Upperline Health

Michael King

Peripheral neuropathy is potentially a very painful, debilitating problem that affects a large number of the population. More than 20 million people in the United States have been estimated to have some form of peripheral neuropathy, but this figure may be significantly higher—not all people with symptoms of neuropathy are tested for the disease and tests currently do not look for all forms of neuropathy. Neuropathy is defined as: disease or dysfunction of one or more peripheral nerves, typically causing numbness or weakness. This numbness, although strangely, can be incredibly painful as well. The dysfunction has been proven to lead to unstable gait, risks of falls, development of open sores (ulcers), and even loss of limb. Diabetic peripheral neuropathy, or DPN, is the most well-known version of this horrible disease state.

The annual costs of DPN and its complications in the U.S. were 0.8 billion US dollars (type 1 diabetes), 10.1 billion US dollars (type 2 diabetes), and 10.9 billion US dollars (total). After allowing for uncertainty in the point estimates of complication rates, the range of costs were between 0.3 and 1.0 billion US dollars (type 1 diabetes), 4.3b and 12.7 billion US dollars (type 2 diabetes), and 4.6 and 13.7 billion US dollars (type 1 and type 2 diabetes).

The total annual cost of DPN and its complications in the U.S. was estimated to be between 4.6 and 13.7 billion US dollars. Up to 27% of the direct medical cost of diabetes may be attributed to DPN.

There are finally some non-invasive options available with no real adverse effects reported. This relatively new 8% topical system is a non-opioid, non-systemic, non-steroidal treatment that is applied by a healthcare provider (in the office) and covered as a medical benefit that can be used with or without an adjunct procedure or treatment. Eight percent capsaicin is a topical treatment option FDA approved for neuropathic pain associated with post-herpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN) of the feet. By virtue of its innovative technology, over the relatively short application period of 30 min (for DPN) or 60 min (for PHN) a sufficiently high amount of capsaicin is released into the skin to provide long-term pain relief for up to 3 months. This therapy provides rapid and durable local pain relief by inhibiting sensations from TRPV1- expressing cutaneous neurons, and by directly and reversibly inactivating pain-sensing neurons that cause the neuropathic pain associated with PHN and DPN. As systemic absorption of capsaicin is negligible, topical treatment with 8% capsaicin is generally well tolerated, with no systemic adverse drug reactions, potential drug-drug interactions, contraindications, or need for dosage adjustments in special populations; making this a breakthrough in the treatment of DPN in particular.

“Peripheral neuropathy is potentially a very painful, debilitating problem that affects a large number of the population”

Each 280 cm2 topical system contains a reservoir of a total of 179 mg of capsaicin (equivalent to 640 μg/cm2). Unlike conventional transdermal patches, this innovative topical system works locally on the skin, with minimal systemic absorption. The brilliance of the topical system technology is that, during the relatively short application of this treatment, the rate of release of capsaicin from the topical system allows absorption of a cutaneous reservoir of capsaicin sufficient to provide long-term pain relief for up to 3 months.

Mechanism of Action

Capsaicin is a highly selective agonist for the transient receptor potential vanilloid-1 receptor (TRPV1), which is an ion channel receptor complex expressed on small-diameter sensory neurons, especially those nerve fibers that specialize in the detection of painful or noxious sensations. When capsaicin binds to the receptor, the TRPV1 calcium channel opens, and calcium enters the intracellular space.

The prolonged exposure of small-diameter sensory neurons to small doses or short exposures to high doses of capsaicin result in a “desensitization” or “defunctionalization” of the nerve terminals. The high concentration of intracellular calcium overwhelms the mitochondria, leading to reversible dysfunction and nerve terminal death6. Robust reduction of epidermal nerve fiber density (ENFD) after the application of high concentrations of capsaicin in human skin was shown by staining skin biopsies with a pan-axonal marker, PGP 9.5.

Clinical Evidence in PDPN:

The efficacy of this therapy was established in the study STEP, which was a 12-week, double-blind, randomized, placebo-controlled, multicenter study. Both treatments were applied as a single, 30-minute application. The percent change in average pain from baseline to Week 12 was higher in the 8% capsaicin group−30% (±3%) compared to the placebo group −22% (±3%). More patients achieved a ≥30% reduction in pain from baseline: 40.9% responders with 8% capsaicin vs 31.7% responders with placebo at Weeks 2–12 (P=0.050). In STEP, the 8% capsaicin patch was shown to provide sustained pain relief and a faster time to treatment response vs placebo in adult patients after a single application.

Another study, the PACE study assessed the long-term safety and efficacy of repeated QUTENZA treatments plus SOC vs SOC alone over 52 weeks in patients with PDPN. The PACE study is a phase 3 randomized, controlled open label. During this period, QUTENZA repeat treatments plus SOC in patients with PDPN was well tolerated; patients had no functional neurologic decline and there were no other safety concerns. Also, although it was not the primary outcome of the study, efficacy data for the PACE study demonstrated that there was a greater proportion of patients with PDPN relief in the QUTENZA group compared with SOC alone, further sustained with long-term treatments.

Clinical safety

Such treatment is well tolerated. The most common adverse reaction (≥5% and greater than control) in all controlled clinical trials are application site erythema, application site pain, and application site pruritus. Pretreatment with topical analgesic medications is recommended to preempt application site discomfort. Local cooling methods, including cool packs and/or appropriate analgesic medication, can be used to treat acute pain during and following the application procedure. In the STEP and PACE study the majority of application site reactions were transient and self-limited. A majority of treated patients in clinical trials (performed by Averitas Pharma) that had any adverse reactions reported a maximum intensity of “mild” or “moderate”.