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Review
. 2021 Feb 3;26(4):778.
doi: 10.3390/molecules26040778.

Injectable Capsaicin for the Management of Pain Due to Osteoarthritis

James N Campbell  1 , Randall Stevens  1 , Peter Hanson  2 , James Connolly  1 , Diana S Meske  1 , Man-Kyo Chung  3 , Benedict Duncan X Lascelles  4   5   6
Affiliations
Review

Injectable Capsaicin for the Management of Pain Due to Osteoarthritis

James N Campbell et al. Molecules. .

Abstract

Capsaicin is a potent agonist of the TRPV1 channel, a transduction channel that is highly expressed in nociceptive fibers (pain fibers) throughout the peripheral nervous system. Given the importance of TRPV1 as one of several transduction channels in nociceptive fibers, much research has been focused on the potential therapeutic benefits of using TRPV1 antagonists for the management of pain. However, an antagonist has two limitations. First, an antagonist in principle generally only affects one receptor. Secondly, most antagonists must have an ongoing presence on the receptor to have an effect. Capsaicin overcomes both liabilities by disrupting peripheral terminals of nociceptive fibers that express TRPV1, and thereby affects all of the potential means of activating that pain fiber (not just TRPV1 function). This disruptive effect is dependent on the dose and can occur within minutes. Thus, unlike a typical receptor antagonist, continued bioavailability at the level of the receptor is not necessary. By disrupting the entire terminal of the TRPV1-expressing nociceptive fiber, capsaicin blocks all the activation mechanisms within that fiber, and not just TRPV1 function. Topical capsaicin, an FDA approved treatment for neuropathic pain, addresses pain from abnormal nociceptor activity in the superficial layers of the skin. Effects after a single administration are evident over a period of weeks to months, but in time are fully reversible. This review focuses on the rationale for using capsaicin by injection for painful conditions such as osteoarthritis (OA) and provides an update on studies completed to date.

Keywords: TRPV1; cooling; defunctionalization; disruption; intra-articular; knee; nociceptive fiber; nociceptor; primary afferent.

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Conflict of interest statement

J.N.C., R.S., J.C. and D.S.M. are employees of Centrexion Therapeutics, a company developing novel, nonopioid therapeutics for pain, including capsaicin. P.H. is a former employee of Centrexion Therapeutics. B.D.X.L. is a paid consultant of Centrexion Therapeutics. M.-K.C. has received research funding support from Centrexion Therapeutics.

Figures

Figure 1
Figure 1
(Reprinted from [17], Copyright 1998 Society for Neuroscience) Confocal images of human epidermal biopsies from one individual who received vehicle and varying doses of capsaicin. Nerve fibers (N) immunoreactive for PGP 9.5 appear yellow-green, and basement membrane (B) and vessels (V) appear red. Biopsies were taken 72 h after injection of vehicle (Veh) or capsaicin doses of 0.2, 2.0 or 20 μg. After the lowest dose of capsaicin, loss of PGP 9.5-immunoreactive nerve fibers was restricted to fibers located in the epidermis. Higher doses of capsaicin resulted in complete loss of PGP 9.5-immunoreactive epidermal nerve fibers plus various degrees of disruption or complete loss of the subepidermal nerve plexus. Scale bars = 100 μm.
Figure 2
Figure 2
(Reprinted with permission from [39]) Plot of the change from baseline in average weekly WOMAC pain with walking scores through week 24 in patients treated with intra-articular capsaicin (CNTX-4975, specifically) versus placebo is shown. A mixed model for repeated measures was used in the modified intent-to-treat population. Week 12 was the prespecified landmark endpoint. Baseline scores (range 0–10): placebo 7.4, CNTX-4975 0.5 mg 7.2, CNTX-4975 1.0 mg 7.2. * = P < 0.1; † = P < 0.05; ‡ = P < 0.001 versus placebo.
Figure 3
Figure 3
Procedural pain was significantly and positively, associated with intra-articular (IA) temperature. In each of 13 individuals with knee OA, different techniques for cooling the left and right knee joints were used, resulting in varying IA temperatures (measured by an IA temperature probe). IA lidocaine, followed by capsaicin (1mg), was administered and procedural pain (on a Numerical Pain Rating Scale, NPRS) and IA temperature were measured at intervals following the injections. The plot of NPRS versus IA temperature demonstrated a positive (r = 0.51) and significant (P = 0.008) correlation. These data support the use of joint cooling as a means to decrease procedural pain associated with IA capsaicin injection. Number of subjects = 13; both knees represented for each subject.
Figure 4
Figure 4
Graph of the change in pain while walking (assessed using an 11-point NPRS on a scale of 0–10) in patients with bilateral knee OA undergoing treatment of the index knee (n = 523) and treatment of the nonindex knee (n = 427). This second injection in the opposite knee was performed 8 days after the first injection into the index knee. The magnitude in pain reduction was similar for the index and nonindex knee.
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