Capsaicin Patches In Knee Osteoarthritis In Obese Patients
Capsaicin Patches In Knee Osteoarthritis In Obese Patients
To assess the efficacy and safety of high concentration capsaicin patches in pain due to
 osteoarthritis (OA) of the knee in patients with obesity
Osteoarthritis is one of the leading causes of pain and disability. In France osteoarthritis
 of the knee, the most common form of osteoarthritis has been recently estimated to affect 4.7
 % of men and 2.5 % of women .

 One particularly exposed population to osteoarthritis is represented by obese patients.
 Obesity, defined as a body mass index (BMI) above 30 kg/m², is considered to be one of the
 most important risk factors for osteoarthritis (OA) in knees. Numerous longitudinal studies
 show a strong association between obesity, and radiographic knee OA, e.g. in the Framingham
 Study, the Chingford Study, the Baltimore Longitudinal Study of Aging, the John Hopkins
 Precursors Study, and in longitudinal studies in UK and the Netherlands. Thus, the WHO
 initiative on counteracting obesity also accepts OA as a consequence of obesity . Each BMI
 increase by 1 kg/m² is associated with a 15% increased risk of OA. A number of recent studies
 involving the association between obesity and knee osteoarthritis have since been published.
 A large, population-based prospective study (n = 823) conducted by Toivanen et al. with a
 follow-up of 22 years found that the risk for knee osteoarthritis was 7 times greater for
 people with BMI ≥30 compared to the control of people with BMI <25. A prospective cohort
 study of the Norwegian population by Grotle et al. (10) that followed 1,675 patients reported
 that BMI >30 was significantly associated with osteoarthritis of the knee, with odds ratio of
 2.81, and 95% CI of 1.32-5.96. Lohmander et al. found that in a large cohort study of 27,960
 patients from the Swedish population, the relative risk for knee osteoarthritis (fourth
 quartile compared to first quartile) was 8.1, with a 95% CI of 5.3-12.4. Finally, a
 case-control study from Holliday et al. with 1,042 knee osteoarthritis patients and 1,121
 matched controls reported that the adjusted odds ratio for knee osteoarthritis in patients
 with BMI >30 was 7.48 with 95% CI of 5.45-10.27.

 Pain is one of the major comorbid conditions that may preclude effective weight management in
 these patients, particularly with regards to physical activity, since pain increases with
 effort and movement. Obese patients generally receive oral analgesics, such as weak opioids
 or tramadol, but due to a number of associated comorbidities, they generally do not tolerate,
 or have contraindications to, centrally acting analgesics. Furthermore an increasing number
 of obese patients are managed by malabsorbtive bariatric surgical procedures, exposing them
 at risk for inefficacity by oral analgesics, in regards to the malabsorptive effect.

 Therefore alternative therapies, and in particular topical treatments, may be indicated in
 these patients as these drugs have less systemic side effects. The use of such treatments in
 patients with obesity should contribute to facilitate rehabilitation and hence contribute to
 weight loss, which may further help to reduce pain.

 One promising topical treatment is represented by capsaicin. Capsaicin is an agonist of the
 transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel. It is well
 established that capsaicin applied in high concentration to the skin can cause initial
 nociceptor sensitization through its agonistic effects on TRPV1 receptors then subsequently
 acts in the skin to attenuate cutaneous hypersensitivity and reduce pain by a process best
 described as "defunctionalisation" of nociceptor fibres (e.g. temporary loss of membrane
 potential, inability to transport neurotrophic factors leading to altered phenotype, and
 reversible retraction of epidermal and dermal nerve fibre terminals). Evidence suggests that
 the utility of topical capsaicin may extend beyond painful peripheral neuropathies, and that
 this treatment may be particularly relevant in patients with osteoarthritis pain. Thus TRPV1
 is mainly expressed by nociceptive neurons in dorsal root and trigeminal ganglia. However,
 there is increasing evidence that TRPV1 is also expressed in various cell types including
 synovial fibroblasts (SF) from patients with symptomatic osteoarthritis (OA) and thus may
 play a role in non-neuronal mechanisms that might modulate nociception in symptomatic
 osteoarthritis.

 An additional effect of high concentration of capsaicin, which does not involve TRPV1, is a
 direct inhibition of mitochondrial respiration. Furthermore, by using the approach of
 patch-clamp, capsaicinoids (capsaicin and dihydrocapsaicin) have been shown to reversibly
 inhibit the currents of T-type voltage-dependent Ca2+channels, suggesting the effect of
 capsaicinoids on pain relief may also be related to the inhibition of T-type Ca2+ channels.

 Capsaicin is metabolized rapidly by several cytochrome enzymes present in human liver, but in
 vitro studies shows that its metabolism in human skin is quite low. Capsaicin reside at the
 site of action (i.e. skin) relatively unchanged, whereas capsaicin which is transdermally
 absorbed is rapidly eliminated and does not have any systemic effect.

 To date, repeated applications of low dose capsaicin cream at different concentrations
 (0.0125 to 0.25 %) have been found moderately effective in OA of the knee or hand, based on
 the basis of six double or single blind trials with sample sizes ranging from 14 to 200
 patients. However repeated applications of capsaicin cream are difficult on the long term
 particularly because of the burning sensation induced by the cream and the necessity to
 repeat applications several times per day.

 Recently high concentration capsaicin patches (8%) (Qutenza) have been developed for the
 treatment of peripheral neuropathic pain. These treatments induce long lasting analgesic
 effects in these conditions lasting up to an average of 3 months after a 30 to 60 minutes
 application. The burning side effect related to the application of the patch is rapidly
 reversible and very few severe side effects have been reported with this procedure.

 If the primary cause of chronic musculoskeletal pain lies deep within joints and topical
 capsaicin does not provide substantial transdermal delivery, then the apparent efficacy of
 topical capsaicin in lower back pain and OA could be postulated to be by CNS modulatory
 mechanisms. Another possibility is that alterations in, or sensitization of, cutaneous
 nociceptors could be a contributing factor. Such alterations might be driven by unusually
 high concentrations of cytokines or growth factors in joints which could either diffuse some
 distance away from the primary site of inflammation or promote excitatory phenotypes in
 nearby collateral axons. Furthermore there is increasing evidence that TRPV1 expression is
 not limited to primary afferent neurons but that the receptor is expressed in various cell
 types throughout the body. TRPV1 is present in synovial fibroblasts from symptomatic OA and
 RA (rheumatoid arthritis) patients and the receptor can be activated by stimulation with the
 vanilloid capsaicin. It is very likely that capsaicin stimulation does not only induce IL-6
 production but also results in the release of other signalling molecules that may transfer
 the information to other non-neuronal or neuronal cells and thereby contribute to a
 modulation of nociception in the inflamed joint.

 Based on the mechanisms described above, there are reasons to believe that Qutenza may also
 be effective in osteoarthritis pain. To date, there are strictly no data regarding potential
 efficacy and safety of this treatment in osteoarthritis pain in obese patients
Inclusion Criteria:

 -  Enrolled patients will be males or females,

 -  aged over 18 years,

 -  have pain for at least 3 months due to mild to moderate osteoarthritis of the knee
 (meeting American College of Rheumatology clinical and radiographic criteria), of at
 least moderate intensity (pain intensity score over the last 24 hours before enrolment
 ≥ 4/10),

 -  with a BMI above 30 kg/m²

 -  and no other pain conditions accounting for their disability.

 -  The skin will be intact and no blessed.

 -  All female patients should take contraception during all study and at least 30 days
 after closer.

 -  All patients must sign informed consent.

 -  All patients will be recruited from the Department of Nutrition, Ambroise Paré
 University Hospital and treatment will be given during a dedicated day care clinic.

 Exclusion Criteria:

 -  Patients necessitating surgery,

 -  with relative contraindications to capsaicin patches, particularly with unstable
 hypertension or cardiac condition,

 -  past history of capsaicin use will not be included.