Topical Loperamide Gel for Pain Reduction During Repeat Finger Lancing (Loperamide)

Topical Loperamide Gel for Pain Reduction During Repeat Finger Lancing: A Randomized Double Blind Trial

This study evaluates topical loperamide 5% gel in reducing pain during repeat finger lancing (finger stick) in healthy adults. Half of participants received 5% loperamide gel applied to their fingertip prior to their second lance and the other half received the gel only.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: Loperamide; Drug: Drug, placebo gel

Detailed Description

Lancing the finger and heel to obtain capillary blood for specimen collection and diagnostic testing is a painful and tissue damaging procedure. With each lance, there is direct splicing of capillaries along with free nerve endings resulting in an immediate localized pain response and hyperalgesia from the release of pain producing substances. Opioid agonists (morphine, fentanyl, loperamide) have demonstrated significant analgesia when locally injected or topically applied to a site of inflammation/injury in animal models.

Loperamide, a piperdine derivative with a structure similar to the synthetic opioid meperidine, has strong affinity for Mu opioid receptors. It was approved by the FDA in 1969 as an anti-diarrheal agent with Mu opioid activity mimicked the constipating effects of other opioids, but with markedly reduced CNS effects due to its affinity for p-glycoprotein, preventing crossing the blood brain barrier (BBB) under normal circumstances.

This prospective, double-blind, repeated measures, randomized investigational new drug trial used loperamide developed as a topical gel in 34 adult participants to determine its analgesic effects during repeat finger lancing. The investigators also assessed for any local skin reaction to the gel application and for any constipation or abdominal cramping which might be evidence of systemic absorption and Mu opioid agonist activity on the gut.

This study would be applicable for use in 28.9 million adults who are diabetic and require finger lancing for blood glucose monitoring and the high risk newborn population who require repeat heel lancing for specimen collection.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Early Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy volunteers willing to have 2 consecutive finger sticks completed.

Exclusion Criteria:

• Participants are excluded if they have a history of drug induced hypersensitivity reactions; took any anti-inflammatory medications in the past 12 hours; if they routinely performed finger lancing for blood specimen monitoring (e.g. diabetes); or had calloused fingers pads.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 5% Loperamide gel; Participants received 5% loperamide gel (0.2gm equivalent to 10 mg) applied following a single surgilance to the 5th digit. The loperamide gel was applied 10 minutes following the first lance, rubbed in for one minute within an 8 mm mold surrounding the lance site. The mold was removed and the gel was covered with a transparent occlusive dressing and left in place for 30 minutes. The forearm was also swabbed with the loperamide gel which was left in place for 30 minutes. The placebo gel contained the same ingredients without the loperamide. The loperamide gel formulation includes: Loperamide 5%, Propylene Glycol; Ethanol (190 proof USP); Ethyl acetate; and Klucel HF 1%.	Drug: Loperamide; Following lance one, 0.2 grams of loperamide 5% gel was applied from a sterile syringe to the participants previous lance site within an 8 mm diameter circular plastic mold. The loperamide gel was rubbed lightly on the skin surface for one minute using a gloved finger swirled into the mold site. The mold was removed and the site was covered with a transparent occlusive dressing for 30 minutes. At 30 minutes the gel was removed with gauze, the skin cleaned with an alcohol wipe and the second lance was done within the same location as the first. The loperamide gel was also swabbed to the forearm within the 8 mm mold and left in place for 30 minutes.; Other Names: Mu opioid receptor agonist
Placebo Comparator: Placebo gel; Participants received placebo gel (0.2gm) applied following a single surgilance to the 5th digit. The placebo gel was applied 10 minutes following the first lance, rubbed in for one minute within an 8 mm mold surrounding the lance site. The mold was removed and the gel was covered with a transparent occlusive dressing and left in place for 30 minutes. The forearm was also swabbed with the placebo gel which was left in place for 30 minutes. .The placebo gel contained the same ingredients without the loperamide. The placebo gel formulation includes: Propylene Glycol; Ethanol (190 proof USP); Ethyl acetate; and Klucel HF 1%.	Drug: Drug, placebo gel; Following lance one, 0.2 grams of gel alone was applied to the participants previous lance site within an 8mm diameter circular plastic mold. The gel was rubbed lightly on the skin surface for one minute using a gloved finger swirled into the mold site. The mold was removed and the site was covered with a transparent occlusive dressing left in place for 30 minutes. At 30 minutes the gel was removed with gauze, the skin cleaned with an alcohol wipe and the second lance was done within the same location as the first. The placebo gel was also swabbed to the forearm within the 8 mm mold and left in place for 30 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain - Numeric Rating Scale	Subject responded to "Please mark the degree of pain you felt following the lance" and drew a line on a 0 (no pain) to 10 (worst possible pain) scale within one minute of the lance.	Within one minute following each lance
Pain - Comparative Pain Scale	Within one minute following the second lance, subjects were asked "In comparison to the first finger stick, how would you rate the pain of the second": much less, a little less, about the same, a little more or much more.	Within one minute of the second lance, participants will be asked to circle their comparison pain rating to the first lance delivered 40 minutes earlier to the same digit.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24 Hour Numeric Pain (0 to 10 Scale) in the Lanced Finger Site.	Numeric pain rating using the numeric rating scale 0-10 (0=no pain and 10 = worst pain ever) at 24 hours following finger lancing	24 hours following the second lance.
24 Hour Sensitivity in Lanced Finger to Touch and Pressure	Sensitivity questions adapted from the pain quality assessment scale: After the application of the gel in both the treatment and control (Placebo) group, each participant from both groups was asked about the sensitivity of the fingerstick site to light or clothing rubbing against it over the past day (24 hours later), the sensitivity scale is as follows: (0=non-sensitive; 1-sensitive). A scale score of 0 means- a better outcome. After the application of the gel in both the treatment and control (Placebo) group, each participant from both groups was asked about the sensitivity of the fingerstick site when something was pressed against it over the past day (24 hours later), the sensitivity scale is as follows: (0=not tender and 1=tender). A scale score of 0 means- a better outcome.	24 hours post lancing.
Change in Beats Per Minute (BPM) Within Groups During Lance One and Lance Two Procedure	BPM obtained using the Kenek Edge Pulse Oximeter System using a flipclop sensor and companion app. Mean BPM during lance initiation through recovery (30 seconds following lance) reported.	Average of BPM during each phase of the lance procedure (lance, specimen collection, recovery)
Safety- Number of Participants With Treatment Related Adverse Events as Assessed by the CTCAE V.4	CTCAE will be utilized for reporting any adverse events with specific focus on skin and tissue disorders. A Standard erythema scale (0=no effect, 0.5=observer indecisive, 1=faint pink-no border, 1.5=faint pink border, 2=faint pink with one border, 2.5=fain pink with two borders, 3=red, 3.5=fiery red 4=violaceous red will also be used to classify skin erythema.	Direct observation of treatment site at one minute and 30 minutes. Participant report at 24 hours if any redness is present on the forearm.
Safety - Number of Participants With Treatment Related Adverse Gastrointestinal Disorders Using the CTCAE V. 4 With Focus on Abdominal Pain, Constipation and Diarrhea	Participant report of any abdominal pain or change in stool pattern (constipation or diarrhea) over the past 24 hours using the CTCAE V.4 with focus on abdominal pain, constipation and diarrhea..	24 hour participant report

Collaborators and Investigators

• Sponsor: Rush University Medical Center

Publications and helpful links

General Publications

• Owens ME, Todt EH. Pain in infancy: neonatal reaction to a heel lance. Pain. 1984 Sep;20(1):77-86. doi: 10.1016/0304-3959(84)90813-3.
• Fruhstorfer H, Schmelzeisen-Redeker G, Weiss T. Capillary blood volume and pain intensity depend on lancet penetration. Diabetes Care. 2000 Apr;23(4):562-3. doi: 10.2337/diacare.23.4.562. No abstract available.
• Johnston CC, Strada ME. Acute pain response in infants: a multidimensional description. Pain. 1986 Mar;24(3):373-382. doi: 10.1016/0304-3959(86)90123-5.
• Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med. 1995 Jun 22;332(25):1685-90. doi: 10.1056/NEJM199506223322506. No abstract available.
• Stein C, Schafer M, Machelska H. Attacking pain at its source: new perspectives on opioids. Nat Med. 2003 Aug;9(8):1003-8. doi: 10.1038/nm908.
• DeHaven-Hudkins DL, Burgos LC, Cassel JA, Daubert JD, DeHaven RN, Mansson E, Nagasaka H, Yu G, Yaksh T. Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther. 1999 Apr;289(1):494-502.
• Nozaki-Taguchi N, Yaksh TL. Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist--loperamide. Anesthesiology. 1999 Jan;90(1):225-34. doi: 10.1097/00000542-199901000-00029.
• Page GG. Are there long-term consequences of pain in newborn or very young infants? J Perinat Educ. 2004 Summer;13(3):10-7. doi: 10.1624/105812404X1725.
• Osborne DW. (2002). Patent No. US 6355657 B1. US. https://www.google.com/patents/US6355657 Accessed June 1, 2014

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: December 11, 2015
• First Submitted That Met QC Criteria: March 16, 2016
• First Posted (Estimated): March 17, 2016

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: April 24, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: opioid; fingerstick; heelstick; loperamide; topical opioid
• Additional Relevant MeSH Terms: Gastrointestinal Agents; Loperamide; Antidiarrheals
• Other Study ID Numbers: 13091401-IRB02; IND 122919 (Other Identifier: Food and Drug Administration)

Plan for Individual participant data (IPD)

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

Study Data/Documents

1. Study Protocol
   Information identifier: Loperamide
   Information comments: Contact the Rush Office of Research Affairs for all materials 312 942-5498
2. Informed Consent Form
   Information identifier: Loperamide
   Information comments: Contact the Rush Office of Research Affairs for all materials 312 942-5498