellknown. They inhibit the action of cyclooxygenases (COXs) responsible for the synthesis of prostaglandins (PGs), which are recognised mediators of inflammation [37]. Locally this reduces pain, swelling and heat. There is a large body of evidence in animal models of NSAIDs also providing central analgesic actions, with mechanisms involving spinal regulation of COXs and PGs as well as the induction of endogenous opioid peptides and blockade of serotonin release [38].

It is clear to see, therefore, why systemic NSAIDs have long been used in management of osteoarthritis. However, significant side effects including gastritis, renal impairment and increased risk of cardiovascular disease has meant that their long-term use has been limited. This has led to the promotion of topical NSAID use, theoretically providing local analgesic and anti-inflammatory benefits without the undesirable systemic adverse effects.

There are many types of topical NSAID. Preparations containing diclofenac, ibuprofen, piroxicam, ketoprofen or felbinac as the active ingredient all exist. Some include a penetration enhancer such as menthol or dimethyl sulfoxide (DMSO), whilst gels and sprays tend to be more penetrative than cream preparations. Once applied, a topical NSAID is absorbed by the underlying tissue or enters the local blood stream. Studies have shown that the absorption of NSAIDs into the underlying tissue gives rise to therapeutic local concentrations of the drug without significant systemic absorption [39, 40]. An estimated 3–7% of the applied dose is thought to be absorbed systemically [39] with plasma concentrations approximately 5% of those achieved with oral administration [39].

The skin acts as a reservoir from which the drug disseminates to the deeper tissue. Peak concentrations in the skin are achieved 2 hours after application with a further spike approximately 19 hours later, likely secondary to systemic absorption. Further proof of their local action is the absence of analgesic effect at joints distant to the point of application [41].

There have been many studies looking into the efficacy of topical NSAIDs in treating osteoarthritis [42–48]. On the whole, these have found topical NSAIDs to be superior to placebo in the treatment of chronic pain. Most of the initial studies found no benefit beyond 2 weeks of treatment [42–48], but larger randomised controlled trials demonstrated long-term benefit for up to 3 months when compared to placebo [49, 50].

When compared to oral NSAID use, the results have been variable. A metaanalysis in 2006 [48] found that topical NSAIDs were less effective than systemic NSAIDs. Since then, however, there have been several studies showing comparable effectiveness. Two studies comparing oral diclofenac with a topical preparation of the drug [51, 52] found no difference in pain scores or physical function. Furthermore, those in the topical treatment arm had a much lower incidence of severe gastrointestinal side effects, deranged liver function tests and abnormal creatinine clearance [51, 52]. These results were replicated in another study comparing oral and topical treatment with ibuprofen for knee osteoarthritis [50].

**111**

*Non-Surgical Regional Therapy for Osteoarthritis: An Update and Review of the Literature*

rate of gastrointestinal side effects in the over 50s to be as high as 15% [53].

Overall, the data suggest that topical NSAIDs may be considered as first-line therapy for osteoarthritis as they are efficacious and associated with fewer adverse events. As with oral use, however, there should still be caution about their longterm application in the elderly as these patients are known to be more prone to

Topical capsaicin cream has been used to treat a multitude of different painful conditions including osteoarthritis, inflammatory arthritis and neuropathic pain. Derived from chilli peppers, capsaicin is a lipophilic alkaloid that acts as a local irritant. It activates local pain receptors (c-nociceptors) leading to the release of substance P [54]. This in turn causes local irritation in the initial phase of treatment. With repeated use, however, levels of substance P are depleted, leading to

In clinical practice, capsaicin is more effective than placebo for the treatment of chronic pain but compares less favourably with other treatments. In a meta-analysis comparing capsaicin with plaster for instance, capsaicin was found to be only marginally effective [56]. Other drawbacks include the need to use the cream four times a day for maximum benefit, as well as the local irritation and burning sensation when the cream is applied (occurring in up to 40% of patients) [57, 58]. These problems cause 10% of patients to discontinue treatment [56]. In view of this, topical capsaicin should be used in conjunction with more traditional treatments. Other topical treatments include the use of salicylate or nicotine esters, which can be classed as local counterirritants and rubefacients, and lidocaine patches. Rubefacients cause localised vasodilatation and reddening of the skin that result in a local sensation of warmth, which often palliates pain. Irritation of the sensory nerve endings in underlying muscle and tissue is a by-product of their application and thought to modify pain pathways [59], but their main action is

The available evidence does not support their use for acute injuries or for chronic

conditions such as osteoarthritis, though they are relatively well tolerated in the short term [60]. When compared to topical NSAIDs, counterirritants performed poorly [60]. This has led to numerous recommendations advising the discontinuation of routine rubefacient prescriptions in England, with patients signposted to

Lidocaine patches are not currently licensed for use in osteoarthritis in the United Kingdom, instead being more commonly utilised in the context of postherpetic neuralgia. There is some anecdotal evidence for their efficacy in OA, however [62]. Lidocaine forms cations following ionisation with hydrogen ions and reversibly inhibits voltage-gated sodium channels on the internal surface of neuronal surface membranes when bound [63]. This prevents an influx of sodium cations (**Figure 2**) which in turn leads to a failure of nerve depolarisation resulting in the

diminished pain signalling that has been observed in some clinical trials.

On the whole, topical NSAID use is associated with fewer systemic adverse events [42, 46, 51, 52] than oral preparations. The main side effect associated with topical NSAID use is local skin irritation, which has been reported in up to 39.3% of patients [53]. However, these skin reactions occur in equal measure with placebo gel application indicating that they may not be related to the active drug itself [46]. Other studies also suggest that skin reactions may be more common with solutions containing DMSO than diclofenac sodium gel (DSG) [44]. There is some contradictory evidence regarding their safety in older patients as some studies have found the

*DOI: http://dx.doi.org/10.5772/intechopen.91458*

adverse events.

**2.5 Other topical treatments**

regional skin irritation.

desensitisation of the pain fibres and hypoalgesia [55].

alternative, more efficacious local treatments [61].

#### *Non-Surgical Regional Therapy for Osteoarthritis: An Update and Review of the Literature DOI: http://dx.doi.org/10.5772/intechopen.91458*

On the whole, topical NSAID use is associated with fewer systemic adverse events [42, 46, 51, 52] than oral preparations. The main side effect associated with topical NSAID use is local skin irritation, which has been reported in up to 39.3% of patients [53]. However, these skin reactions occur in equal measure with placebo gel application indicating that they may not be related to the active drug itself [46]. Other studies also suggest that skin reactions may be more common with solutions containing DMSO than diclofenac sodium gel (DSG) [44]. There is some contradictory evidence regarding their safety in older patients as some studies have found the rate of gastrointestinal side effects in the over 50s to be as high as 15% [53].

Overall, the data suggest that topical NSAIDs may be considered as first-line therapy for osteoarthritis as they are efficacious and associated with fewer adverse events. As with oral use, however, there should still be caution about their longterm application in the elderly as these patients are known to be more prone to adverse events.

#### **2.5 Other topical treatments**

*Recent Advances in Bone Tumours and Osteoarthritis*

cellular effects seen modify disease progression.

undesirable systemic adverse effects.

those achieved with oral administration [39].

to the point of application [41].

when compared to placebo [49, 50].

**2.4 Topical non-steroidal anti-inflammatory drugs**

Recent studies have tended to be more positive with those treated with laser therapy and exercise faring better than those treated with exercise alone in terms of pain measurements as well as function [34, 35]. These studies suggest that LLLT in combination with standard physiotherapy could provide advantages over standard therapy, and it shows potential as a non-invasive, safe and cost-efficient treatment modality [36]. Once again, however, evidence is lacking regarding long-term effects and whether the

The mechanism of action of non-steroidal anti-inflammatory drugs is wellknown. They inhibit the action of cyclooxygenases (COXs) responsible for the synthesis of prostaglandins (PGs), which are recognised mediators of inflammation [37]. Locally this reduces pain, swelling and heat. There is a large body of evidence in animal models of NSAIDs also providing central analgesic actions, with mechanisms involving spinal regulation of COXs and PGs as well as the induction

It is clear to see, therefore, why systemic NSAIDs have long been used in management of osteoarthritis. However, significant side effects including gastritis, renal impairment and increased risk of cardiovascular disease has meant that their long-term use has been limited. This has led to the promotion of topical NSAID use, theoretically providing local analgesic and anti-inflammatory benefits without the

There are many types of topical NSAID. Preparations containing diclofenac, ibuprofen, piroxicam, ketoprofen or felbinac as the active ingredient all exist. Some include a penetration enhancer such as menthol or dimethyl sulfoxide (DMSO), whilst gels and sprays tend to be more penetrative than cream preparations. Once applied, a topical NSAID is absorbed by the underlying tissue or enters the local blood stream. Studies have shown that the absorption of NSAIDs into the underlying tissue gives rise to therapeutic local concentrations of the drug without significant systemic absorption [39, 40]. An estimated 3–7% of the applied dose is thought to be absorbed systemically [39] with plasma concentrations approximately 5% of

The skin acts as a reservoir from which the drug disseminates to the deeper tissue. Peak concentrations in the skin are achieved 2 hours after application with a further spike approximately 19 hours later, likely secondary to systemic absorption. Further proof of their local action is the absence of analgesic effect at joints distant

There have been many studies looking into the efficacy of topical NSAIDs in treating osteoarthritis [42–48]. On the whole, these have found topical NSAIDs to be superior to placebo in the treatment of chronic pain. Most of the initial studies found no benefit beyond 2 weeks of treatment [42–48], but larger randomised controlled trials demonstrated long-term benefit for up to 3 months

When compared to oral NSAID use, the results have been variable. A metaanalysis in 2006 [48] found that topical NSAIDs were less effective than systemic NSAIDs. Since then, however, there have been several studies showing comparable effectiveness. Two studies comparing oral diclofenac with a topical preparation of the drug [51, 52] found no difference in pain scores or physical function. Furthermore, those in the topical treatment arm had a much lower incidence of severe gastrointestinal side effects, deranged liver function tests and abnormal creatinine clearance [51, 52]. These results were replicated in another study compar-

ing oral and topical treatment with ibuprofen for knee osteoarthritis [50].

of endogenous opioid peptides and blockade of serotonin release [38].

**110**

Topical capsaicin cream has been used to treat a multitude of different painful conditions including osteoarthritis, inflammatory arthritis and neuropathic pain. Derived from chilli peppers, capsaicin is a lipophilic alkaloid that acts as a local irritant. It activates local pain receptors (c-nociceptors) leading to the release of substance P [54]. This in turn causes local irritation in the initial phase of treatment. With repeated use, however, levels of substance P are depleted, leading to desensitisation of the pain fibres and hypoalgesia [55].

In clinical practice, capsaicin is more effective than placebo for the treatment of chronic pain but compares less favourably with other treatments. In a meta-analysis comparing capsaicin with plaster for instance, capsaicin was found to be only marginally effective [56]. Other drawbacks include the need to use the cream four times a day for maximum benefit, as well as the local irritation and burning sensation when the cream is applied (occurring in up to 40% of patients) [57, 58]. These problems cause 10% of patients to discontinue treatment [56]. In view of this, topical capsaicin should be used in conjunction with more traditional treatments.

Other topical treatments include the use of salicylate or nicotine esters, which can be classed as local counterirritants and rubefacients, and lidocaine patches. Rubefacients cause localised vasodilatation and reddening of the skin that result in a local sensation of warmth, which often palliates pain. Irritation of the sensory nerve endings in underlying muscle and tissue is a by-product of their application and thought to modify pain pathways [59], but their main action is regional skin irritation.

The available evidence does not support their use for acute injuries or for chronic conditions such as osteoarthritis, though they are relatively well tolerated in the short term [60]. When compared to topical NSAIDs, counterirritants performed poorly [60]. This has led to numerous recommendations advising the discontinuation of routine rubefacient prescriptions in England, with patients signposted to alternative, more efficacious local treatments [61].

Lidocaine patches are not currently licensed for use in osteoarthritis in the United Kingdom, instead being more commonly utilised in the context of postherpetic neuralgia. There is some anecdotal evidence for their efficacy in OA, however [62]. Lidocaine forms cations following ionisation with hydrogen ions and reversibly inhibits voltage-gated sodium channels on the internal surface of neuronal surface membranes when bound [63]. This prevents an influx of sodium cations (**Figure 2**) which in turn leads to a failure of nerve depolarisation resulting in the diminished pain signalling that has been observed in some clinical trials.

**Figure 2.**

*The effect of lidocaine on a voltage-gated sodium channel. Abbreviations: LA, lidocaine; Na, sodium; H, hydrogen, ECF, extracellular fluid, ICF, intracellular fluid.*

One open-label multicentre study investigated the effect of application of lidocaine to the area of maximal OA pain in OA of the knee [62]. A 5% lidocaine patch was applied for 12 hours at the same time each day for a period of 2 weeks with significant improvement in pain and functional scores when this treatment was used as an adjunct to more conventional systemic analgesia. Furthermore, there were minimal adverse effects seen, and the treatment was well tolerated in the patient cohort.

Clearly, randomised control trials are required to support the anecdotal data, as a sustained benefit has yet to be proven. It should also be noted that the symptomatic improvement observed was related to the use of a lidocaine patch as an adjunct to therapy, rather than a lone therapeutic agent in the management of OA. As in the case of capsaicin or rubefacients, lidocaine acts as a painkiller but has no diseasemodifying capacity.
