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17 Articles in Volume 19, Issue #7
Analgesics of the Future: Inside the Potential of 3 Drug Delivery Systems
Balancing Pain Care - and Opioids - in the Aging Adult
Book Review: A Useful Guide for New Pain Practitioners
Correspondence: Opioid Tapering & Discontinuation
Effective Interventions for Post-Stroke Shoulder Subluxation and Pain
Family: Their Role and Impact on Pain Management
Introducing the "Phoenix Sign:" Improved Vascular Perfusion of the Dorsalis Pedis Artery after a Subanesthetic Dose of Lidocaine
Medication Management of Chronic Pain in Patients with Comorbid Cardiovascular Disease
Multisite Pain May Be Associated with Fractures in the Elderly
Reconciling the New HHS Opioid Tapering Guideline with CDC and State Policies
Research Insights: Impaired Motor Imagery in Chronic Pain Conditions
Tapentadol: A Real-World Look at Misuse, Abuse, and Diversion
Temporomandibular Disorders in Performance Artists (Part 2)
Thoracic Outlet Syndrome Presenting as an Acute Stroke Mimic
Untangling Chronic Pain and Hyperarousal with Heart Rate Variability: A Case Report
What topicals exist for post-herpetic neuralgia pain?
When to Keep Your License: Older Physicians and Boundary Issues

Analgesics of the Future: Inside the Potential of 3 Drug Delivery Systems

A review of ZTlido (topical lidocaine), Zalviso and Dsuvia (sublingual sufentanil), and Wafermine (sublingual ketamine).
Pages 55-59


For some patients, traditional oral or intravenous (IV) formulations may not be sufficient for pain control, come with undesirable adverse effects, or may not be clinically optimal. Therefore, alternative routes of delivery must be considered. Scilex Pharmaceuticals, AcelRx Pharmaceuticals, and iX Biopharma have created novel dosage formulations of analgesic medications. Scilex has developed a new adhesive property to the lidocaine patch that provides patients with the potential for enhanced results due to improved adhesion technology, while AcelRx has two delivery system containing sufentanil sublingual tablets. Lastly, iX Biopharma has manufactured a ketamine-containing sublingual wafer product. Below are the details and data on each.



The Data

Lidocaine Topical System

ZTlido offers a single-layer drug-in-adhesive system approved for the treatment of pain associated with post-herpetic neuralgia (PHN). As clinicians know, lidocaine is a local anesthetic that blocks sodium ion channels required for the initiation and conduction of neural impulses; they may be most familiar with the use of Lidoderm (Teikoku Pharma USA) patches (transdermal lidocaine 5%) for the management of painful symptoms related to PHN.1 Bioequivalence has been established between the ZTlido and Lidoderm systems, whereas one ZTlido (lidocaine 1.8%) patch provides equal lidocaine exposure to one Lidoderm (lidocaine patch 5%).1 A noteworthy distinction to the ZTlido product is its skin-adhesion performance. Transdermal delivery systems require optimal skin adhesion in order to achieve optimal efficacy from the product. When studied, 87% of patients demonstrated scores indicating ≥ 90% adhesion during the 12-hour administration period.2

Another clinical concern with the use of transdermal drug delivery is skin temperature, as this may increase absorption of the drug. Higher levels of lidocaine in the body can produce symptoms that can range from mild drowsiness and headache to confusion, seizures, coma, and cardiac arrest.3 When plasma levels were studied after exposure to external heat compared and to exposure at rest, the mean (± SD) lidocaine concentrations were 160.3 ± 100.1 ng/mL and 97.6 ± 36.9 ng/mL, respectively. The concentrations returned to normal within 4 hours after the heat was removed.2

In general, providers should educate patients to not apply heat directly to the patch to avoid elevated concentrations of the medication entering the body, however, patients may exercise while utilizing transdermal drug systems. Studies of ZTlido demonstrated no significant differences in absorption while patients were exercising (mean plasma concentrations of 90.5 ± 25.4 ng/mL), indicating that patients may exercise up to a moderate intensity while wearing the patch. (More on lidocaine for pain)

Sufentanil Nanotablets

Sufentanil nanotablets for sublingual administration have been formulated in two delivery mechanisms. Dsuvia is a 30-mcg single-dose applicator indicated for use in adults in a medically supervised healthcare setting for the management of acute pain, when alternative treatments are inadequate. Zalviso is a hand-held patient-controlled anesthesia (PCA) device that allows individuals to self-administer 15 mcg tablets of sufentanil every 20 minutes as needed for acute pain during in-patient admissions. Both products have been studied for up to 72 hours of use.

These medications are of great clinical importance due to their faster onset to meaningful pain relief, which has been associated with decreased overall opioid utilization in Phase 3
trials.3 Other pharmacokinetic benefits include rapid transmucosal absorption, adequate sublingual bioavailability, and rapid analgesic response. There are no clinically relevant active metabolites, thus avoiding the need for dosage adjustments due to renal or hepatic issues.4 Sufentanil also demonstrates low oral bioavailability, which provides safety in the event of accidental ingestion.

Further, sublingual drug delivery provides a noninvasive route of administration that allows easy administration when a patient has poor IV access or is unable to tolerate oral medications. These products also enhance the ease of mobility for patients by not tethering the patient to infusion equipment. Finally, the risk for delivery system-related programming errors should be avoided, as the Zalviso delivery system is pre-programmed by the manufacturer.

The risks attributed to sufentanil nanotab are similar to those of other opioids. In clinical trials examining safety, there was no sign of increase in rates of respiratory depression compared to other opioid analgesics.5 There has been controversy over these medications due to concern over opioid addiction and overdose, however, according to Dsuvia’s clinical program, there were no new safety signals identified. Even with similar safety profiles to other opioids, these products’ use will be restricted to administration by healthcare professionals in a medically supervised setting under a comprehensive Risk Evaluation and Mitigation Strategies to reduce the risk of abuse, misuse, and diversion.6 Table I details the various studies for Dsuvia, which had design differences across study groups.7-10

Sublingual Ketamine

iX Biopharma’s wafer formulation allows pharmaceutical products to be administered sublingually. The WaferiX technology consists of a small wafer that is prepared using a freeze-drying process. This process produces a medication carrier matrix with numerous amorphous holes which encapsulate the drug molecules;11 and the technology has the potential to lower the administered dose and reduce side effects due to lower peak blood concentrations, when compared to IV administration. The manufacturer has several products in development utilizing this delivery technology.

The Wafermine product contains the non-opioid drug ketamine. Ketamine has been shown to be effective for the management of pain, reducing hyperalgesia that can occur in patients who have long-term use of opioids, and when used in conjunction with opioids may demonstrate a dose-sparing effect on the amount of opioids required.12 A Phase 1, open-label, two-way crossover study determined the absolute bioavailability for the sublingual dosage of Wafermine to be 29%, which is similar to orally administered ketamine. The first plasma ketamine detection occurs in less than 5 minutes, demonstrating its rapidm absorption.13 Two Phase 2 randomized, double-blind, parallel, placebo-controlled dose-ranging studies assessed the analgesic efficacy, tolerability, safety and pharmacokinetic profile of Wafermine following molar extractions. Both studies confirmed that ketamine has rapid absorption with good tolerability and mild, short-lived side effects. Analgesia in all dosing cohorts was apparent within 10 minutes with maximal effects demonstrated at 20 to 30 minutes and subsiding over 1 to 2 hours.

Another randomized, double-blind, placebo-controlled trial in participants who underwent either abdominoplasty or bunionectomy surgery showed a strong analgesic efficacy at 75 mg in both groups. Therefore, the 75-mg dose has been chosen as the strength to move forward in Phase 3 analgesic clinical trials (a 25 mg and 50 mg dose showed limited efficacy).11 (More on ketamine for chronic pain.)


Skin adhesion is important for the effectiveness of transdermal dosage formulations. The findings of the adhesion trials of ZTlido establish it as a promising treatment option for postherpetic neuralgia-associated pain. The limiting factor to health systems and patients switching to this product from Lidoderm or other lidocaine patches would be the cost associated with the product. Hypothetically, the improved adhesion of the product could lead to better patient compliance and analgesic results. Although the ZTlido patch appears to be superior to other topical lidocaine products currently available in terms of adhesion, cost of the product may be a prohibitive factor and will depend on individuals’ insurance coverage or a health system’s acquisition cost.

Sufentanil nanotablets have highly consistent Cmax and Tmax. Currently, patients who experience moderate-to-severe acute pain in in-patient settings are typically administered IV products as an option to rapidly address their pain. The rapid onset of action of sufentanil nanotab products could replace intravenous pain medications in some cases. The delivery systems containing sufentanil nanotablets are only available for use in the in-patient setting in the United States and could be beneficial in the emergency department and post-anesthesia care unit, where patients often experience acute pain crises.

Wafermine has been studied for pain related to abdominoplasty or bunionectomy. The wafer formulation was found to have bioavailability similar to that of oral ketamine. The sublingual wafer formulation could be advantageous for patients unable to tolerate oral medications, such as those with high levels of nausea or vomiting, difficulty swallowing, or contraindications for the use of oral route of administration.

Author Bios: Jordan O’Leary, PharmD, is a PGY1 resident at Kent County Memorial Hospital in Rhode Island, and a recent graduate of the University of Rhode Island College of Pharmacy. Jayne Pawasauskas, PharmD, BCPS, is a clinical professor of pharmacy at the University of Rhode Island College of Pharmacy, with a clinical practice site at Kent County Memorial Hospital. Dr. Pawasauskas discloses that she is on the Advisory Board and Speakers’ Bureau of Mallinckrodt Pharmaceuticals, and the Advisory Board of Heron Therapeutics.

Traditional formulations may not be sufficient for pain control, come with undesirable effects, or may not be clinically optimal. Alternative routes of delivery must be considered.

Expert Weighs In: by Dmitry M. Arbuck, MD

This review essentially covers three agents that have been pharmaceutically augmented to maximize absorption from non-traditional routes compared to their legacy products. The specific products reviewed include ZTlido (lidocaine topical system), Zalviso (a sufentanil sublingual microtablet PCA system), Dsuvia (a sufentanil sublingual tablet), Wafermine (sublingual ketamine) two of which have received FDA approval (Ztildo and Dsuvia). Each product has been rated* separately.

The lidocaine topical system ZTlido offers a topical lidocaine alternative with enhanced absorption properties and a patch that clearly has better adhesion properties. Studies to support these claims are comprehensive and sufficient, including heat and exercise, dermal sensitivity and comparative adhesion studies. The cost for this product is comparable to branded lidocaine patches but exceeds that of generic patches. Of note, lidocaine patches are available over the counter, but these products mostly lack publicly available PK and safety data. Given that the patch contains 20 times less lidocaine and yet delivers the same amount through the skin, this agent is given 3.75 STARS.

The sufentanil nanotablets overcome the inability to administer sufentanil by a non-injectable route of administration. They offer a unique opportunity on the battlefield and in acute care settings as well as superior pharmacokinetic advantages over traditional opioids in terms of time to peak and use in hepatic or renal impairment, duration of analgesia, side effect profile, and respiratory depression. The unique administration of Zalviso and Dsuvia may prove useful for other products as well. The research clearly supports product claims to date, although convincing hospitals to change opioid dispensing and administration habits may be an uphill battle. These products are given 4 STARS based on their novel delivery methods.

The sublingual ketamine agent Wafermine promises a potential new route of administration for ketamine. This is an exciting sublingual product that uses novel technology employing an enhanced mediation transporter. This product could potentially help catapult ketamine utilization for various acute and chronic pain conditions, including use in the palliative care setting, especially if traditional administration routes are not an option. Although this product is still in development/clinical trials, its potential is exciting as a novel delivery system: 4 STARS.

*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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