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15 Articles in Volume 21, Issue #4
Advanced Practice Matters: Needs Assessment in Pain Management Training
Analgesics of the Future: Novel Capsaicin Formulation CNTX-4975
Ask the PharmD: How to Improve Medication Adherence in Chronic Pain Management
Behavioral Medicine: Applying Mindfulness-Based Stress Reduction for Comorbid Pain and PTSD
Case Report: Multimodal Management of Osteoarthritis
Commentary: The PCP's Role in Preventing Chronic Back Pain
Guest Editorial: Structural Racism in Pain Practice and How to Combat the “Hidden Curriculum”
Hypermobile Ehlers-Danlos Syndrome: An Update on Therapeutic Approaches for Pain Management
Male Clinicians as Allies in Women’s Leadership: What Your Female Peers Want You to Know
Meet the Women Changing Pain Medicine
Perspective: It’s Time to Advocate for Early Interventional Pain Management
Research Insights: Is Spinal Fusion Surgery Being Overused in Back Pain Care?
Tips from the Field: Treating Pain in an Under-Resourced State
Utilizing Music Therapy to Manage Chronic Pain
Woman to Woman: Leaders Share Advice for the Next Generation of Pain Medicine Clinicians

Analgesics of the Future: Novel Capsaicin Formulation CNTX-4975

This intra-articular injection is being studied for pain relief in osteoarthritis of the knee and Morton’s neuroma.

Capsaicin Formulation CNTX-4975 Snapshot

Product/Class: CNTX-4975 (high-purity synthetic trans-capsaicin), intra-articular injection from Centrexion Therapeutics

Dosage and Frequency: 0.5 mg or 1.0 mg injection; studied as a one-time injection or administered every 6 months; Elimination half-life < 4 hours; most commonly reported side effects in trials to date:

  • analgesic effects restricted to the joint
  • arthralgia
  • upper respiratory tract infection
  • increased hepatic enzyme
  • joint effusion

Potential Indications: Chronic moderate-to-severe osteoarthritis (OA), associated knee pain; pain associated with Morton’s neuroma

Timeframe/Status: Concluding Phase 3 trials

 

Capsaicin Formulations: An Overview

Topical capsaicin formulations are available both over-the-counter and by prescription for pain management. Over-the-counter formulations include creams, patches, liquids, lotions, and gels as capsaicin alone or combined with other agents. Capsaicin ranges in concentrations from 0.025% to 0.25%, and is labeled for musculoskeletal, arthritic, or neuropathic pain. Frequency of application is three to four times daily. The most notable side effect for these products is local skin irritation that often leads to discontinuation.1

Qutenza (capsaicin 8% patch) is a prescription-only formulation of capsaicin that is FDA-approved for postherpetic neuralgia and neuropathic pain associated with diabetic peripheral neuropathy of the feet.2 Qutenza is applied by a healthcare provider for 30 minutes to feet or 60 minutes to other approved areas, and administration can be repeated after 3 months. The most frequent adverse drug events for the Qutenza patch include initial application site pain, burning sensation, and erythema, all of which subside.3,4

Capsaicin is the active compound in hot chili peppers; it is what causes the pepper to feel hot when consumed.5 It is an agonist at the transient receptor potential vanilloid type 1 (TRPV1 receptor), a nonselective, cation channel that is an integrator of noxious chemical and physical stimuli.6 TRPV1 is expressed in small- and medium-diameter nociceptor sensory neurons, and plays a role in visceral sensation.6 It is proposed that defunctionalization of nociceptor fibers causes its analgesic effect, wherein cutaneous nociceptors have reduced spontaneous activity and loss of responsiveness to sensory stimuli.7 Nociceptors regenerate after weeks to months, and in the meantime, there is attenuation of pain sensibility.8

A novel intra-articular formulation of capsaicin, CNTX-4975, is in development for the treatment of osteoarthritis of the knee and pain associated with Morton’s neuroma. Of those aged 65 years or older, 49.6% report arthritis; this risk increases with age.9 Current guideline-recommended pharmacologic options for knee osteoarthritis include oral and topical NSAIDs, intra-articular steroids, acetaminophen, tramadol, duloxetine, and topical capsaicin.10

However, a majority of current medications have adverse effect profiles that may preclude patients with certain comorbidities from using them and limit options. Intra-articular capsaicin could provide an effective, well-tolerated option for patients with knee osteoarthritis pain (see also, a new case report on treating OA knee pain). Morton’s neuroma is a degenerative neuropathy featuring fibrosis of the common interdigital nerve. Treatment consists of conservative measures initially including avoiding tight shoes, avoiding high-heels, and orthotics. If this fails, local anesthetics, corticosteroids, or radio-frequency ablation may be used. Surgical treatment is last line, as it is more invasive and comes with higher complication rates.11

Note that another formulation of capsaicin, vocacapsaicin, is also in development. 

The Data on CNTX-4975

CNTX-4975 is an intra-articular formulation of highly purified trans-capsaicin, developed for osteoarthritis of the knee12 and pain associated with Morton’s neuroma. In January 2018 the FDA granted it Fast Track designation for the treatment of pain associated with knee osteoarthritis. It had previously been granted orphan drug designation and Fast Track designation by the FDA for treatment of Morton’s neuroma pain.13This injection is expected to provide long-term analgesia (lasting at least the time it takes for regeneration of nociceptors) with brief systemic exposure and rapid onset of action. The effects are likely to be limited to the joint area. Pharmacokinetic data were not available at the time of this writing.

Treating Osteoarthritis with Intra-Articular Capsaicin: TRIUMPH and VICTORY Trials

The TRIUMPH study is a phase IIb randomized, double-blind, placebo-controlled dose-ranging trial to evaluate the 24-week efficacy and safety of a single 0.5 mg or 1.0 mg injection of CNTX-4975 in patients with chronic, stable, moderate-to-severe knee osteoarthritis with unsuccessful previous treatment.12 The trial enrolled adults aged 45 to 80 years who had a BMI less than or equal to 45 kg/m2, radiographic evidence of chronic OA in the index knee (Kellgren-Lawrence grade 2-4), moderate-to-severe pain in the index knee stable for greater than or 2 months prior to screening, a mean pain score of 5-9 at screening and baseline day 1 according to the pain with walking question in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and an inadequate response or adverse event resulting in discontinuation of prior treatment that was standard-of-care (systemic NSAIDs, opioid analgesics, intra-articular glucocorticoid, or hyaluronic acid).14

Those enrolled (n = 157) who met inclusion criteria were randomly assigned in a 2:1:2 ratio to three treatment groups of placebo, CNTX-4975 0.5 mg, or CNTX-4975 1.0 mg and stratified across treatment groups by K-L grade. Patients, investigators, and study personnel involved in the conduct of the study were blinded. Participants received a single treatment on day 1 and then had a 24-week follow-up period. Participants were premedicated according to the investigator’s discretion, with a maximum of two premedications (opioid, NSAID, or local anesthetic).

For administration of the study medication, subjects had 15 minutes of joint cooling with a wrap placed around the knee, then were administered 15 mL intra-articular 2% lidocaine. The lidocaine helps to achieve the targeted concentration of capsaicin, improve distribution of capsaicin in the joint, and decrease the injection-site pain initially. Cooling was reapplied for 30 minutes, then a single intra-articular injection of placebo, CNTX-4975 0.5 mg or 1.0 mg was administered. Cooling was removed for injection then reapplied immediately for 30 minutes to 1 hour afterward.

The primary efficacy outcome was the area under the curve (AUC) change from baseline to week 12 in daily WOMAC pain with walking scores in patients with CNTX-4975 versus placebo. Secondary endpoints included a similar AUC analysis of scores in patients treated with 0.5 mg CNTX-4975 and at 24-weeks. Outcomes were analyzed by analysis of covariance.

The mean baseline scores for pain with walking were 7.4 in the placebo group, 7.2 in the CNTX-4975 0.5 mg group, and 7.2 in the CNTX-4975 1.0 mg group. For the primary efficacy outcome of AUC change from baseline to week 12 in daily WOMAC pain with walking scores, CNTX-4975 1.0 mg group compared to placebo had a significant least-squares mean difference of –1.6, P < 0.0001 (90% confidence interval –2.2, -1.0). Results are displayed in Table I below.

For secondary endpoints, the AUC analysis of scores in patients treated with 0.5 mg CNTX-4975 compared to placebo has a significant least square mean difference of –0.8, P = 0.07 (90% confidence interval –1.5, -0.06). The AUC from baseline through week 24 in daily WOMAC pain with walking scores  reached significance for the 1.0 mg dose (LSMD –1.4 [90% CI –1.9, -0.77], P < 0.001), but not for the 0.5 mg dose compared to placebo (LSMD –0.6 [90% CI –1.3, 0.15, P = 0.19). The NNT for greater than or equal to 50% pain improvement for CNTX-4975 1.0 mg dose at 12 weeks was 3.6 and at 24 weeks was 10.3. Onset of improvement was stated to be rapid by the authors, and a significant reduction in pain with walking was noted as early as one week after treatment.

 

The most common adverse events were arthralgia, upper respiratory tract infection, increased hepatic enzyme, joint effusion, and osteoarthritis. The number needed to harm (NNH) at 12 and 24 weeks with the 1.0 mg dose of CNTX-4975 was 58 and 237 patients. Other treatment-emergent adverse events seen during this trial are summarized in Table II.

An important clinical program examining the effects of CNTX-4975 is the Phase 3 VICTORY clinical program, which includes the VICTORY-1, VICTORY-2, and VICTORY-3 trials.15 The VICTORY-1 and VICTORY-2 trials are pivotal Phase 3 randomized, double-blind, placebo-controlled, 52-week studies to evaluate the safety and efficacy of CNTX-4975 injections in patients with chronic moderate-to-severe osteoarthritis of the knee.16 The VICTORY-1 trial is specifically looking at a single injection, while the VICTORY-2 trial is specifically examining repeated doses, administered at 6 months apart. The VICTORY-3 trial is currently active and is an open-label, eight-week trial evaluating the tolerability of a single 1.0 mg intraarticular injection of the medication.

One challenge of injecting capsaicin is the induction of transient discomfort and pain.17 Pre-injection of lidocaine was found to be helpful, and cooling systems have been reported to reduce post-injection pain. VICTORY-3 is also evaluating 5 different techniques of the procedure of injection (ie, circumferential cooling, one vs. two needles for injection of lidocaine and capsaicin), which will allow physicians to select patient-individualized options for injection techniques should CNTX-4975 become FDA-approved.15

Preliminary findings were reported in the fall of 2020 at the American Society of Interventional Pain Physicians (ASIPP) virtual meeting.18 In total, 848 participants with moderate-to-severe OA knee pain received unilateral or bilateral CNTX-4975 1.0 mg intra-articular injections. A total of 427 out of 523 participants who had bilateral pain received bilateral capsaicin injections. On a 10-point numerical pain rating scale (NPRS), mean baseline scores for pain with walking were 7.4 in the index knee and 6.1 in the non-index knee.

Participants with bilateral knee OA pain who received the CNTX-4975 injection had less pain when walking. Effects were seen as early as in 3 days in the index knee, with a mean change from baseline in NRPS score -4.21, 95% CI -4.41 to -4.01, P < 0.0001. In the non-index knee, reductions were seen as early as 8 days plus the 3 days, mean change from baseline in NRPS score -3.84, CI -4.02 to-3.65, P < 0.0001. These effects were maintained by the end of the open-label trial at 8 weeks.

In reference to circumferential cooling wraps, VICTORY-3 showed equivalent effects between ice water or gel-based wraps. The trial showed that the use of two separate needles, one to inject lidocaine and one to capsaicin, separated by 30 minutes was no better than cooling and using one needle total to inject lidocaine first, then capsaicin. Based on adequate pain and satisfaction scores, it was determined that all cooling and administration techniques in the VICTORY-3 trial were clinically acceptable. Adverse effects have not yet been reported. Overall, the findings support those of the Phase 2 TRIUMPH study described above.

Morton’s Neuroma and Intra-Articular Capsaicin

Besides OA, CNTX-4975 is also being studied for Morton’s neuroma, a thickening of the tissue around one of the nerves leading to the toes that causes pain in the foot and numbness in the toes. Two separate Phase 2 trials were completed to determine the efficacy and safety of CNTX-4975 in relieving neuroma foot pain, however, results have not been posted.19,20

Discussion: Non-Opioid Treatment Options for Knee OA

Non-opioid treatment options have become an important area of research, especially with an increasing prevalence of other comorbidities and warnings that limit the use of various non-opioid alternatives. Information on capsaicin is growing, with the most recent FDA-approved formulation being the Qutenza (R) 8% patch approved in 2009 for the management of neuropathic pain associated with postherpetic neuralgia and extended to painful diabetic neuropathy in 2019. Other formulations and indications are currently being studied. This article focuses on  -4975 (intra-articular capsaicin injection) for knee osteoarthritis and Morton’s neuroma.

CNTX-4975 at doses of 0.5 mg and 1.0 mg has been shown through the TRIUMPH trial to be significantly efficacious in 12 weeks vs. placebo in terms of change in WOMAC pain with walking scores. Additionally, the 1.0 mg dose showed the same efficacy in 24 weeks vs. placebo. An important takeaway from the trial was that onset of improvement after the CNTX-4975 injections was noted to be rapid, seen at one week after treatment.

Preliminary results of the VICTORY-3 trial presented at the ASIPP virtual meeting support the results of the TRIUMPH trial. The VICTORY-3 trial aimed to assess administration techniques of CNTX-4975, in addition to efficacy for bilateral knee pain. This trial showed a decrease in mean pain with walking scores with 1.0 mg intra-articular injections of CNTX-4975. Similar to the TRIUMPH trial, onsets of improvement with the injections were noted to be rapid, with decreases in pain with walking scores as early as 3 days after the injection in the index knee and 8 days plus the 3 days for the non-index knee.

To decrease procedural pain, the VICTORY-3 trial also evaluated 5cooling and administration techniques. All were determined to be acceptable. Notably, there were equivalent effects between ice water or gel-based wraps. The use of two separate needles, one to inject lidocaine and one to inject capsaicin separated by 30 minutes, was found to be no better than cooling and using one single needle to inject lidocaine, then capsaicin.

Current data from the TRIUMPH trial show CNTX-4975 to be well tolerated. Adverse effects seen include arthralgia, upper respiratory tract infection, increased hepatic enzyme, joint effusion, and osteoarthritis. Notable is the NNH at 12 and 24 weeks with 1.0 mg dose was 58 and 237. This is much higher than for low concentration topical formulations of capsaicin, where the NNH for local adverse effects is 2.5 (2.1 - 3.1). No adverse effects have yet been reported with the VICTORY-3 trial.

It also notable that these injections are hypothesized to have a long duration of action, even after plasma levels decrease and the medications are out of patients’ systems. Although more data is needed in this area, longer effects have been seen with CNTX-4975 so far in comparison to over-the-counter topical formulations, which often have to be applied several times daily for maximum benefit. While Qutenza is applied every 3 months, it does not have an FDA indication for osteoarthritis.

Overall, CNTX-4975 is another therapeutic option to treat knee osteoarthritis and Morton’s neuroma. It appears to be well tolerated and effective; however, the injections must be performed by a healthcare provider, which may be less convenient. More data is also needed on the pharmacokinetics of these new capsaicin injections. Based on current available data, the effects of this medication may last as long as 24 weeks with a 1.0 mg injection, which may be even more appealing than 12-week injections. Ultimately, intra-articular capsaicin may offer an effective therapeutic option for patients with comorbidities that limit the use of other treatments. 

 

Experts Weigh In: Review by PPM Editors-at-Large Jeff Gudin, MD, and Jeffrey Fudin, PharmD

With the American Academy of Family Practice and American College of Physicians 2020 guidelines for the treatment of non-low back musculoskeletal pain calling for first-line use of topical analgesics, there has been a renewed interest in capsaicin as an analgesic. Drs. Zhang, Muzzio, and Dragic do a great job herein reviewing CNTX-4975, a novel capsaicin formulation that is administered intra-articularly. There appears to be an unmet need in this arena, as the debate remains regarding the long-term effectiveness of intraarticular corticosteroid or visco-supplementation.

Many patients are not optimal candidates for NSAIDs or surgical intervention, and often fail acetaminophen and physical therapy modalities. Having an injectable capsaicin for these patients would be a welcome addition to our analgesic arsenal. FDA approval of this product would support the efficacy and safety noted in the clinical trials. We give this product a 4.5-star rating (out of 5) for being novel, effective, safe, and filling an unmet need in OA pain management.

*Star-rating based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewer’s expertise and opinion. 

 

Prior Analgesics of the Future Columns

Last updated on: September 8, 2021
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