Effect of Ketamine, Amitriptyline and Their Combination on Itch

Effect of Ketamine, Amitriptyline and Their Combination on Histaminergic and Non-histaminergic Itch

Chronic itch affects approximately a fifth of the global population and is associated with substantial negative consequences for the affected individuals. Furthermore, there is a lack of efficient treat-ment options for chronic itch. Topical ketamine cream has been used successfully to relieve various forms of pain, and we hypothesize that topical ketamine relieves itch through a mechanism of action comparable to that in pain relief.

The aim of this project is to evaluate the effects of ketamine both alone and in combination with amitriptyline on histaminergic and non-histaminergic itch induced by histamine and cowhage, respectively.

Study Overview

• Status: Completed
• Conditions: Itch
• Intervention / Treatment: Drug: Ketamine 0.5%; Drug: Amitriptyline; Drug: ketamine + amitriptyline; Other: Vehicle; Other: Histamine; Other: Cowhage

Detailed Description

The main action of ketamine, 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone, is to antagonize the glutamate N-methyl-D-aspartate (NMDA) receptors. In the clinical setting, topical ketamine cream has been used successfully to relieve various pathogenic forms of pain. In addition to its pain-relieving effects, the cream was also reported to have itch-relieving properties in a very limited study. However, its efficacy on itch has not been established, and the mechanism of action remains uncertain. Ketamine cream is used not only by itself, but also in conjunction with other analgesics. One of these is amitriptyline, which may enhance the analgesic effects of ketamine. The aim of this human experimental study is to use the well-characterized anesthetic Ketamine, both alone and in combination with amitriptyline, as a tool to modulate different histaminergic and non-histaminergic itch modalities evoked by histamine and cowhage.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aalborg
    • Gistrup, Aalborg, Denmark, 9260
      • Center for Neuroplasticity and Pain Faculty of Medicine, Aalborg University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy men and women
• 18-60 years
• Speak and understand English

Exclusion Criteria:

• Pregnancy or lactation
• Drug addiction defined as any use of cannabis, opioids, or other drugs
• Previous or current history of neurological, dermatological, immunological, musculoskeletal, cardiac disorder or mental illnesses (psychiatric diagnosis) that may affect the results (e.g., neuropathy, muscular pain in the upper extremities, anxiety, depression, schizophrenia etc.)
• Moles, wounds, scars, or tattoos in the area to be treated or tested
• Current use of medications that may affect the trial such as antihistamines and pain killers.
• Participants had known allergy/discomfort to ketamine or amitriptyline
• Skin diseases
• Consumption of alcohol or painkillers 24 hours before the study days and between these
• Acute or chronic pain and itch
• Participation in other trials within 1 week of study entry (4 weeks in the case of pharmaceutical studies)
• Lack of ability to cooperate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Cream application; This subproject will be conducted in two sessions one week apart. Each session will last approximately 3 hours. In each forearm of the participant, two 4x4 cm areas will be selected as Area of Interest (AOI). In these selected areas, the four different creams will be applied in a randomized position for 1½ hours. After the cream removal, itch will be induced using histamine in one session and cowhage in the other session (the order of histamine and cowhage will be randomized). During the application of the substances, the itch/pain elicited will be monitored for 10 minutes using a VAS (Visual analog scale). After the removal of the substances, measurements of SBP, TP, MEI, MPT, MPS, and thermal sensitivity will be conducted.

Drug: Ketamine 0.5%; Ketamine cream 0.5% will be applied in a 4x4 area in the forearm of each participant.; Drug: Amitriptyline; Amitriptyline cream 1% will be applied in a 4x4 area in the forearm of each participant.; Drug: ketamine + amitriptyline; A cream containing ketamine 0.5%, amitriptyline 1%, will be applied in a 4x4 area in the forearm of each participant.; Other: Vehicle; A vehicle cream will be applied in a 4x4 area in the forearm of each participant.; Other: Histamine; After the cream removal, itch will be induced using histamine in the first session; Other: Cowhage; After the cream removal, itch will be induced using cowhage in the second session

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measuring itch by computerized Visual Analog Scale Scoring	We will ask the subjects to rate the sensation of itch on a 100 mm VAS scale ranging from 0 to 100 where 0 indicates "no itch" and 100 indicates "worst itch imaginable".	Immediately after the intervention
Measuring pain by computerized Visual Analog Scale Scoring	We will ask the subjects to rate the sensation of pain on a 100 mm VAS scale ranging from 0 to 100 where 0 indicates "no pain" and 100 indicates "worst pain imaginable".	Immediately after the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Superficial blood perfusion	Superficial blood perfusion (SBP) is measured by a Speckle contrast imager	Immediately after the intervention
Touch Pleasantness	Pleasant touch sensation measured using a standardized sensory brush exerting a force of 200 to 400 mN.	Immediately after the intervention
Mechanically evoked itch (MEI), intensity approach	MEI is measured by using mildly pruritic, non-painful von Frey nylon filaments of a predetermined intensity (generally 5-30 miliNewton of force).	Immediately after the intervention
Mechanically evoked itch, spatial approach	The von-Frey filament that better evokes the itch sensation during the assessment of mechanically evoked itch as well as a template of soft plastic are used to map the area of hyperkinesis in the test areas (forearms).	Immediately after the intervention
Mechanical Pain Thresholds (MPT)	This test is conducted using a pinprick set. The set consists of 7 needles each with a diameter of 0.6 mm and different force applications: 8, 16, 32, 64, 128, 256, and 512 mN.	Immediately after the intervention
Mechanical Pain Sensitivity (MPS), intensity approach	This test is conducted with the same pinprick set used to test the MPT.	Immediately after the intervention
Mechanical Pain Sensitivity (MPS), spatial approach	The pinprick that was selected in the MPT as well as a template of soft plastic are used to map the area of hyperalgesia in the test areas (forearms).	Immediately after the intervention
Cold Detection Thresholds (CDT)	The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device	Immediately after the intervention
Warm Detection Thresholds (WDT)	The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device	Immediately after the intervention
Cold Pain Thresholds (CPT)	The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device	Immediately after the intervention
Heat Pain Thresholds (HPT)	The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device	Immediately after the intervention
Pain to Supra-threshold Heat Stimuli (STHS)	The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device	Immediately after the intervention

Collaborators and Investigators

• Sponsor: Aalborg University

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2024
• Primary Completion (Actual): December 31, 2024
• Study Completion (Actual): December 31, 2024

Study Registration Dates

• First Submitted: January 25, 2024
• First Submitted That Met QC Criteria: February 4, 2024
• First Posted (Actual): February 7, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 28, 2025
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Histamine Agents; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Adrenergic Agents; Neurotransmitter Uptake Inhibitors; Antidepressive Agents; Adrenergic Uptake Inhibitors; Excitatory Amino Acid Agents; Anesthetics, Dissociative; Excitatory Amino Acid Antagonists; Antidepressive Agents, Tricyclic; Histamine Agonists; Ketamine; Amitriptyline; Histamine
• Other Study ID Numbers: N-20230046

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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