Ibuprofen Gel or Capsaicin Cream for my Painful Knee Osteoarthritis?

Identifying Treatment Responders to a Topical Non-steroidal Anti-inflammatory Drug (NSAID) or Topical Capsaicin in Painful Knee Osteoarthritis: A Pilot Series of N-of-1 Trials

Despite evidence that topical non-steroidal anti-inflammatory drugs (NSAIDs) and capsaicin are effective in osteoarthritis (OA), it is still unclear why they work for some people but not others. The investigators are undertaking an individual patient data (IPD) meta-analysis to identify responders according to patient characteristics, however, no studies report the presence of synovial hypertrophy or neuropathic-like pain. These two traits are of interest as they may be used to optimise the treatment effects of the two drugs which work via different mechanisms to reduce pain in OA. The investigators are therefore conducting this pilot n-of-1 trial series.

This pilot n-of-1 trial series will investigate whether a person with OA, who has a different balance between inflammatory and neuropathic pain, shows a preference between these mechanistically different treatments. The trial will also be used to offer recommendations on the use of n-of-1 trial series for individualised (precision) medicine in OA.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Drug: Topical NSAID; Drug: Topical Capsaicin

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
      • Academic Rheumatology, University of Nottingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and non-pregnant women who have had ultrasound and radiographic assessments in the Knee Pain in the Community study

  o Premenopausal women will need to be on an acceptable contraceptive method

• Aged 40-95 years
• Knee pain between 4-8 on the NRS

• Knee osteoarthritis - defined as knee pain plus radiographic changes, based on previous questionnaire responses and radiographic findings

  • Knee pain: individuals with knee pain in and around the knee on most days for at least a month.
  • Radiographic changes: definite joint space narrowing and definite osteophytes (each scoring two or more on the Nottingham Line Drawing Atlas) in the tibiofemoral and/or patellofemoral compartments

• Predominantly neuropathic or inflammatory phenotypes based on previous questionnaire responses (not current status)

  • Predominantly neuropathic phenotype: painDETECT Questionnaire (PDQ) > 13 and synovial hypertrophy (SH) <4 mm
  • Predominantly inflammatory phenotype: SH > 4 mm and PDQ < 13
  • If we cannot recruit enough people with the above thresholds, we will base recruitment on the overall distribution of PDQ and SH scores from the population. The third tertile of PDQ and the first tertile of SH for neuropathic and the first tertile of PDQ and the third tertile of SH for inflammatory phenotypes.

Exclusion Criteria:

• Inability to give informed consent
• Daily use of oral NSAIDs for the last two weeks
• Prior use of Ibuprofen gel or Zacin on the affected knee(s)
• Terminal or untreated major mental illness
• Pregnancy or breastfeeding
• Hypersensitivity or allergy to topical NSAIDs, capsaicin, or other ingredients in the preparations. This includes individuals that experience attacks of asthma, urticaria, or acute rhinitis that are precipitated by NSAIDs
• Current treatment for stomach or duodenal ulcers
• Total joint replacement of affected joint
• Renal failure
• Taking anticoagulants

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• 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: Topical NSAID and topical capsaicin; Within each participant: Topical NSAID (A) or capsaicin (B) are taken for a treatment period of four weeks. This is followed by another four week treatment period with the other treatment. These two treatment periods comprise one treatment cycle. The order of treatments within a treatment cycle is determined randomly (AB or BA). This treatment cycle is repeated so that all participants undergo a maximum of three topical NSAID treatment periods and three topical capsaicin treatment periods (i.e., three treatment cycles). This is reduced to two cycles if they are found to meet the criteria for response at the interim analysis (after cycle two).

Drug: Topical NSAID; Applied four times daily; Other Names: Ibuprofen 5% gel; Drug: Topical Capsaicin; Applied four times daily; Other Names: Zacin 0.025% cream

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline knee pain on 0-10 numeric rating scale (NRS)	Pain experienced in the most painful knee in the past week will be recorded. The following question will be asked for this purpose: "In the past week, on average, how intense was your knee pain rated on a 0-10 scale, where 0 is 'no pain' and 10 is 'pain as bad as could be'?". The change in pain score between period baseline and period end will be calculated	Baseline and end of each treatment period (i.e., after four weeks of treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
End-of-cycle treatment preference	"Considering only the pain relief experienced in this most recent cycle, which treatment do you feel provided satisfactory pain relief?"	At the end of each treatment cycle (i.e., after 4 weeks of NSAID and 4 weeks of capsaicin).
End-of-study overall treatment preference	"Considering all the aspects of the treatment, including its effectiveness and ease of application, which treatment do you prefer?"	At study completion - following six treatment periods (24 weeks of treatment, excluding washouts) or 4 treatment periods for responders at the interim analysis (16 weeks of treatment, excluding washouts)
Weekly knee pain on 0-10 numeric rating scale (NRS)	Pain experienced in the most painful knee in the past week will be recorded. The following question will be asked for this purpose: "In the past week, on average, how intense was your knee pain rated on a 0-10 scale, where 0 is 'no pain' and 10 is 'pain as bad as could be'?".	At end of week 1, week 2, week 3, and week 4 of each treatment period.

Collaborators and Investigators

• Sponsor: University of Nottingham
• Collaborators: Arthritis Research UK Pain Centre; Nottingham University Hospitals Charity
• Investigators: Principal Investigator: Weiya Zhang, PhD, University of Nottingham

Publications and helpful links

General Publications

• Persson MSM, Stocks J, Sarmanova A, Fernandes G, Walsh DA, Doherty M, Zhang W. Individual responses to topical ibuprofen gel or capsaicin cream for painful knee osteoarthritis: a series of n-of-1 trials. Rheumatology (Oxford). 2021 May 14;60(5):2231-2237. doi: 10.1093/rheumatology/keaa561.

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2017
• Primary Completion (Actual): October 16, 2018
• Study Completion (Actual): October 16, 2018

Study Registration Dates

• First Submitted: May 3, 2017
• First Submitted That Met QC Criteria: May 5, 2017
• First Posted (Actual): May 10, 2017

Study Record Updates

• Last Update Posted (Actual): April 18, 2019
• Last Update Submitted That Met QC Criteria: April 16, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: osteoarthritis; ibuprofen; NSAID; topical; capsaicin; n-of-1
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Dermatologic Agents; Antipruritics; Ibuprofen; Capsaicin
• Other Study ID Numbers: B 10022017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Requests for the IPD can be made to the Prof Weiya Zhang. Raw de-identified data may be shared
• IPD Sharing Time Frame: After publication of the study
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No