Pain Phenotyping of Patients With Bone Cancer Pain (BonemetPAIN)

The study aims to describe and quantify pain related to metastatic bone disease. The study will include 50 subjects with disseminated breast cancer and 20 healthy subjects. The pain will be described and quantified through (1) pain specific questionnaires, (2) quantitative sensory testing that assess sensory changes to cold, heat and mechanical stimulation of the skin overlying the metastatic site, and (3) conditioned pain modulation that investigates impairment of the endogenous inhibitory pain pathway in humans.

Study Overview

• Status: Unknown
• Conditions: Pain; Metastatic Breast Cancer; Bone Metastases

Detailed Description

Cancer patients in palliative care point to pain as their most important and most feared symptom. Bone metastases are a common cause of cancer pain, and the patients are prone to transient severe pain exacerbations (breakthrough pain), which can occur spontaneously or be triggered by movement. Patients with bone metastases experience pain of such high intensity, that it affects not only physical activity, but also sleep, mood and social relations. This results in poor quality of life for the patients and poses an increasing clinical and socio-economical problem. The pain is difficult to treat and often requires high opioid doses which results in unacceptable adverse effects, and there is an unmet need of novel therapeutic options and treatment strategies.

Animal models of cancer-induced bone pain have suggested that pain arising from metastatic bone disease involve neuropathic and nociceptive pain mechanisms and, importantly, mechanisms that are specific to cancer-induced bone pain. Significant neuronal sprouting can occur at the metastatic site, and the inherent pain control system is found altered in animal models of cancer-induced bone pain; a system that can be exploited for treatment strategies and in the development of new analgesia. Yet, it is not known how the pre-clinical findings translate to patients.

Quantitative sensory testing is a psychophysical method that uses a battery of sensory stimuli with predetermined physical properties, thus allowing the capture and quantification of stimulus-evoked negative and positive sensory phenomena in humans. Conditioned pain modulation is a psychophysical experimental measure of the endogenous pain inhibitory pathway in humans, which can be used to detect an impairment of the descending inhibitory pain pathway.

This study aims to perform pain phenotyping of patients suffering from cancer-induced bone pain, through pain specific questionnaires, quantitative sensory testing and conditioned pain modulation.

• Study Type: Observational
• Enrollment (Anticipated): 70

Contacts and Locations

• Study Contact: Name: Anne-Marie Heegaard, PhD; Phone Number: +45 35336322; Email: amhe@sund.ku.dk
• Study Contact Backup: Name: Rie B Hansen, PhD; Phone Number: +45 35332139; Email: rikkerie.hansen@sund.ku.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Oncology, Rigshospitalet
    • Contact: Rie B Hansen, PhD
  • Herlev, Denmark, 2730
    • Recruiting
    • The Department of Oncology, Herlev Hospital
    • Contact: Rie B Hansen, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

50 subjects with bone metastases caused by primary breast cancer and 20 healthy volunteers.

Description

Inclusion Criteria:

• Woman
• Primary breast cancer
• Bone metastases
• Competent

Exclusion Criteria:

• Not fluent in spoken Danish
• Chemotherapy or radiation within the last 3 months
• Other chronic pain disease that may affect the quantitative sensory testing or conditioned pain modulation
• Alcohol or medicine abuse
• Pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients; Subjects with painful bone metastases caused by primary breast cancer.
Controls; Gender and age matched healthy volunteers.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conditioned pain modulation (CPM) determined by cuff pressure algometry	CPM will be determined by placing two inflatable cuffs around the lower legs; one providing a test stimulus and the other a conditioning stimulus. First, the pressure pain detection and tolerance thresholds (kPa) are determined on each lower leg using an increasing pressure of 1 kPa/s; next a constant conditioning stimulus is applied to the dominant lower leg and 10 seconds later the pain pressure detection and tolerance threshold (kPa) are simultaneously determined on the non-dominant leg. The CPM effect is assessed as the percent difference between the measured thresholds on the non-dominant lower leg.	1 day
Sensory mapping with thermorollers and brush	Sensory changes to cold, warm and dynamic mechanical stimulation with thermo rollers (25°C and 40°C) and a standardized brush (No. 5, Somedic). Determination of area with either increased, decreased or painful changes.	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mechanical pain threshold with PinPrick.	Determination of the mechanical pain threshold with PinPricks using a series of five ascending and five descending stimulus intensities (range 8 mN - 512 mN). The threshold is calculated as the geometric mean of the supra- and sub-threshold readings (mN).	1 day
Wind up ratio with Pin Prick	Determination of the pain rating (numeric rating scale, range 0-100) to 10 repeated stimuli with either a standardized brush or a PinPrick (256 mN). The wind up ratio is calculated as the arithmetic mean of the pain intensity rating for the series of stimuli divided by the arithmetic mean of the pain intensity rating for the single stimulus.	1 day
Cuff pressure pain threshold and pressure pain tolerance determined by cuff pressure algometry	Pressure pain detecting threshold and pain tolerance threshold (kPa) will be determined by placing two inflatable cuffs around the lower legs. The two thresholds are determined at the same time using an increasing pressure of 1 kPa/s.	1 day
Temporal summation of pressure pain	Determination of the pain rating (VAS, range 0-10) to 10 repeated stimuli with cuff pressure (pain tolerance threshold). The wind up ratio is calculated as the difference between the normalized mean of the pain intensity rating for the last series of stimuli divided by the normalized mean of the pain intensity rating for first stimuli.	1 day
Questionnaire - The Short Form Brief Pain Inventory	The short form Brief Pain Inventory measures pain intensity, localization of pain and influence on daily activities and quality of life through 9 items. All items cover the last 24 hours. Measurement of worst, least, average and current pain on a scale from 0-10, where 0 equals "no pain" and 10 equals "pain as bad as you can imagine"; the measures are used individually or combined into a mean severity score. Determination of pain localization using a pain drawing (human figure); the information is used qualitatively. Determination of pain relief on a scale from 0-100%. Measurement of how much pain interferes with daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others, and sleep; the measurement is done on a scale from 0-10, where 0 equals "does no interference" and 10 equals "completely interferes"; the seven interference items are combined into a mean score.	1 day
Questionnaire - PainDETECT	Screens for neuropathic pain components through 13 items. Measurement of current, strongest and average pain within the last 4 weeks on a scale from 0-10, 0 equals "none" and 10 equals "maximal"; the measures are used individually. Marking of pain pattern (persistent, fluctuating) according to 4 pictures; a score from -1 to +1 is given depending on pain pattern. Determination of pain localization using a pain drawing and indication of pain radiating to other body regions; radiating pain will give a score of +2. Determination of the sensation of the pain (e.g. burning, prickling, numbness) using 7 items; the scale includes the following choices resulting in the indicated scores; never (0), hardly noticed (+1), slightly (+2), moderately (+3), strongly (+4), and very strongly (+5). The total score is calculated (ranging from 0-38) and the number used to determine the likelihood of a neuropathic pain component with 0-12 resulting in negative, 13-18 unclear and 19-30 positive.	1 day
Questionnaire - The Breakthrough Pain Questionnaire	The Breakthrough Pain Questionnaire is used to assess breakthrough pain intensity, frequency, duration, and triggering and relieving factors through 9 items. The obtained measures are used individually and some only qualitatively. Measurement of average background and breakthrough pain within the last 24 hours on a scale from 0-10, where 0 equals "no pain" and 10 equals "worst pain imaginable". Indication of breakthrough pain episodes within the last 24 hours. Indication of average duration of breakthrough pain episodes using six time intervals ranging from "less than one minute" to "more than 120 minutes"; indication of the time from onset to peak pain using five time intervals ranging from "less than 10 seconds" to "31-60 minutes"; and indication of the predictability of breakthrough pain episodes ranging from "never" to "always". Indication of triggering and relieving factors choosing statements such as "when I move", "when I sit" and "taking prescribed pain medication".	1 day
Questionnaire - Pain Catastrophizing Scale	The Pain Catastrophizing Scale assess catastrophising related to pain experience through 13 items. The subject evaluates 13 statements describing thoughts and feelings that may be associated to pain, e.g. "I feel I can't go on" and "I keep thinking of other painful events", and indicates the degree to which she has these thoughts when experiencing pain. The scale for all items includes the following choices resulting in the scores indicated in brackets; not at all (0), to a slight degree (+1), to a moderate degree (+2), to a great degree (+3), and all the time (+4). The total score is calculated (ranging from 0-52) with a score of 30 or more representing a clinically relevant level of catastrophizing. Three subscales can be calculated: rumination (sum of four items), magnification (sum of three items), and helplessness (sum of six items), with cut-off scores of for clinically relevant levels at 11, 5 and 13, respectively.	1 day

Collaborators and Investigators

• Sponsor: University of Copenhagen
• Collaborators: The Novo Nordic Foundation
• Investigators: Principal Investigator: Anne-Marie Heegaard, PhD, University of Copenhagen

Publications and helpful links

General Publications

• Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012 Jun;153(6):1193-1198. doi: 10.1016/j.pain.2012.02.021. Epub 2012 Apr 3.
• Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, Treede RD. Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur J Pain. 2006 Jan;10(1):77-88. doi: 10.1016/j.ejpain.2005.02.003.
• Kennedy DL, Kemp HI, Ridout D, Yarnitsky D, Rice ASC. Reliability of conditioned pain modulation: a systematic review. Pain. 2016 Nov;157(11):2410-2419. doi: 10.1097/j.pain.0000000000000689.
• Stromgren AS, Sjogren P, Goldschmidt D, Petersen MA, Pedersen L, Groenvold M. Symptom priority and course of symptomatology in specialized palliative care. J Pain Symptom Manage. 2006 Mar;31(3):199-206. doi: 10.1016/j.jpainsymman.2005.07.007.
• Banning A, Sjogren P, Henriksen H. Treatment outcome in a multidisciplinary cancer pain clinic. Pain. 1991 Nov;47(2):129-134. doi: 10.1016/0304-3959(91)90195-4. No abstract available.
• Mercadante S. Managing difficult pain conditions in the cancer patient. Curr Pain Headache Rep. 2014 Feb;18(2):395. doi: 10.1007/s11916-013-0395-y.
• Laird BJ, Walley J, Murray GD, Clausen E, Colvin LA, Fallon MT. Characterization of cancer-induced bone pain: an exploratory study. Support Care Cancer. 2011 Sep;19(9):1393-401. doi: 10.1007/s00520-010-0961-3. Epub 2010 Aug 1.
• Hald A, Nedergaard S, Hansen RR, Ding M, Heegaard AM. Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. Eur J Pain. 2009 Feb;13(2):138-45. doi: 10.1016/j.ejpain.2008.03.014. Epub 2008 May 21.
• Bloom AP, Jimenez-Andrade JM, Taylor RN, Castaneda-Corral G, Kaczmarska MJ, Freeman KT, Coughlin KA, Ghilardi JR, Kuskowski MA, Mantyh PW. Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers. J Pain. 2011 Jun;12(6):698-711. doi: 10.1016/j.jpain.2010.12.016. Epub 2011 Apr 15.
• Donovan-Rodriguez T, Urch CE, Dickenson AH. Evidence of a role for descending serotonergic facilitation in a rat model of cancer-induced bone pain. Neurosci Lett. 2006 Jan 30;393(2-3):237-42. doi: 10.1016/j.neulet.2005.09.073. Epub 2005 Oct 25.
• Honore P, Rogers SD, Schwei MJ, Salak-Johnson JL, Luger NM, Sabino MC, Clohisy DR, Mantyh PW. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience. 2000;98(3):585-98. doi: 10.1016/s0306-4522(00)00110-x.
• Falk S, Patel R, Heegaard A, Mercadante S, Dickenson AH. Spinal neuronal correlates of tapentadol analgesia in cancer pain: a back-translational approach. Eur J Pain. 2015 Feb;19(2):152-8. doi: 10.1002/ejp.530. Epub 2014 Jun 11.

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2019
• Primary Completion (Anticipated): February 1, 2022
• Study Completion (Anticipated): February 1, 2023

Study Registration Dates

• First Submitted: March 28, 2019
• First Submitted That Met QC Criteria: April 8, 2019
• First Posted (Actual): April 9, 2019

Study Record Updates

• Last Update Posted (Actual): March 2, 2021
• Last Update Submitted That Met QC Criteria: March 1, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Pain; Neurologic Manifestations; Musculoskeletal Diseases; Bone Diseases; Bone Neoplasms; Cancer Pain
• Other Study ID Numbers: H-18041465

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