lIfestyle iNterventionS for PaIn ReliEf (INSPIRE) (INSPIRE)

Molecular Signatures of Endocannabinoid Induced Pain Relief in Humans: Lifestyle Interventions, Systemic and Localised Changes

This is a 2x2 factorial design randomised controlled trial in which participants with knee pain will be grouped into the diet intervention, exercise intervention, diet and exercise intervention or placebo arm. The study involves intake of dietary supplements and performing routine exercises which are commonly used and are not pharmacological agents. N= 117. 2x2 intervention with individuals per block: placebo (n=27), diet only (n=26), exercise only (n=40), diet + exercise (n=24)

Study Overview

• Status: Completed
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Dietary supplement: Maltodextrin (Placebo); Dietary supplement: Inulin Fibre supplement; Behavioral: Exercise

• Study Type: Interventional
• Enrollment (Actual): 117
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
      • University of Nottingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participants with any pain in or around a knee on most days for more than 3 months
• Participant is willing and able to give informed consent for participation in the study
• Participant eligibility includes those aged >18 years who have a body mass index (BMI) between 18.5 and 39.9 kg/m2

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:

• Have psychosocial or gastrointestinal (e.g. malabsorptive conditions such as IBS/IBD, coeliac)
• Are taking the following medications: immunosuppressants, anticoagulants, amiodarone and/or perhexiline
• Are currently following or anticipated to commence a specialised commercially available weight loss diet and/or program
• Pregnant or breast feeding
• History or current psychiatric illness
• History or current neurological condition (e.g. epilepsy)
• Those undergoing revision, having severe hip OA, inflammatory arthropathies
• Diagnosed non-OA cause of knee pain (e.g. rheumatoid arthritis)
• Neuropathy or diabetes mellitus
• Having taken part in a research study in the last 3 months involving invasive procedures or an inconvenience allowance (this must remain for ALL UoN FMHS UREC approved studies)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise only arm; Joint Academy An app-based exercises platform (Joint Academy®) will be used as an intervention given to the treatment arm. The programme consists of a mixture of open and close chain exercises, a combination of concentric, eccentric and focusing on the global strength of legs including the muscles around the hips and knee joints as well as balance enhancement exercises. The intervention also includes educational sessions integrated into the programme covering the basics of OA, its treatment, self-managing symptoms of OA and the benefits of maintaining a healthy lifestyle. The exercise intervention focuses on core stability and performance, neuromuscular leg strengthening and balance enhancement.	Behavioral: Exercise; Joint Academy An app-based exercises platform (Joint Academy®) will be used as an intervention given to the treatment arm. The programme consists of a mixture of open and close chain exercises, a combination of concentric, eccentric and focusing on the global strength of legs including the muscles around the hips and knee joints as well as balance enhancement exercises.
Placebo Comparator: Placebo arm; The participants in the placebo/control arm will be required to take 10g of maltodextrin for the same period of 6 weeks.	Dietary supplement: Maltodextrin (Placebo); 10g/ day which can be consumed by adding to breakfast cereal/ smoothie/ yogurt or drink of choice
Experimental: Diet only Arm; The participants in the dietary intervention arm will be required to take 20g of inulin for a period of 6 weeks.	Dietary supplement: Inulin Fibre supplement; 20g/ day. Inulin is easily dissolvable in liquid and can be incorporated into the usual diet - by adding to water, juice, smoothies, cereal, yogurt etc.
Experimental: Diet + exercise intervention arm; The participants in this arm will be required to take 20g of inulin for a period of 6 weeks and doing exercise at the same time.	Dietary supplement: Inulin Fibre supplement; 20g/ day. Inulin is easily dissolvable in liquid and can be incorporated into the usual diet - by adding to water, juice, smoothies, cereal, yogurt etc.; Behavioral: Exercise; Joint Academy An app-based exercises platform (Joint Academy®) will be used as an intervention given to the treatment arm. The programme consists of a mixture of open and close chain exercises, a combination of concentric, eccentric and focusing on the global strength of legs including the muscles around the hips and knee joints as well as balance enhancement exercises.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Numerical Rate Score (NRS) for Pain	The Numerical Rate Score (NRS) will be used to assess the changes in the level of pain in response to the intervention between baseline and follow-up. Participants reported their pain on a scale ranging from 0 to 10, where 0 represents no pain and 10 the worst pain imaginable.	Baseline and 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Functional Outcome 30-seconds Sit-to-stand (30CST)	Measures how many times a participant can rise from a chair to a full standing position in 30 seconds.	Baseline and 6 weeks
Change in Functional Outcome Timed-up and go (TUG)	Time in seconds to stand up, walk 3m, return, and sit. Average of 3 trials at baseline and follow-up (at the end of 6 weeks).	Baseline and 6 weeks
Change in Functional Outcome Grip Strength	Measured with dynamometer; average of 3 trials on dominant hand in seated position with participant applying as much grip pressure as possible on the dynamometer. The maximum reading (kg) in taken for each repetition.	Baseline and 6 weeks
Change in Pain Sensitisation Outcome Temporal Summation (TS)	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from at baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality temporal summation (TS). TS assesses sensitivity to sharpness by applying a brief "pinprick" stimulus (256 mN Pinprick; MRC-Systems, Heidelberg, Germany) to the skin with higher ratings potentially suggesting increased spinal cord pain sensitivity. A single stimulus was applied to the rectus femoris (5cm above the mid-point of the patella of the most painful knee), followed by 10 repetitive stimuli at 1/s. Participants rated pain/sharpness intensity on a 0-10 Visual Analogue Scale after both the single and the average of the repeated stimuli. Each test was performed twice, with a 2-minute break between repetitions and the average was taken.	Baseline and 6 weeks
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Superolateral Patella Site	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from at baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at anatomical position: quadricep (2cm above superolateral edge of patella). PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the most painful knee, with lower PPT threshold suggestive of increased pain sensitivity.	Baseline and 6 weeks
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Superomedial Patella Site	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from at baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at anatomical position: quadricep (2cm above superomedial edge of patella). PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the most painful knee, with lower PPT threshold suggestive of increased pain sensitivity.	Baseline and 6 weeks
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Medial Joint Line Site	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from abeline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at the anatomical position: medial joint line (3cm medially from medial edge of patella). PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the most painful knee, with lower PPT threshold suggestive of increased pain sensitivity.	Baseline and 6 weeks
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Tibialis Anterior Muscle Site	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from at baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at anatomical position: tibialis anterior (5 cm distal and 1 cm lateral to the tibial tuberosity). PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the most painful knee, with lower PPT threshold suggestive of increased pain sensitivity.	Baseline and 6 weeks
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Brachioradialis Muscle Site	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at anatomical position: brachioradialis (5 cm medial and distal to the lateral epicondyle) on the arm opposite the painful knee. PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the arm opposite the painful knee, with lower PPT threshold suggestive of increased pain sensitivity.	Baseline and 6 weeks
Change in Short Chain Fatty Acid Butyric Acid	Change in serum levels of short-chain fatty acid (SCFA) butyric acid in response to the interventions. SCFA levels in serum will be measured using mass spectrometry.	Baseline and 6 weeks
Change in Short Chain Fatty Acid Acetic Acid	Change in serum levels of short-chain fatty acid (SCFA) acetic acid in response to theinterventions. SCFA levels in serum will be measured using mass spectrometry.	Baseline and 6 weeks
Change in Inflammatory Protein Interleukin-6 (IL-6) Levels	Change in Interleukin-6 (IL-6) inflammatory protein levels measured with the Olink for a subset of individuals. For Olink cytokine assay panels data is reported in either Normalized Protein eXpression units (NPX) units or absolute concentration units (pg/mL), with the lower limit of detection typically below 1 pg/mL for most assays.	Baseline and 6 weeks
Change in Tumor Necrosis Factor (TNF) Inflammatory Protein Levels	Change in Tumor Necrosis Factor (TNF) inflammatory protein levels measured with the Olink for a subset of individuals. For Olink cytokine assay panels data is reported in either Normalized Protein eXpression units (NPX) units or absolute concentration units (pg/mL), with the lower limit of detection typically below 1 pg/mL for most assays.	Baseline and 6 weeks
Change in Inflammatory Protein Interferon Gamma (IFN-γ) Levels	Change in Interferon gamma (IFN-γ) inflammatory protein levels measured with the Olink for a subset of individuals. For Olink cytokine assay panels data is reported in either Normalized Protein eXpression units (NPX) units or absolute concentration units (pg/mL), with the lower limit of detection typically below 1 pg/mL for most assays.	Baseline and 6 weeks
Changes in Gut Microbiome (Shannon Diversity Index)	The gut microbiome will be measured with shotgun metagenomic sequencing of stool samples and the Shannon Diversity Index will be calculated. The Shannon Diversity Index assesses both the richness (number of different species) and evenness (distribution of individuals among species) within the gut microbiome. A higher Shannon index indicates a more diverse microbiome, while a lower index suggests less diversity.	Baseline and 6 weeks
Change in Serum Endocannabinoid Anandamide (AEA) Levels	Serum levels of Endocannabinoid Anandamide (AEA) will be measured using mass spectrometry in samples collected at baseline and at follow-up (at the end of six weeks). This will help us ascertain the change in levels of Endocannabinoid Anandamide (AEA) in response to the intervention.	Baseline and 6 weeks
Change in Serum 2-arachidonoylglycerol (2-AG) Endocannabinoid Levels	Serum levels of 2-arachidonoylglycerol (2-AG) Endocannabinoid will be measured using mass spectrometry in samples collected at baseline and at follow-up (at the end of six weeks). This will help us ascertain the change in levels of 2-arachidonoylglycerol (2-AG) Endocannabinoid in response to the intervention.	Baseline and 6 weeks
Changes in Calcium Voltage-gated Channel Subunit alpha1 B Gene Expression Levels Using Transcriptomics on a Subset of Individuals	Transcriptomics will be measured using RNA sequencing of blood samples collected at baseline and at follow-up (at the end of six weeks). RNA was extracted from whole blood, and sequencing libraries were prepared and analysed using standard RNA-seq pipelines.	Baseline and 6 weeks
Changes in Solute Carrier Family 12 Member 5 Gene Expression Levels Using Transcriptomics on a Subset of Individuals	Transcriptomics will be measured using RNA sequencing of blood samples collected at baseline and at follow-up (at the end of six weeks). RNA was extracted from whole blood, and sequencing libraries were prepared and analysed using standard RNA-seq pipelines.	Baseline and 6 weeks
Changes in Sodium Voltage-gated Channel Alpha Subunit 11 Gene Expression Levels Using Transcriptomics on a Subset of Individuals	Transcriptomics will be measured using RNA sequencing of blood samples collected atbaseline and at follow-up (at the end of six weeks). RNA was extracted from whole blood,and sequencing libraries were prepared and analysed using standard RNA-seq pipelines.	Baseline and 6 weeks

Collaborators and Investigators

• Sponsor: University of Nottingham
• Investigators: Principal Investigator: Ana Valdes, PhD, Professor in Genetic and Molecular Epidemiology

Publications and helpful links

General Publications

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• Jones CJ, Rikli RE, Beam WC. A 30-s chair-stand test as a measure of lower body strength in community-residing older adults. Res Q Exerc Sport. 1999 Jun;70(2):113-9. doi: 10.1080/02701367.1999.10608028.
• Hjermstad MJ, Fayers PM, Haugen DF, Caraceni A, Hanks GW, Loge JH, Fainsinger R, Aass N, Kaasa S; European Palliative Care Research Collaborative (EPCRC). Studies comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manage. 2011 Jun;41(6):1073-93. doi: 10.1016/j.jpainsymman.2010.08.016.
• Thorstensson CA, Garellick G, Rystedt H, Dahlberg LE. Better Management of Patients with Osteoarthritis: Development and Nationwide Implementation of an Evidence-Based Supported Osteoarthritis Self-Management Programme. Musculoskeletal Care. 2015 Jun;13(2):67-75. doi: 10.1002/msc.1085. Epub 2014 Oct 24.
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• Cui A, Li H, Wang D, Zhong J, Chen Y, Lu H. Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. EClinicalMedicine. 2020 Nov 26;29-30:100587. doi: 10.1016/j.eclinm.2020.100587. eCollection 2020 Dec.
• Barry E, Galvin R, Keogh C, Horgan F, Fahey T. Is the Timed Up and Go test a useful predictor of risk of falls in community dwelling older adults: a systematic review and meta-analysis. BMC Geriatr. 2014 Feb 1;14:14. doi: 10.1186/1471-2318-14-14.
• Millar B, McWilliams DF, Abhishek A, Akin-Akinyosoye K, Auer DP, Chapman V, Doherty M, Ferguson E, Gladman JRF, Greenhaff P, Stocks J, Valdes AM, Walsh DA. Investigating musculoskeletal health and wellbeing; a cohort study protocol. BMC Musculoskelet Disord. 2020 Mar 21;21(1):182. doi: 10.1186/s12891-020-03195-4.
• Luan L, El-Ansary D, Adams R, Wu S, Han J. Knee osteoarthritis pain and stretching exercises: a systematic review and meta-analysis. Physiotherapy. 2022 Mar;114:16-29. doi: 10.1016/j.physio.2021.10.001. Epub 2021 Oct 11.
• Yu D, Peat G, Bedson J, Jordan KP. Annual consultation incidence of osteoarthritis estimated from population-based health care data in England. Rheumatology (Oxford). 2015 Nov;54(11):2051-60. doi: 10.1093/rheumatology/kev231. Epub 2015 Jul 9.
• Moseng T, Vliet Vlieland TPM, Battista S, Beckwee D, Boyadzhieva V, Conaghan PG, Costa D, Doherty M, Finney AG, Georgiev T, Gobbo M, Kennedy N, Kjeken I, Kroon FPB, Lohmander LS, Lund H, Mallen CD, Pavelka K, Pitsillidou IA, Rayman MP, Tveter AT, Vriezekolk JE, Wiek D, Zanoli G, Osteras N. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis: 2023 update. Ann Rheum Dis. 2024 May 15;83(6):730-740. doi: 10.1136/ard-2023-225041.
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• Gohir SA, Eek F, Kelly A, Abhishek A, Valdes AM. Effectiveness of Internet-Based Exercises Aimed at Treating Knee Osteoarthritis: The iBEAT-OA Randomized Clinical Trial. JAMA Netw Open. 2021 Feb 1;4(2):e210012. doi: 10.1001/jamanetworkopen.2021.0012.
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• Karandikar N, Vargas OO. Kinetic chains: a review of the concept and its clinical applications. PM R. 2011 Aug;3(8):739-45. doi: 10.1016/j.pmrj.2011.02.021.
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Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Actual): February 25, 2025
• Study Completion (Actual): February 25, 2025

Study Registration Dates

• First Submitted: November 18, 2022
• First Submitted That Met QC Criteria: December 20, 2022
• First Posted (Actual): January 4, 2023

Study Record Updates

• Last Update Posted (Estimated): September 16, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Osteoarthritis; Osteoarthritis, Knee; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Substandard Drugs; Pharmaceutical Preparations; Exercise; Counterfeit Drugs; maltodextrin
• Other Study ID Numbers: 22025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: To comply with the data protection act, personal data will be deleted as soon as possible after it is no longer needed for the study.

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