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12 Articles in Volume 21, Issue #2
Advanced Practice Matters with Theresa & Jeremy: MAT and the DATA Waiver Debate
Analgesics of the Future: The Potential of Vocacapsaicin Injections for Knee Pain
Authorities Update Opioid and Naloxone Prescribing Policies as Overdoses Soar
Autologous Adipose-Derived Biocellular (Stem Cell-Rich) Prolotherapy into Hoffa’s Fat Pad Improves Knee Osteoarthritis
Behavioral Medicine: How to Utilize Acceptance and Commitment Therapy in Primary Care
Case Report: How We Grew Our Pain Practice Amidst Pandemic, Opioid Crisis
Chronic Overlapping Pelvic Pain Disorders: Differential Diagnoses and Treatment
Fentanyl Transdermal Patch: Variability is Key When Prescribing
Optimizing Opioid Therapy with Pharmacogenetics
Research Insights: Advances in Shoulder Arthroplasty and Revision Surgery
Research Insights: How to Address Osteoarthritis Treatment Gaps in Women
Topical Anti-Inflammatories: Analgesic Options for Arthritis Beyond NSAIDs

Analgesics of the Future: The Potential of Vocacapsaicin Injections for Knee Pain

The data behind vocacapsaicin’s ability to provide effective analgesia and opioid-sparing in knee osteoarthritis, knee pain, and postsurgical pain.

Vocacapsaicin (CA-008) Snapshot

  • Product/Class: Vocacapsaicin (CA-008, Concentric Analgesics) is a first-in-class non-opioid, water-soluble injectablethat rapidly converts to capsaicin, a potentTRPV1-agonist
  • Features: When injected into surgical sites, vocacapsaicin is rapidly converted to lipophilic capsaicin and can cross the membranes to reach the desired amino acid target on TRVP1 channels
  • Potential Indication: Perioperative pain management, opioid alternative 
  • Expected Market Entry: FDA has granted CA-008 Fast Track Designation (2017) and Breakthrough Therapy Designation (2018); Phase 2 trial data on its use in total knee arthroplasty was published in January 2021 
  • Star Rating: 4.5 out of 5 STARS (see full review below)

 

Background

Postoperative Opioids for Inpatient Surgery

Approximately 51 million Americans undergo inpatient surgery each year. For many years, traditional postoperative pain management options have consisted primarily of select opioid therapies indicated for the relief of moderate to severe pain. A study from 2004 to 2012 evaluated the use of opioids prescribed in patients who underwent low-risk surgical procedures. The findings indicated that, within 7 days of surgery, 80% of these patients filled a prescription for an opioid, and more than 86% of the opioids prescribed consisted of either oxycodone or hydrocodone in combination with acetaminophen.1

Since 1999, the rate of opioid-related overdoses has tripled and is continually increasing across our country; giving rise to a dangerous and ongoing national public health crisis.2  Initial opioid use has weight in the likelihood for long-term opioid use. The CDC reported that any initial opioid use greater than 8 days increased the rate of long-term opioid use to 13.5%. The rate increased to 29.9% when the first episode of opioid use was greater than 31 days.3

Acknowledging the risks of using opioids for pain management postoperatively, perioperative care teams face difficult decisions in ensuring appropriate pain relief. The Guidelines on the Management of Postoperative Pain, published in 2016 by several accredited pain and anesthesiology groups, recommends multimodal regimens and to consider several patient specific factors such as the setting, patient, and surgical procedure to find the best individualized treatment plan.  The guidelines also go onto outline a systematic pharmacologic approach to therapy that includes opioids, NSAIDs and/or acetaminophen, gabapentin or pregabalin, and IV ketamine.4

NSAID use should be not be relied on as a large population of patients have contraindications to the therapy; those at risk range from the elderly, gastrointestinal sensitive, renally impaired, and at-risk cardiovascular patients. The limited selection of adequate analgesic therapies leaves little to no room in selecting non-opioid therapeutics for pain management regimens where opioids may not be appropriate, tolerated, or desired.

Pain Management for Knee Replacement: Current Approaches

Total knee arthroplasty (TKA) is a common procedure done to relieve joint pain of osteoarthritis (OA) or rheumatoid arthritis (RA) etiology. Postoperative pain impacts rehabilitation and time to resumption of activities of daily living. Multimodal analgesia methods are being reviewed and trialed as a safer option than opioids for managing postoperative pain.

COX-2 inhibitors, for example, when used preoperatively and perioperatively have been shown to have opioid-sparing effects in patients undergoing TKA.5 Additionally, local infiltration analgesia (LIA) – composed of a mixture of agents including ropivacaine or immediate or prolonged-release bupivacaine – are showing promising results for postoperative pain management based on the visual analog scale (VAS).6

Femoral nerve block is considered the standard of care for pain management after TKA. The analgesic effects reduce opioid consumption and length of hospital stay. However, side effects such as blood vessel damage and nerve damage, are of concern with the procedure.7 Spinal anesthesia has increasing evidence revealing its benefit for wound infections, length of surgery, and postoperative length of hospital stay.8 Infiltration between the popliteal artery and capsule of the knee (IPACK) is a technique of controlling the posterior knee pain common after joint replacement by an anesthesiologist delivering analgesics in this specific anatomical location. When this method is used in TKA patients, it has demonstrated lower pain scores postoperatively.9

Capsaicin

Capsaicin, a chemical compound isolated from chili peppers, has been used medicinally since its discovery in the late 19th century. Following its early isolation from the pepper into crystalline form, scientists discovered the burning sensation generated by the compound when exposed to mucous membranes. Currently, capsaicin is an FDA approved staple in self-care and over-the-counter medicine. It is available in topical form for use on the skin to relieve pain for multiple indications, including arthritis and musculoskeletal injury.10

Capsaicin works primarily by binding to TRPV1 channels, leading to depolarization of nociceptive neurons. By binding to TRPV1 channels, capsaicin is able to activate the channels and lead to their desensitization.11 Small-scale studies have demonstrated the benefits of capsaicin instillation perioperatively on pain scores and decreased opioid use, however, this practice is not routinely incorporated into perioperative care.12

The reason for TRPV1 agonists not being used perioperatively is likely due to potential adverse events and difficulty of managing its pharmacokinetic formulations.

TRPV1 Channels and Analgesic Mechanism of Action

TRPV1 channel are a subclass of ion channels of the TRP (transient receptor potential) family. TRVP1 is expressed in all sensory ganglia, the CNS, as well as C and Aδ fibers. The channels contain six transmembrane domains that assemble to form cation selective channels with several phosphorylation sites, voltage-gated potassium channels, and single amino acid residues that allow agonists, such as capsaicin, to activate the channel.13

TRVP1 activation in nociceptive neurons releases neurotransmitters and potentiates an action potential to higher CNS areas that are perceived as pain. Channel activation also leads to release of pro-inflammatory molecules that can sensitize other neurons to stimuli. Capsaicin – a TRPV1 agonist – is a lipophilic compound that is able to cross cell membranes and bind to residue Tyr511 in order to activate the channel.

Tyr511 is an amino acid residue that is responsible for the hydrophobic interactions with one of the binding sites of capsaicin. After capsaicin binds, the TRPV1 channels open and Ca2+ is permeable. Ca2+ then binds to calcium-calmodulin, which causes desensitization by inducing a closed state of the TRPV1 channel.13

Enter Vocacapsaicin (CA-008)

Vocacapsaicin (CA-008, Conentric Analgesics) – an investigational TRPV agonist being studied for long-lasting pain – works through the same TRPV1 agonism mechanism but its localized delivery is thought to minimize activation of a large array of neurons, such as capsaicin topical products.14

Often, capsaicin is formulated in topical creams due to the rapid metabolism when consumed orally. The nature of the mechanism of TRPV1 agonists often causes heat sensitivity, erythema, and acute hyperalgesia.15 A recently formulated capsaicin 8% topical system (Qutenza, Averitas Pharma), for instance, demonstrated significant reductions in numeric pain rating scales but not benignly. At the application site, 63% of patients experienced erythema and 42% experienced application site pain.16

Concentric Analgesics’ vocacapsaicin (CA-008) has had promising Phase 2 results for pain reduction and reduction in opioid use following TKA when used concomitantly with a standard of care regimen. Of note, as of March 2021, the side effect profile released was not significantly different than current standard of care. FDA has granted this agent breakthrough therapy designation for postoperative pain.14

CA-008 is a hydrophilic molecule that is a prodrug of capsaicin. When injected into surgical sites via aqueous solution, it is rapidly converted to lipophilic capsaicin and can cross the membranes to reach the desired amino acid target on TRVP1 channels. Vocacapsaicin has shown the potential to reduce, and in some patients, eliminate the need for opioids in the postsurgical recovery period and provide clinically meaningful pain relief for 1 week or more (more below).

The Data on Vocacapsaicin (CA-008)

A recently completed Phase 2 clinical trial of vocacapsaicin displayed significant pain reductions in patients undergoing TKA. The study was randomized, double-blinded, and placebo-controlled.

Every TKA patient received standard of care treatment, which included spinal anesthesia, ketorolac, acetaminophen, and ropivacaine in the form of joint filtration, femoral nerve, and IPACK blocks. Two intervention arms included administration of vocacapsaicin 36 mg (n = 61) and vocacapsaicin 60 mg (n = 62), each given via infiltration to the surgical site. The control arm (n = 64) received the standard of care regimen as well as opioid rescue as needed. The primary outcome was pain reductions  recorded based on the numerical rating scale (NRS). The NRS is an 11-point scale with “0” being no pain and “10” being the most intense pain imaginable. The number being selected is expressed verbally by a patient based on the pain they have experienced in the last 24 hours.6

Pain reductions at rest – expressed when vocacapsaicin 36 mg was delivered – are displayed in Table I. Pain reductions with ambulation – when vocacapsaicin 36 mg was delivered – are expressed in Table II. 


 


 

Opioid consumption was significantly reduced among the vocacapsaicin 36-mg arm following a period of 96 hours and 168 hours after administration. Concentric Analgesics noted consistently better results with vocacapsaicin 36 mg compared to vocacapsaicin 60 mg. In light of side effect profiles, parameters among the intervention arms and control arm appeared consistent. Neither local nor systemic safety concerns were identified in the Phase 2 trial.14 A manuscript has yet to be published so further explanations of data including exclusion and inclusion criteria, definitions of AUC, specific adverse events, and rates, are not available. Further information will be welcomed to adequately assess the utilization of this therapy.

Among a previous Phase 2 study of CA-008, Concentric Analgesics reports significant pain reductions for up to 1 week post bunionectomy at a dose of 4.2 mg. The longest data that had been reported from both the TKA study and the bunionectomy study was opioid use within the 28-day observation period. In the first Phase 2 study of the 4.2 mg dose of CA-008 in bunionectomy patients, 26% of patients in the intervention arm were opioid free during the full 28-day period, whereas only 5% of patients (P = 0.039) remained opioid-free in this time frame in the control group.17

Discussion 

An injectable, non-opioid therapy that promises effective pain relief while reducing the need for postoperative opioid consumption is not only innovative but widely needed in the world of pain management and postoperative care. Current postoperative care regimens still require the need for rescue opioid medication.7-9 The ability of vocacapsaicin to decrease opioid intake when added on to operative regimens contributes to its potential.14

Vocacapsaicin infiltration has the ability to contribute further to the multimodal analgesic approach postoperatively. Desensitization of the TRPV1 channel via infiltration is novel to the operative world, but the mechanism itself has already demonstrated benefit in the postoperative setting.18 The pain reduction and opioid sparing effects seen 1 week postoperatively in TKA patients offer significant benefit and compelling reasons for use. Decreased pain scores can lead to decreased length of hospital stay and decreased time to activities of daily living. It also goes without saying that the reduction in opioid use can greatly help in the fight against the opioid crisis. 

This medication yielded significant results in the acute setting of postoperative pain, but its mechanism of desensitization offers hope for potential utilization of osteoarthritic pain outside of the operative setting in chronic circumstances. Mechanistically, the desensitization of TRPV1 ion channels should lead to increased analgesic effects, as the analgesia arises from continually decreased ability of neuronal signaling. Additionally, the long-lasting effects of other TRPV1 agonist therapies, such as the Qutenza topical system lasting 3 months, suggest the long duration of vocacapsaicin is possible.19 The significant decreased opioid consumption 28 days after bunionectomy further reveals that the vocacapsaicin infiltration method could have long analgesic duration.17

Vocacapsaicin has demonstrated significant pain relief and opioid-sparing effects in the operative setting, and one can only hope that use in osteoarthritis will be just as promising. This exciting therapy offers a new mechanism to decreased opioid consumption with minimal systemic adverse effects. Positive results in Phase 2 studies in the surgical models, TKA and bunionectomy, allowed for identification of the effective dose – 36 mg.

At the time of this writing, tThese results are expected to be further evaluated at an End of Phase 2 Meeting with FDA in April 2021, at which Phase 3 trial plans will also likely be shared.

Experts Weigh In: Review by PPM Editors-at-Large

Jeff Gudin, MD, and Jeffrey Fudin, PharmD

We commend the authors on their summary of the challenges of postoperative pain treatment and the introduction of a novel capsaicin prodrug analog. We give this product 4.5 out of 5 STARS.* Researchers continue their search for the holy grail of acute, chronic, and postoperative pain therapies, constantly searching for effective, opioid-sparing treatments.

Anesthesiologists and surgeons now have a growing arsenal to choose from, including oral and IV NSAIDS/COX-2s, oral and IV acetaminophen, nerve blocks, long-acting local anesthetics, and even new classes of opioid-like molecules that may prove to provide effective relief with an improved safety profile. The addition of vocacapsaicin would add to this growing list of analgesic therapies that allow for improved ambulation, discharge, and rehabilitation from painful surgical procedures.

*Potential analgesics of the future are rated based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewers’ expertise and opinion.

 

Prior Analgesics of the Future Colulmns

Last updated on: March 3, 2021
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