Decreased Opioid Use and Pain Scores Following Therapy with a Compounded Topical/Transdermal Analgesic: Update on Case-Control Matched

and
Formulation Comparison Results from the Optimizing Patient Experience and Response to Topical Analgesics (OPERA) Observational Study
Jeffrey Gudin, MD1, Michael Brennan, MD2, Edmund Harris, MD3, Peter Hurwitz3, Derek Dietze4
1
Englewood Hospital and Medical Center, Englewood, NJ, 2The Pain Center of Fairfield, Fairfield, CT, 3Clarity Science, Austin, TX, 4Metrics for Learning, LLC, Queen Creek, AZ

Introduction Results Conclusions

Chronic, noncancer pain affects over 100 million Americans and is one of the most frequent reasons for individuals to seek medical care.1 Although Table 1. Patient Characteristics (n= 631 for each) Figure 3. Change in Mean Overall BPI Interference Score and its 7 Components and Overall Severity Score from • Results from this interim analysis suggest that the topical/transdermal analgesics used in this study may:
achieving pain relief and improved quality of life are the primary clinical goals, most patients and healthcare professionals recognize, and the litera- Survey 1 to Survey 3 (n= 631 for each, paired data) – Reduce the use of opioid, anti-inflammatory, and OTC analgesics.
ture supports, 30% pain improvement to be clinically significant—a success level that would be unacceptable in other areas of medicine.2 Despite Mean± SD Range
a wealth of treatment options, as many as 40% of patients treated for chronic pain do not attain adequate analgesia, which can lead to physical 
– Reduce BPI Severity and Interference scores for adult patients with arthritic, neuropathic and musculoskeletal pain.
and social dysfunction and diminished quality of life.1 Female/Male(n) 383/248 – Reduce the number of primary pain complaints for each of arthritis, neuropathy or radiculopathy, and myofascial/musculoskeletal pain or
Further compounding the issue, patients who experience chronic pain often have multiple comorbidities and take multiple medications. Unfortu-  6XUYH\ 6XUYH\ spasm.
AgeatSurvey1(years) 46.3± 11.1 18.2– 64.3
nately, most pain therapies, including opioids and NSAIDs, are associated with adverse effects and the addition of further systemic medications *P<.001 • There was a trend towards more positive effects on BPI Severity and Interference scores for patients using a diclofenac-containing topical/

to control pain increases the risk of drug-drug interactions and side effects.3,4 Moreover, opioids are subject to regulatory control due to the risk DaysbetweenSurveys1&3 75.5± 22.5 40Ͳ 140 transdermal analgesic compared to those using the flurbiprofen- or ketoprofen-containing topical/transdermal analgesics. Further study is
of abuse, misuse, and/or diversion, and therefore may not be appropriate for all patients.5 Successful pain management must provide adequate required to confirm this.

analgesia without excessive adverse effects or risk. SD=standarddeviation • Overall patient satisfaction with topical/transdermal analgesics was high. Topical/transdermal analgesics were safe and well-tolerated.
Topical/transdermal analgesics have the advantage of local application with limited systemic levels of drug.3 Because of the lower systemic  * * * * * * * * * •
• No side effects were reported by 99.5% of patients, with 0.5% (n= 3) reporting a transient rash—none were serious adverse events.
exposure observed with topical/transdermal therapies, there may be a benefit from reduced side effects, a lower risk of drug-drug interactions, Figure 1. Change in Reported Use of Pain Medications from Survey 1 to Survey 3 by Type (n= 631 for each, paired data)

BPIRating(0Ͳ10Scale)


and improved tolerability.3,6 Therefore, evaluation of opioid-sparing treatments including topical/transdermal compounded formulations is critical     • Findings were consistent with previous interim analysis results, and include 32 more investigators and 214 more patients.
  
to identification of safer and more effective approaches to the treatment of pain. Previous research has shown that topical/transdermal treatments • Control group data have been compared with case-control matched test group data (n=76), with statistically significant and positive results
are effective.7 ϯϱй 
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within and between groups. These results will be reported in a peer-reviewed publication.

 

 
• Results from the interim analysis warrant and justify continuation of the OPERA trial.

Purpose ϯϬй Ϯϴ͘ϳй



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OPERA is an ongoing observational survey study of patients ages 18-64 who experience chronic neuropathic or musculoskeletal pain and who have Ϯϱй
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been prescribed a topical/transdermal analgesic in various combinations (e.g., diclofenac, ketoprofen, amitriptyline, gabapentin, bupivacaine or other Ͳ35.3% Ͳ45.5% Ͳ38.6% Ͳ39.6% Ͳ43.3% Ͳ39.1% Ͳ44.7% Ͳ40.0% Ͳ31.3%

pain-relieving transdermal cream). The study protocol did not dictate the treatment decisions for the patients (i.e., number of applications per day). *HQHUDO 0RRG :DONLQJ 1RUPDO 5HODWLRQV 6OHHS (QMR\PHQW 2YHUDOO 2YHUDOO •
Most of the patients had been prescribed opioids or other analgesics.
The purpose of this pre-planned interim analysis of the OPERA study reported here was to:
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1. Validate findings from previous 2015-2016 interim analyses, *Averagescoreonascaleof0=Doesnotinterfere,to10=Completelyinterferes CaseͲcontrolmatchedresults •
ϭϱй **Averagescoreonascaleof0=Nopain,to10=Painasbadasyoucanimagine confirmedthesefindings. • This was a fourth interim analysis. Additional analyses will be conducted at the conclusion of the study.
2. Assess changes in concurrent use of opioids and other pain medications (no change, de-escalation, escalation), •
• Results include all respondents, regardless of number/types of complaints/symptoms and regardless of number/types of pain medications
3. Evaluate the efficacy of the topical/transdermal analgesic in reducing pain in patients experiencing either neuropathic or musculoskeletal pain, ϭϬ͘ϯй currently being taken.
using the Brief Pain Inventory (BPI) Short Form,8 ϭϬй
• This is an observational study. Control group data have been compared to case-control matched test group data, and will be reported in a
4. Compare changes in BPI scores between diclofenac-, flurbiprofen-, and ketoprofen-containing compounded topical/transdermal analgesics,
peer-reviewed publication.
5. Assess patient satisfaction with the topical/transdermal analgesic,
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6. Identify any adverse effects, and Ϯϳ͘ϱй ϲϰ͘ϭй Figure 4. Comparison of Diclofenac- to Flurbiprofen- to Ketoprofen-containing Topical/Transdermal Analgesics:
7. Compare test results (n=631) with unmatched control group results (n=76), and compare case-control matched group results (n=76, paired ĞĐƌĞĂƐĞ ĞĐƌĞĂƐĞ Change in Mean Overall BPI Interference and Severity Score from Survey 1 to Survey 3
data). Ϭй
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Methods
KƉŝŽŝĚƐ ŶƚŝͲ/ŶĨůĂŵŵĂƚŽƌLJ;ZdžͿ Ϭ͘ϬϬ References
Use of OTC pain medicaƟons also decreased (a 51.4% decrease from 66.2% to 32.2%, P<.001). Case-control matched results
hƐĞŽĨKdƉĂŝŶŵĞĚŝĐĂƚŝŽŶƐĂůƐŽĚĞĐƌĞĂƐĞĚ;Ăϱϭ͘ϰйĚĞĐƌĞĂƐĞĨƌŽŵϲϲ͘ϮйƚŽϯϮ͘Ϯй͕Wф͘ϬϬϭͿ͘
Following IRB approval and patient consent, data were collected beginning in 2014 via paper survey forms completed by study participants from found a significantly greater de-escalaƟon of overall pain medicaƟon use in the test group as compared to the control group. 1. Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education: Relieving Pain in America, A Blueprint for
85 physicians who treat patients with chronic pain. The top four physician specialties were: anesthesiology, general medicine, pain management, ͲϬ͘ϱϬ Transforming Prevention, Care, Education and Research. The National Academies Press, 2011.

DĞĂŶŚĂŶŐĞŝŶW/ZĂƚŝŶŐ
and podiatry. Investigator sites were in 12 different states across the USA. Figure 2. Changes in Percentage of Patient-Reported Primary Pain Complaints/Symptoms from Survey 1 to 2. Farrar JT, Young JP, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating
Observation Study Design Survey 3 (n= 631 for each, paired data) scale. Pain. 2001;94:149–158.
Survey 1 (at first patient visit before use of topical/transdermal analgesic): Ͳϭ͘ϬϬ 3. Peppin JF, Albrecht PJ, Argoff C et al. Skin Matters: A Review of Topical Treatments for Chronic Pain. Part One: Skin Physiology and Delivery
Wс͘ϵϴϴ Systems. Pain Ther. 2015 Jan 28. [Epub ahead of print]
• Questions regarding primary pain complaint/symptoms (and location)
Survey1 Survey3 Wс͘ϯϯϲ Wс͘ϭϴϬ 4. Wehling M. Non-steroidal anti-inflammatory drug use in chronic pain conditions with special emphasis on the elderly and patients with relevant
• The BPI Short Form (Severity and Interference components)—used with permission from MD Anderson. comorbidities: management and mitigation of risks and adverse effects. Eur J Clin Pharmacol. 2014;70:1159-72.
• Current medication usage P=.008 Ͳϭ͘ϱϬ Ͳϭ͘ϯϳ
70% Ͳϭ͘ϰϳ Wс͘ϲϲϵ Ͳϭ͘ϰϴ 5. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep
65.5%
Survey 2 (at second patient visit—approximately 45 days since starting use of the topical/transdermal analgesic): 2016;65(No. RR-1):1–49.
• Data not used for this interim analysis. Study designed called for an analysis at approximately half way through the entire study (at Survey 3).
Ͳϭ͘ϲϴ
59.6% 6. Schug SA and Goddard C. Recent advances in the pharmacological management of acute and chronic pain. Ann Palliat Med. 2014;3:263-75.
A more in-depth summative analysis will be conducted at study conclusion.
60% P<.001 P<.001 ͲϮ͘ϬϬ Ͳϭ͘ϴϱ
7. Derry S, Wiffen P, Moore A. Topical Nonsteroidal Anti-inflammatory Drugs for Acute Musculoskeletal Pain. JAMA. 2016 Feb 23;315(8):813-4.
• Same questions as used for Survey 3 below 50.7% Wс͘Ϯϴϳ ͲϮ͘Ϭϯ 8. Cleeland CS. The Brief Pain Index, Short Form. 1991. Pain Research Group.
Survey 3 (at third patient visit—approximately 90 days since starting use of the topical/transdermal analgesic): 50% 46.4%
• All Survey 1 questions ͲϮ͘ϱϬ Wс͘Ϭϯϯ;ƐƚĂƚŝƐƚŝĐĂůůLJƐŝŐŶŝĨŝĐĂŶƚͿ
39.8%
• Questions related to use of the topical/transdermal analgesic 40% 36.8% P=1.000
Percent

All Surveys included queries on any side effects of the topical/transdermal analgesic.
30.9% 31.1%
P=.009
ŝĐůŽĨĞŶĂĐ;ŶсϮϴϬͿ &ůƵƌďŝƉƌŽĨĞŶ;ŶсϴϵͿ <ĞƚŽƉƌŽĨĞŶ;ŶсϭϯϬͿ Study funded by:
Completed forms were collected and entered into Microsoft Excel. 30% Annie’s Apothecary, Kerrville, TX
• For patients with 40 to 140 days between Survey 1 and Survey 3, Survey 1 and Survey 3 records were matched using a unique identifier (n= 723). Annie’s Apothecary, Boerne, TX
92 records were removed due to incomplete/misaligned data. Thus, 631 total paired records used in this third interim analysis. 20.4% Boothwyn Pharmacy, Boothwyn, PA
20% 15.5% Cypress Compounding Pharmacy, Houston, TX
• Control group data were collected from 76 patients who completed Survey 1 (pretreatment questions) and Survey 3 (at 3 months), but did not
receive treatment. Matching of test group patients with control group patients based on gender, number of primary complaint categories and Financial Disclosures
age resulted in 76 paired records. Statistical analyses of results within and between these groups were conducted. 10% Table 2. Overall Patient-Reported Observations on the Use of Topical/Transdermal Analgesics J. Gudin: Honoraria paid by Clarity Science
20.7% 21.5% 9.0% 0.6% 24.0% M. Brennan: Honoraria paid by Clarity Science
• For the subgroup analysis reported here, paired records were found for 280/631 patients using a diclofenac-containing, 89/631 for those using E. Harris: Study funded by the 4 pharmacies listed above
a flurbiprofen-containing, and 130/631 for those using a ketoprofen-containing topical/transdermal analgesic. 0%
Decrease Decrease Decrease Increase Decrease Observation Yes%,No% n Overallsatisfactionwithtopicalanalgesic(n=624)
P. Hurwitz: Study funded by the 4 pharmacies listed above
Data were transferred from Excel into the Statistics Package for the Social Sciences (SPSS, IBM, version 23) for statistical analysis. Descriptive
Arthritis Neuropathyor Myofascial/Musculoskeletal Tendinitis Other Convenient 86%, 14% 626 Very=50% D. Dietze: Analysis paid by Clarity Science
Radiculopathy PainorSpasm
statistics were run for all questions. Statistically significant differences between Survey 1 and Survey 3 results were calculated using the McNemar Easy toapply 95%,5% 627 Somewhat=42%
test for binomial data and the Wilcoxon Signed Ranks test for scale data. The Mann-Whitney test was used for the subgroup analysis. Alpha was Further analysis is needed, as 55% of patients reported more than one primary complaint (Survey 1 mean = 2.1 complaints, Survey 3 mean = 1.8 complaints, statistically Correspondence
significant decrease: P<.001, n= 631, paired data). Preferredoveroralmedication 76%,24% 618 Notatall=8% Peter Hurwitz: peterh@crcsciences.com
set at .05.

Poster #12, International Conference on Opioids, Harvard Medical School, June 11-13, 2017, Boston Massachusetts