A Relation of Morphine-induced Itch and Pain Processing

Sponsor

Aalborg University (Other)

Overall Status

Completed

CT.gov ID

NCT04115462

Collaborator

(none)

Enrollment

Location

Arms

5.7

Actual Duration (Months)

4.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In This experiment, the investigators would like to test the two following hypotheses regarding the mechanisms by which opioids cause itch:

Opioids cause itch by a spinal disinhibition mechanism (central nervous system (CNS) effect).
Opioids cause itch through a mast cell-destabilizing effect leading to release of histamine and tryptase in the skin where itch is evoked (peripheral mechanism).

Condition or Disease	Intervention/Treatment	Phase
Morphine Itch	Drug: Morphine Drug: Placebo oral tablet Drug: Histamine Drug: Cowhage (Mucuna Pruriens) Drug: isotonic saline Drug: Histamine Drug: Cowhage (Mucuna Pruriens)	N/A

Detailed Description

Intrathecal and orally administered opioids are heavily used for the treatment of several acute pain conditions. However, while opioids are effective analgesics for acute pain, they are well-known to frequently cause itch (pruritus) as a side effect according with the two hypotheses stated above. So far, these two hypotheses have never been tested in humans.The present study describes a proposed study design for the purpose of confirming these two hypotheses in parallel in human subjects.

Primary endpoints of the study:

To evaluate changes itch and pain perception, and superficial perfusion after each itch provocations.

Secondary endpoints of the study:

To evaluate the existence of a correlation between itch sensitization and analgesic efficacy.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

A Mechanistic Study on Morphine-induced Orthogonal Neural Plasticity for Itch and Pain Processing in Humans (a Relation of Morphine-induced Itch and Pain Processing)

Actual Study Start Date :

Jan 15, 2020

Actual Primary Completion Date :

May 1, 2020

Actual Study Completion Date :

Jul 7, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Morphine Each participant will receive a single dose of 20 mg morphine tablet. At estimated peak-plasma concentration testing is conducted. The subject and the assessor are both blinded to the drug administrations.	Drug: Morphine A 20 mg tablet of morphine Drug: Histamine Histaminergic itch will be evoked by a 1% histamine solution. A droplet of histamine solution will be placed on the predetermined area on the forearm, and the SPT lancet will be pierced through the histamine with 120 g of pressure for 1-2 seconds. Drug: Cowhage (Mucuna Pruriens) 25 spicules will be inserted in the centre of the predefined skin area on the forearm. The spicules will be gently rubbed for 15-20 seconds in circular motion to facilitate epidermal penetration Drug: isotonic saline A droplet of saline (0.9%) as vehicle control will be placed on the predetermined area on the forearm and the lancet will be pierced through the droplet. Other Names: saline Drug: Histamine Histaminergic itch will be evoked by a 1% histamine solution. A droplet of histamine solution will be placed on the predetermined area on the mandibular area, and the SPT lancet will be pierced through the histamine with 120 g of pressure for 1-2 seconds. Drug: Cowhage (Mucuna Pruriens) 25 spicules will be inserted in the centre of the predefined skin area on the mandibular area. The spicules will be gently rubbed for 15-20 seconds in circular motion to facilitate epidermal penetration
Placebo Comparator: Placebo Each participant will receive a single dose of an identical placebo tablet. At estimated peak-plasma concentration testing is conducted. The subject and the assessor are both blinded to the drug administrations.	Drug: Placebo oral tablet Matching tablet of placebo Drug: Histamine Histaminergic itch will be evoked by a 1% histamine solution. A droplet of histamine solution will be placed on the predetermined area on the forearm, and the SPT lancet will be pierced through the histamine with 120 g of pressure for 1-2 seconds. Drug: Cowhage (Mucuna Pruriens) 25 spicules will be inserted in the centre of the predefined skin area on the forearm. The spicules will be gently rubbed for 15-20 seconds in circular motion to facilitate epidermal penetration Drug: isotonic saline A droplet of saline (0.9%) as vehicle control will be placed on the predetermined area on the forearm and the lancet will be pierced through the droplet. Other Names: saline Drug: Histamine Histaminergic itch will be evoked by a 1% histamine solution. A droplet of histamine solution will be placed on the predetermined area on the mandibular area, and the SPT lancet will be pierced through the histamine with 120 g of pressure for 1-2 seconds. Drug: Cowhage (Mucuna Pruriens) 25 spicules will be inserted in the centre of the predefined skin area on the mandibular area. The spicules will be gently rubbed for 15-20 seconds in circular motion to facilitate epidermal penetration

Arm

Intervention/Treatment

Active Comparator: Morphine

Each participant will receive a single dose of 20 mg morphine tablet. At estimated peak-plasma concentration testing is conducted. The subject and the assessor are both blinded to the drug administrations.

Drug: Morphine

A 20 mg tablet of morphine

Drug: Histamine

Histaminergic itch will be evoked by a 1% histamine solution. A droplet of histamine solution will be placed on the predetermined area on the forearm, and the SPT lancet will be pierced through the histamine with 120 g of pressure for 1-2 seconds.

Drug: Cowhage (Mucuna Pruriens)

25 spicules will be inserted in the centre of the predefined skin area on the forearm. The spicules will be gently rubbed for 15-20 seconds in circular motion to facilitate epidermal penetration

Drug: isotonic saline

A droplet of saline (0.9%) as vehicle control will be placed on the predetermined area on the forearm and the lancet will be pierced through the droplet.

Other Names:

saline

Drug: Histamine

Histaminergic itch will be evoked by a 1% histamine solution. A droplet of histamine solution will be placed on the predetermined area on the mandibular area, and the SPT lancet will be pierced through the histamine with 120 g of pressure for 1-2 seconds.

Drug: Cowhage (Mucuna Pruriens)

25 spicules will be inserted in the centre of the predefined skin area on the mandibular area. The spicules will be gently rubbed for 15-20 seconds in circular motion to facilitate epidermal penetration

Placebo Comparator: Placebo

Each participant will receive a single dose of an identical placebo tablet. At estimated peak-plasma concentration testing is conducted. The subject and the assessor are both blinded to the drug administrations.

Drug: Placebo oral tablet

Matching tablet of placebo

Drug: Histamine

Drug: Cowhage (Mucuna Pruriens)

25 spicules will be inserted in the centre of the predefined skin area on the forearm. The spicules will be gently rubbed for 15-20 seconds in circular motion to facilitate epidermal penetration

Drug: isotonic saline

A droplet of saline (0.9%) as vehicle control will be placed on the predetermined area on the forearm and the lancet will be pierced through the droplet.

Other Names:

saline

Drug: Histamine

Drug: Cowhage (Mucuna Pruriens)

Outcome Measures

Primary Outcome Measures

Microvascular reactivity [Before and 70 minutes after morphine/placebo administration]
The evoked cutaneous inflammation (quantified by superficial blood perfusion) will be measured by full-field laser perfusion imaging.
Microvascular reactivity [10 minutes after every itch inductions]
The evoked cutaneous inflammation (quantified by superficial blood perfusion) will be measured by full-field laser perfusion imaging.
Assessment of itch [1 minute after every itch inductions]
Immediately following the itch provocations, participants will be instructed to rate the itch intensity for 10 minutes using a digital visual analogue scale (VAS; eVAS Software: Aalborg, University, Denmark), on a tablet. The scale will be measured from 0 to 100, where 0 represents 'no itch' and 100 'worst itch imaginable'.
Assessment of pain [1 minute after every itch inductions]
Immediately following the itch provocations, participants will be instructed to rate the pain intensity for 10 minutes using a digital visual analogue scale (VAS; eVAS Software: Aalborg, University, Denmark), on a tablet. The scale will be measured from 0 to 100, where 0 represents 'no pain' and 100 'worst pain imaginable'.

Secondary Outcome Measures

Cold (CPT) and heat (HPT) pain thesholds [10 minutes before morphine/placebo administration]
Thermal cold and heat stimuli will be applied by a contact heat-evoked potential stimulator (PATHWAYS; Medoc Ltd, Ramat Yishai, Israel), placed 5 cm distal to the elbow on the right dorsal forearm.
Cold (CPT) and heat (HPT) pain thesholds [60 minutes after morphine/placebo administration]
Thermal cold and heat stimuli will be applied by a contact heat-evoked potential stimulator (PATHWAYS; Medoc Ltd, Ramat Yishai, Israel), placed 5 cm distal to the elbow on the right dorsal forearm.
Pressure Pain Threshold [10 minutes before morphine/placebo administration]
Pressure will be applied to the supinator muscle on the left forearm, 15 cm distal to the elbow by a handheld electronic pressure algometer (Somedic AB, Stockholm, Sweden) with a standard probe of 1 cm2.
Pressure Pain Threshold [60 minutes after morphine/placebo administration]
Pressure will be applied to the supinator muscle on the left forearm, 15 cm distal to the elbow by a handheld electronic pressure algometer (Somedic AB, Stockholm, Sweden) with a standard probe of 1 cm2.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy men and women in the age of 20-65 years
The participants must be able to speak and understand English

Exclusion Criteria:

Participants with any clinically significant abnormalities that in the opinion of the investigator may increase the risk associated with trial participation or may interfere with the interpretation of the trial results.
Pregnant or lactating female persons
Drug addiction defined as the use of cannabis, opioids or other drugs
Previous or present neurologic, musculoskeletal or mental illnesses
Current pain and itch causing diseases or psychiatric disorders
Participants unable to understand or follow the instructions
Participating in another study where investigational drug is used
Participants had known allergy/discomfort to morphine
Lack of ability to cooperate

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mech-Sense, Medicinsk Gastroenterologisk ambulatorium, Medicineshus, Aalborg Universitetshospitalet,	AAlborg	Nordjylland	Denmark	9000

Sponsors and Collaborators

Aalborg University

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Silvia Lo Vecchio, Principal Investigator, Aalborg University

ClinicalTrials.gov Identifier:

NCT04115462

Other Study ID Numbers:

N-20190049

First Posted:

Oct 4, 2019

Last Update Posted:

Jul 8, 2020

Last Verified:

Jul 1, 2020

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Morphine

Histamine

Histamine phosphate

Study Results

No Results Posted as of Jul 8, 2020