Validating a New Non-invasive Approach to Testing Lidocaine Effectiveness

Reliability Testing of a Non-invasive, Pain-free, Taste-based Assessment Approach to Lidocaine Effectiveness

This work will assess the reliability of a simple painless test for the effectiveness of the commonly used local anesthetic lidocaine

Study Overview

• Status: Completed
• Conditions: ADHD; Controls
• Intervention / Treatment: Drug: Lidocaine gel; Drug: Placebo; Drug: Injected lidocaine

Detailed Description

In prior tests with a convenience sample, subjects who reported that they had no trouble getting numb at the dentist, also got numb with lidocaine gel on the surface of the tongue. That numbness prevented them from being able to taste any flavor until the numbness had worn off. Subjects who reported having trouble getting numb at the dentist, could still taste flavors after the application of lidocaine.

This work will assess the reliability of a taste-based approach for creating a non-invasive way to test lidocaine effectiveness. The controlled trial will assess the ability of lidocaine oral gel to block taste (e.g., sweet) in 20 adults (ages 18-49) half with history of trouble getting numb at the dentist (Arm 2) and half with no trouble (Arm 1). To determine reproducibility, the taste-based test will be done 4 times on different days, twice with lidocaine and twice with a placebo, with randomization and double-blinding. These repeated results will be compared to a fifth assessment, against the "gold standard" of injection of lidocaine, assessed using a dental probe.

On each of four separate visits, in randomized order, the subject will be tested with tastants to the tongue twice after application of a lidocaine gel to the tongue and twice with a placebo gel. After a wait of two-minutes, the three tastants will be tested. The subject is blinded to the taste and the identity of the gel, which have been compounded to look the same.

On the fifth (last) visit, the subject will get an oral injection of lidocaine and the numbness assessed.

The results across the five tests will then be analyzed.

We are testing in separate studies NCT 03563573 and NCT 03676725 the prevalence of lidocaine ineffectiveness in those with Attention Deficit Hyperactivity Disorder (ADHD) and in the general population without ADHD. We believe the prevalence will be higher in ADHD. As a result, in this evaluation we have one Arm "gets numb at the dentist" where exclusion criteria includes ADHD and a second Arm "has trouble getting numb at the dentist" that does not have that exclusion.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Jacobi Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Arm 1 Eligibility

Inclusion Criteria:

- Report "get numb at dentist"

Exclusion Criteria:

• ADHD, ADD, and other inattention disorders
• Known adverse reactions to lidocaine;
• Epilepsy
• IQ <80
• Severe head trauma
• Birth weight <2270 grams
• Severe autism
• Generalized anxiety disorders (but dental-specific anxiety will not be an exclusion because many of these individuals may be ones with anxiety because of painful dental experiences with lidocaine ineffectiveness)
• Mouth sores
• Ehlers Danlos syndrome
• Red hair
• Current pregnancy
• Treatment currently with potassium or potassium-elevating drugs such as renin-angiotensin-aldosterone blockers

Angiotensin Converting Enzyme Inhibitors

• Alacepril (not available in US)
• Benazepril (Lotensin)
• Captopril (trade name Capoten)
• Cilazapril (Inhibace)
• Delapril (not available in US)
• Enalapril (Vasotec/Renitec)
• Fosinopril (Fositen/Monopril)
• Imidapril (Tanatril)
• Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril)
• Moexipril (Univasc)
• Perindopril (Coversyl/Aceon/Perindo)
• Quinapril (Accupril)
• Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace)
• Spirapril (Renormax)
• Temocapril (not available in US)
• Teprotide (but not active by oral administration and not used in US)
• Trandolapril (Mavik/Odrik/Gopten)
• Zofenopril

Angiotensin receptor blockers

• Azilsartan (Edarbi)
• Candesartan (Atacand)
• Eprosartan (Teveten)
• Fimasartan (Kanarb)
• Irbesartan (Avapro)
• Losartan (Cozaar)
• Olmesartan (Benicar/Olmetec)
• Telmisartan (Micardis)
• Valsartan (Diovan)

Aldosterone antagonists

• Spironolactone (Aldactone)
• Eplerenone (Inspra)

Renin inhibitors - Aliskiren (Tekturna, Rasilez)

Other potassium elevating agents

• Antibiotics, including penicillin G and trimethoprim
• Azole antifungals
• Beta-blockers
• Herbal supplements, including milkweed, lily of the valley, Siberian ginseng, Hawthorn berries
• Heparin
• Nonsteroidal anti-inflammatory medications (NSAIDs)
• Oral contraceptives containing drospirenone

Arm 2 Eligibility

Inclusion Criteria:

- Report "trouble getting numb at dentist"

Exclusion Criteria:

• Known adverse reactions to lidocaine;
• Epilepsy
• IQ <80
• Severe head trauma
• Birth weight <2270 grams
• Severe autism
• Generalized anxiety disorders (but dental-specific anxiety will not be an exclusion because many of these individuals may be ones with anxiety because of painful dental experiences with lidocaine ineffectiveness)
• Mouth sores
• Ehlers Danlos syndrome
• Red hair
• Current pregnancy
• Treatment currently with potassium or potassium-elevating drugs such as renin-angiotensin-aldosterone blockers

Angiotensin Converting Enzyme Inhibitors

• Alacepril (not available in US)
• Benazepril (Lotensin)
• Captopril (trade name Capoten)
• Cilazapril (Inhibace)
• Delapril (not available in US)
• Enalapril (Vasotec/Renitec)
• Fosinopril (Fositen/Monopril)
• Imidapril (Tanatril)
• Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril)
• Moexipril (Univasc)
• Perindopril (Coversyl/Aceon/Perindo)
• Quinapril (Accupril)
• Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace)
• Spirapril (Renormax)
• Temocapril (not available in US)
• Teprotide (but not active by oral administration and not used in US)
• Trandolapril (Mavik/Odrik/Gopten)
• Zofenopril

Angiotensin receptor blockers

• Azilsartan (Edarbi)
• Candesartan (Atacand)
• Eprosartan (Teveten)
• Fimasartan (Kanarb)
• Irbesartan (Avapro)
• Losartan (Cozaar)
• Olmesartan (Benicar/Olmetec)
• Telmisartan (Micardis)
• Valsartan (Diovan)

Aldosterone antagonists

• Spironolactone (Aldactone)
• Eplerenone (Inspra)

Renin inhibitors

- Aliskiren (Tekturna, Rasilez)

Other potassium elevating agents

• Antibiotics, including penicillin G and trimethoprim
• Azole antifungals
• Beta-blockers
• Herbal supplements, including milkweed, lily of the valley, Siberian ginseng, Hawthorn berries
• Heparin
• Nonsteroidal anti-inflammatory medications (NSAIDs)
• Oral contraceptives containing drospirenone

Study Plan

How is the study designed?

Design Details

• Primary Purpose: HEALTH_SERVICES_RESEARCH
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Reports getting numb at dentist; Subjects will be tested twice with lidocaine gel, twice with a Placebo and once with Injected Lidocaine to assess effectiveness of lidocaine. Each assessment will be on a different day.	Drug: Lidocaine gel; Lidocaine gel 5%, PEG with FD&C Blue No.1 (Brilliant Blue FCF); Other Names: Intervention; Drug: Placebo; PEG with FD&C Blue No.1 (Brilliant Blue FCF); Other Names: Control gel; Drug: Injected lidocaine; Standard FDA-approved dental injectable lidocaine; Other Names: Current practice
ACTIVE_COMPARATOR: Reports trouble getting numb at dentist; Subjects will be tested twice with lidocaine gel, twice with a Placebo and once with Injected Lidocaine to assess effectiveness of lidocaine. Each assessment will be on a different day.	Drug: Lidocaine gel; Lidocaine gel 5%, PEG with FD&C Blue No.1 (Brilliant Blue FCF); Other Names: Intervention; Drug: Placebo; PEG with FD&C Blue No.1 (Brilliant Blue FCF); Other Names: Control gel; Drug: Injected lidocaine; Standard FDA-approved dental injectable lidocaine; Other Names: Current practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Taste sensation after lidocaine or placebo	The subject is blinded to the tastant and gel identities. The 3 tastants are tested in randomized order. After application of lidocaine gel or placebo to the tongue, and a wait of 2 minutes, the subject's tongue is rubbed with a swab that has been wet with the tastant on the subject's tongue. The subject is asked to identify the taste (e.g., sweet). Then, on a 5-point scale (0-4, ranging from none to very intense) they are asked to rate the intensity of the taste. The process is repeated for each of the three tastants. The consistency of the subject responses over the 4 sessions will be analyzed.	4 visits each of 30 minutes within weeks of one another, average ~1 month total
Ability to feel pressure and discomfort after injection of lidocaine into the cheek	Inject lidocaine as would be done in a dental visit, assess numbness to pressure and discomfort using the Baker Wong FACES scale (0-10) scale of discomfort, ranging from none to intense pain. The effectiveness of lidocaine will be assessed, and then the results compared to Outcome 1.	1 visit of 30 minutes after other 4 visits, average ~1 month total

Collaborators and Investigators

• Sponsor: PhenoSolve, LLC
• Collaborators: Jacobi Medical Center

Publications and helpful links

General Publications

• Mintz M, Badner V, Feldman LK, Mintz P, Saraghi M, Diaz J, Mezhebovsky I, Axelrod I, Gleeson J, Liu C, Smith C, Chow H, Zurakowski D, Segal MM. Lidocaine Ineffectiveness Suggests New Psychopharmacology Drug Target. Psychopharmacol Bull. 2022 Jun 27;52(3):20-30.
• Infante MA, Moore EM, Nguyen TT, Fourligas N, Mattson SN, Riley EP. Objective assessment of ADHD core symptoms in children with heavy prenatal alcohol exposure. Physiol Behav. 2015 Sep 1;148:45-50. doi: 10.1016/j.physbeh.2014.10.014. Epub 2014 Oct 23.
• Levitt JO. Practical aspects in the management of hypokalemic periodic paralysis. J Transl Med. 2008 Apr 21;6:18. doi: 10.1186/1479-5876-6-18. Erratum In: J Transl Med. 2014;12:198. Dosage error in article text.
• Nakai Y, Milgrom P, Mancl L, Coldwell SE, Domoto PK, Ramsay DS. Effectiveness of local anesthesia in pediatric dental practice. J Am Dent Assoc. 2000 Dec;131(12):1699-705. doi: 10.14219/jada.archive.2000.0115.
• Segal MM. We cannot say whether attention deficit hyperactivity disorder exists, but we can find its molecular mechanisms. Pediatr Neurol. 2014 Jul;51(1):15-6. doi: 10.1016/j.pediatrneurol.2014.04.014. Epub 2014 Apr 18. No abstract available.
• Segal MM, Rogers GF, Needleman HL, Chapman CA. Hypokalemic sensory overstimulation. J Child Neurol. 2007 Dec;22(12):1408-10. doi: 10.1177/0883073807307095.
• Segal MM, Douglas AF. Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin. J Neurophysiol. 1997 Jun;77(6):3021-34. doi: 10.1152/jn.1997.77.6.3021.
• Teicher MH, Polcari A, Fourligas N, Vitaliano G, Navalta CP. Hyperactivity persists in male and female adults with ADHD and remains a highly discriminative feature of the disorder: a case-control study. BMC Psychiatry. 2012 Nov 7;12:190. doi: 10.1186/1471-244X-12-190.

Helpful Links

• Rozanski RJ, Primosch RE, Courts FJ (1988). Clinical efficacy of 1 and 2% solutions of lidocaine. Pediatr Dent.10:287-90
• Segal MM (2015) Devices, Kits, and Methods for Determining Sensitivity to Anesthetics. US Patent Filing 62/210,747, Filed 09/14/2015
• Saul R (2014) "ADHD Does Not Exist". HarperCollins
• Segal MM, Jurkat-Rott K, Levitt J, Lehmann-Horn F (2014) Hypokalemic periodic paralysis - an owner's manual

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2019
• Primary Completion (ACTUAL): March 30, 2020
• Study Completion (ACTUAL): March 30, 2020

Study Registration Dates

• First Submitted: September 17, 2018
• First Submitted That Met QC Criteria: September 19, 2018
• First Posted (ACTUAL): September 21, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 15, 2020
• Last Update Submitted That Met QC Criteria: July 14, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: ADHD; ADD; Lidocaine ineffectiveness
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Lidocaine
• Other Study ID Numbers: 2018-271

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We plan to share with the FDA the validation of the taste approach to testing lidocaine effectiveness, as part of an IDE application.
• IPD Sharing Time Frame: 9-12 months
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes