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Postgraduate Medicine

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Reduction of opioid use and improvement inchronic pain in opioid-experienced patientsafter topical analgesic treatment: an exploratoryanalysis

Jeffrey A Gudin, Michael J Brennan, E. Dennis Harris, Peter L Hurwitz, DerekT Dietze & James D Strader

To cite this article: Jeffrey A Gudin, Michael J Brennan, E. Dennis Harris, Peter L Hurwitz, DerekT Dietze & James D Strader (2018) Reduction of opioid use and improvement in chronic pain inopioid-experienced patients after topical analgesic treatment: an exploratory analysis, PostgraduateMedicine, 130:1, 42-51, DOI: 10.1080/00325481.2018.1414551

To link to this article: https://doi.org/10.1080/00325481.2018.1414551

Accepted author version posted online: 11Dec 2017.Published online: 22 Dec 2017.

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CLINICAL FOCUS: PAIN MANAGEMENTORIGINAL RESEARCH

Reduction of opioid use and improvement in chronic pain in opioid-experiencedpatients after topical analgesic treatment: an exploratory analysisJeffrey A Gudina, Michael J Brennanb, E. Dennis Harrisc, Peter L Hurwitzc, Derek T Dietzed and James D Stradere

aEnglewood Hospital and Medical Center, Englewood, NJ, USA; bThe Pain Center of Fairfield, Fairfield, CT, USA; cClarity Science, Austin, TX, USA;dMetrics for Learning, LLC, Queen Creek, AZ, USA; eSafe Harbor Compliance and Clinical Services, LLC, Austin, TX, USA

ABSTRACTObjective: There is a need to identify safe and effective opioid-sparing multimodal alternative treat-ment strategies and approaches, including topical analgesics, for opioid-experienced chronic painpatients to mitigate the risk of addiction, misuse, and abuse of opioids.Methods: This subset analysis from a prospective, observational study evaluated changes in opioid use,other concurrent medication use, and pain severity and interference in opioid-experienced patients(OEP) treated with topical analgesics for chronic pain with measures obtained at baseline and 3- and 6-month follow-up.Results: The 3-month opioid-experienced patient (3-month OEP) group included 121 patients whocompleted baseline and 3-month follow-up assessments; 27 opioid-experienced patients completedbaseline and 6-month follow-up assessments (6-month OEP). Demographic characteristics, and meanpain severity and interference scores were similar between groups at baseline. After treatment withtopical analgesics, 49% of patients in the 3-month and 56% of patients in the 6-month group reportedthey had completely discontinued use of opioids. In addition, 31% of patients at the 3-month assess-ment and 30% at the 6-month assessment reported that they were no longer taking any painmedication. Other concurrent medications decreased by 65% after 3 months, and 74% after 6 months.There were statistically significant decreases from baseline in pain severity and interference scoreswithin the 3- (CI:0.7–1.4, 1.4–2.2) and 6-month (CI:0.7–2.4 (severity); CI:1.2–3.5 (interference)) OEP groups.Conclusions: Opioid use and other concurrent medications decreased among opioid-experiencedchronic pain patients after 3- and 6- months of treatment with topical analgesics. Pain severity andinterference scores also decreased. The topical analgesics were reported to be effective and safe for thetreatment of chronic pain, with randomized controlled trials needed to confirm these findings.

ARTICLE HISTORYReceived 1 November 2017Accepted 5 December 2017

KEYWORDSChronic pain; opioids; opioidepidemic; opioid-experienced; topicalanalgesics; pain interference;pain severity

Introduction

Clinicians have been called on to modify the way they assessand effectively manage pain in their patients. Standards andrecommendations have been put forth by national pain socie-ties and health-care accrediting organizations with a goal ofimproving the safe and effective treatment of pain, includingthe reported 100 million Americans experiencing chronic pain[1–6]. Focusing on a patient’s pain was instrumental consider-ing it ‘a fifth vital sign’ [7]. Prescription opioids have beenconsidered one element in the clinical approach to achieveoptimal pain management, including acute, cancer, andchronic noncancer pain. As pain management strategies andapproaches evolved, so did the available treatments. Theopioid crisis in the United States was partially an unexpectedconsequence of these changes in pain management strategiesand priorities.

In recent years, concerns about the massive increase inopioid prescriptions and associated adverse events (AEs)have contributed to renewed efforts to find alternative painmanagement options. These increases in opioid prescribinghave been attributed to treatment for chronic noncancer pain

[8,9]. In addition, the package insert/label for these analgesicsis not typically disease/condition specific but state they areindicated for the management of pain severe enough torequire opioid treatment and for which alternative treatmentoptions are inadequate. When it comes to opioids, the corre-sponding increased rates of dependence, misuse, abuse, diver-sion, addiction, overdose, and death are of significantconcerns to practitioners [10–15]. In 2016, approximately64,000 people died from drug overdoses. Of these, approxi-mately 50,000 were attributed to opioids [16]. This number ishigher than the deaths from the HIV epidemic at its peak, carcrashes at their peak, and gun-related deaths at their peak[16]. In addition, death rates in some patient populations havebeen reported to be higher (>55%) among patients prescribedopioids than those who are not treated with opioids [17,18].Despite the increased deaths from opioids in the past decade,opioid prescriptions have decreased by approximately 13%over the past few years [19]. To address these issues, initiativesfocusing on the proper use of opioids including CDC guide-lines, a National Pain Strategy, changes to regulatory policies,and a risk evaluation and mitigation strategy (REMS) for

CONTACT Jeffrey A Gudin healthmd@optonline.net Englewood Hospital and Medical, 350 Engle Street, Englewood, NJ 07631

POSTGRADUATE MEDICINE, 2018VOL. 130, NO. 1, 42–51https://doi.org/10.1080/00325481.2018.1414551

© 2017 Informa UK Limited, trading as Taylor & Francis Group

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clinicians were introduced to ensure that the benefits ofopioids outweigh inherent risks [1–5].

Once patients have started on opioid treatment for 5 days,patients are at risk for continuing these medications long term[20] and are not likely to discontinue opioids after they havereceived them for 90 days [21]. This enhances recent efforts tominimize potentially unnecessary initial opioid therapy andalso highlights the challenges in addressing those patientswho have already been prescribed them [20,21]. Long-termuse of opioids can lead to tolerance and physical dependencewith increased doses needed to achieve optimal pain control[22]. Further, patients may experience increased side effects ofopioids, with the necessity for close monitoring [23,24].

Utilizing a multimodal and a multi-disciplinary approach topain management is encouraged to reduce opioid consump-tion [25]. In 2016, the American Pain Society released newguidelines for postsurgical pain management, which recom-mends an interdisciplinary approach as well as incorporatingmultimodal strategies, including a focus on nonpharmacologi-cal options and nonopioid medications [26].

One component of these efforts focuses on topical agents,which have the potential to provide analgesic effects withoutthe risk of abuse, misuse, and addiction or many of the sys-temic AEs associated with oral analgesics [27–31]. Topicalmedications lower the risk of systemic AEs and drug–druginteractions, have limited systemic absorption, offer simpledose determination, provide direct access to the target site,and are easy for patients to apply [30,32–34]. A systematicreview concluded that topical analgesics have an importantplace in the management of acute and chronic pain condi-tions [35]. Chronic pain conditions that have been shown tohave been successfully treated with topical analgesics includeosteoarthritis, musculoskeletal, and other chronic joint-relatedissues [36–38].

The Optimizing Patient Experience and Response to TopicalAnalgesics (OPERA) observational study [39] evaluated topicalanalgesic formulations effectiveness and safety in chronic painpatients, changes in pain severity and interference scores, andthe changes in their use of concurrent pain medications at 3-and 6-month intervals [39]. Key findings showed that topicalanalgesics were suggested to be an effective and safe treatmentalternative to opioids and prescription NSAIDs for the manage-ment of chronic pain and that they were effective and safe forthe relief of moderately severe chronic pain attributed to arthri-tis, neuropathic conditions, and musculoskeletal disorders [39].

The purpose of the current analysis was to evaluate theeffect and safety of topical analgesic treatment for chronicpain, decreases in opioid use, decreases in other concurrentmedication usage, changes in severity and intensity of pain,and satisfaction with treatment in a subset of patients fromthe OPERA observational study with a self-reported history ofprior opioid use (opioid experienced).

Materials and methods

Study design

This analysis focused on opioid-experienced patients (OEPs)from the OPERA study [39]. These patients reported being on

an opioid medication at study enrollment. Baseline surveyresponses were compared with responses at 3- and 6-monthtime points after being treated with topical analgesics.Validated tools were used to evaluate and report on painseverity scores, pain interference levels, and changes in con-current medications via self-report.

The research was approved by the IntegReview InstitutionalReview Board and was performed in full accordance with therules of the US Health Insurance Portability and AccountabilityAct of 1996 and the principles of the Declaration of Helsinkiand the International Council for Harmonisation/Good ClinicalPractice [39].

Patients

The OPERA study included 85 clinical sites in the UnitedStates [39]. Prior to being enrolled into the study, patientswho met the study eligibility criteria were consented toparticipate in this study. Inclusion criteria included patients:(1) age 18–64 years, (2) currently experiencing chronic pain,(3) who were prescribed topical analgesics, and (4) who hadinsurance benefits to cover the costs of prescribed medica-tion(s). Patients were excluded from the study if they had acurrent or history of misuse of illicit or prescription drugs orwere a current beneficiary of a government-funded health-care program [39]. Patients who were being treated withopioids upon enrollment were categorized as opioid experi-enced. A total of 121 of the 631 patients enrolled in theOPERA study indicated that they were taking an opioidmedication at the baseline assessment and completed a 3-month follow-up assessment. This group of patients formedthe 3-month OEP group. There were 27 of the 121 patientsof the 3-month OEP group who were taking an opioidmedication at baseline assessment and completed both the3- and the 6-month assessment. This group of patientsformed the 6-month OEP group. These OEPs also had similartraits, including average age and gender, as compared tothe total population of the OPERA study. At time of enroll-ment, all patients reported if they took any additional med-ication(s) for pain relief and any other concurrentmedications and in the 3 days prior to completion of thefollow-up assessments. In addition to the baseline questionsabout current medication usage and the data reported from3- and 6-month assessments, data relating to current med-ication use and the frequency of their use were also col-lected from participants at each month between baselineand the 6-month assessment. The results of 3- and 6-monthdata collection points are reported here. One of the ques-tions asked of patients was ‘What treatments or medicationsare you receiving for your pain?’ These data, along withother data collected, were used to evaluate what percentageof patients de-escalated, escalated, or reported no change intheir medication usage.

Topical intervention and observation

Patients could be prescribed four classes of prescription com-pounds based on the major constituent in each formulation.These included compounds consisting primarily of (1)

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diclofenac, (2) ketoprofen, (3) flurbiprofen, or (4) other formu-lations not containing an NSAID [39].

Study procedures and assessments

Eligible patients completed the validated Brief Pain Inventoryshort form (BPI-sf) [40] and noted any side effects they experi-enced while using the topical medication at baseline and atthe 3- and 6-month follow-up intervals. Concurrent medica-tions included over-the-counter (OTC) agents (e.g. ibuprofen,naproxen, or acetaminophen), prescription NSAIDs (e.g.naproxen sodium, celecoxib, meloxicam), prescription opioids(e.g. fentanyl, hydrocodone, hydromorphone, morphine, oroxycodone), or prescription anticonvulsants (gabapentin orpregabalin). Patients could indicate more than one type ofmedication in these four classes [39].

Study end points

End points evaluated changes from baseline assessment tothe 3- and 6-month follow-up surveys in reported use ofopioid medications, mean BPI-sf pain severity and interferencescores, and changes in concurrent pain medication(s).

Additional end points included an analysis of patient- andinvestigator-reported AEs or serious adverse events (SAEs) inthe 3- and 6-month follow-up groups.

Alternative hypotheses were that in this group of OEPs atbaseline, from baseline to 3 and 6 months, opioid use woulddecrease, BPI-sf scores would decrease, and the use of con-current medications would de-escalate.

Statistical analysis

All variables and maximum sample sizes were used whencalculating descriptive statistics. All continuous variableswere evaluated using the Shapiro–Wilk test to determine nor-mality. Nonparametric statistical tests were used to evaluatethose that were not distributed normally.

Concurrent medication usage was compared between base-line responses and follow-up assessments at 3 or 6 months.Categorized as either de-escalation, escalation, or no change inconcurrent medication, the data were reported as frequenciesand percents. The calculation of de-escalation, escalation, andno change included only patients who reported changes in theuse of opioid, prescription NSAID, and OTC pain medications.Reported reductions of medication at the follow-up assessmentcompared to baseline responses were categorized as de-escala-tion. If a patient indicated the use of one or more concurrentmedications or medication classes at baseline and subse-quently reported decreasing that number at the follow-upassessment, they were categorized as a de-escalation.Reported increases in medications or medication class at thefollow-up assessment compared to the baseline assessmentwere categorized as an escalation. If a patient reported nochange in the medication class(es) from baseline to follow-upassessment, they were categorized as no change [39].

BPI-sf severity and interference scores were evaluated usingthe Wilcoxon Signed Ranks test for continuous paired data at 3-and 6-month assessments, as compared to baseline responses.

Results for each analysis were reported as mean, SD, statistic,and 95% confidence interval for the difference from baseline tothe 3-month follow-up and baseline to the 6-month follow-up.

A two-tailed alpha was set to 0.05 for all statistical compar-isons. All analyses were performed with SPSS v. 23 [41].

Results

Baseline demographic and clinical characteristics ofpatients

An analysis of 121 out of 631 patients enrolled in the OPERAobservational study indicated that they were taking an opioidmedication at the baseline assessment and completed a 3-month follow-up assessment after being prescribed a topicalanalgesic (3-month OEP group). Of these, there were 27patients who completed both the 3- and the 6-month assess-ments (6-month OEP group).

Demographic characteristics were similar between the 3-and 6-month OEP groups and the total OPERA study patientpopulation [39]. A mean age of 47 years for the 3-month OEPgroup was calculated at baseline and a mean age of 49 yearswas calculated for those in the 6-month OEP group (Table 1).The most frequently prescribed topical formulation at baselinewas diclofenac for patients in the 3-month OEP group (42.1%)and 6-month OEP group (44.4%). At baseline, patients in the 3-month OEP group at baseline most frequently reported theuse of an OTC agent and opioid. For the 6-month OEP group,an OTC agent and opioid, or an OTC agent, opioid, and pre-scription NSAID, were most reported at baseline (Table 1). Ahigher percentage (21% vs. 11%) of patients in the 3-monthOEP group indicated all four primary pain complaints than theoverall OPERA 3-month patient population (Table 2).

Change from baseline in the use of Opioids andconcurrent Pain Medications within the 3- and 6-monthOEP Groups

Almost one-half of patients (48.8%) in the 3-month OEP groupdiscontinued their use of opioids at 3 months. In the 6-monthOEP group, 55.6% of patients reported that they no longerwere taking opioids at the 6-month follow-up assessment(Figure 1).

Notedly, approximately 30% of patients in both the 3- and6-month OEP groups reported discontinuing all pain medica-tions at their 3- and 6-month follow-up assessments.

More than 64 percent of patients in the 3-month OEPgroup reported a de-escalation in the use of concurrent painmedications (Figure 2). The percentage of de-escalationsincreased to over 74% in the 6-month OEP group (Figure 3).Medication escalation was reported by 5.8% of patients in the3-month OEP group and 0.0% of those in the 6-month OEPgroup (Figures 2 and 3). No change in patient-reported use ofconcurrent pain medications was reported by 29.8% of the 3-month OEP group and 25.9% of those in the 6-month OEPgroup (Figures 2 and 3).

In the 3- and 6-month OEP groups, one patient changedfrom using opioid and prescription NSAID categories of

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medication at baseline to opioid and OTC categories at follow-up. Their change was categorized as a de-escalation.

In the paired OEP group that completed baseline, 3-month,and 6-month assessments (n = 27), 59.3% of patients de-

escalated their medication at the 3-month follow-up assess-ment (Figure 4). From the 3–6-month assessments for thissame paired group of patients, there was a de-escalation of48.1% (Figure 5).

Table 1. Baseline demographic and clinical characteristics for the 3- and 6-month overall test, overall control, and opioid-experienced patient (OEP) groups.

3-month groups 6-month groups

VariableOverall test group

[39]Overall control group

[39]OEP

groupOverall test group

[39]Overall control group

[39]OEP

group

Number of patients 631 76 121 158 51 27Age, yearsMean (SD) 46.3 (11.1) 45.4 (11.5) 47.0 (10.2) 46.8 (11.4) 43.2 (11.6) 49.8 (9.6)Median 48.0 46.9 48.7 49.8 44.4 50.6Min, max 18.2, 64.3 21.8, 64.6 19.7, 63.4 18.2, 63.9 21.7, 63.5 30.2, 63.4

Age group, years, n (%)18–29 59 (9.4) 8 (10.5) 9 (7.4) 15 (9.5) 8 (15.7) 0 (0.0)30–39 126 (20.0) 18 (23.7) 20 (16.5) 29 (18.4) 11 (21.6) 4 (14.8)40–49 166 (26.3) 19 (25.0) 37 (30.6) 37 (23.4) 16 (31.4) 9 (33.3)50–64 280 (44.4) 31 (40.8) 55 (45.5) 77 (48.7) 16 (31.4) 14 (51.9)

Sex, n (%)Female 383 (60.7) 58 (76.3) 66 (54.5) 93 (58.9) 44 (86.3) 14 (51.9)Male 248 (39.3) 18 (23.7) 55 (45.5) 65 (41.1) 7 (13.7) 13 (48.1)

Prescribed formulation, n (%)● Diclofenac with no ketoprofen orflurbiprofen

280 (44.4) – 51 (42.1) 76 (48.1) – 12 (44.4)

● Ketoprofen with no diclofenac orflurbiprofen

131 (20.8) – 22 (18.2) 36 (22.8) – 7 (25.9)

● Flurbiprofen with no diclofenac orketoprofen

89 (14.1) – 22 (18.2) 24 (15.2) – 4 (14.8)

● Other with no NSAID 131 (20.8) – 26 (21.5) 22 (13.9) – 4 (14.8)Concurrent medication, n (%)None 108 (17.1) 15 (19.7) 0 (0.0) 19 (12.0) 12 (23.5) 0 (0.0)OP alone 26 (4.1) 0 (0.0) 26 (21.5) 4 (2.5) 3 (5.9) 3 (11.1)Prescription NSAID alone 71 (11.3) 0 (0.0) 0 (0.0) 37 (23.4) 0 (0.0) 0 (0.0)Prescription NSAID AND OP 8 (1.3) 0 (0.0) 8 (6.6) 3 (1.9) 0 (0.0) 3 (11.1)OTC alone 262 (41.5) 57 (75.0) 0 (0.0) 54 (34.2) 33 (64.7) 0 (0.0)OTC AND OP 54 (8.6) 2 (2.6) 54 (44.6) 12 (7.6) 1 (2.0) 10 (37.0)OTC AND prescription NSAID 69 (10.9) 1 (1.3) 0 (0.0) 17 (10.8) 1 (2.0) 0 (0.0)OTC AND prescription NSAID AND OP 33 (5.2) 1 (1.3) 33 (27.3) 12 (7.6) 1 (2.0) 11 (40.7)

Bold ‘AND’ indicates patient-reported use of each medication.OEP: opioid-experienced patient; Min: minimum; max: maximum; NSAID: nonsteroidal anti-inflammatory drug; OP: opioid; OTC: over-the-counter; SD: standarddeviation.

Table 2. Baseline primary pain complaint for the 3- and 6-month overall test groups and opioid-experienced patient (OEP) groups.

3-month groupsn (%)

6-month groupsn (%)

Variable Overall test group [39] OEP group Overall test group [39] OEP group

Number of patients 631 121 158 27Not specified 44 (7.0) 4 (3.3) 7 (4.4) 2 (7.4)Tendonitis 27 (4.3) 3 (2.5) 6 (3.8) 0 (0.0)Neuropathy or radiculopathy 99 (15.7) 8 (6.6) 15 (9.5) 3 (11.1)Neuropathy or radiculopathy AND tendonitis 30 (4.8) 0 (0.0) 9 (5.7) 0 (0.0)Myofascial or musculoskeletal 39 (6.2) 10 (8.3) 9 (5.7) 0 (0.0)Myofascial or musculoskeletal AND tendonitis 5 (0.8) 1 (0.8) 3 (1.9) 1 (3.7)Myofascial or musculoskeletal AND neuropathy or radiculopathy 65 (10.3) 17 (14.0) 23 (14.6) 4 (14.8)Myofascial or musculoskeletal AND neuropathy or radiculopathy AND tendonitis 29 (4.6) 5 (4.1) 8 (5.1) 2 (7.4)Arthritis 46 (7.3) 6 (5.0) 10 (6.3) 0 (0.0)Arthritis AND tendonitis 11 (1.7) 1 (0.8) 4 (2.5) 0 (0.0)Arthritis AND neuropathy or radiculopathy 36 (5.7) 9 (7.4) 9 (5.7) 2 (7.4)Arthritis AND neuropathy or radiculopathy AND tendonitis 18 (2.9) 0 (0.0) 3 (1.9) 0 (0.0)Arthritis AND myofascial or musculoskeletal 40 (6.3) 3 (2.5) 11 (7.0) 1 (3.7)Arthritis AND myofascial or musculoskeletal AND tendonitis 6 (1.0) 3 (2.5) 1 (0.6) 1 (3.7)Arthritis AND myofascial or musculoskeletal AND neuropathy or radiculopathy 67 (10.6) 26 (21.5) 23 (14.6) 7 (25.9)Arthritis AND myofascial or musculoskeletal AND neuropathy or radiculopathy ANDtendonitis

69 (10.9) 25 (20.7) 17 (10.8) 4 (14.8)

Bold ‘AND’ indicates that the patient reported each pain complaint.OEP: opioid-experienced patient.

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Figure 1. Paired analysis flow chart of changes from baseline in the use of concurrent pain medications for the 3- and 6-month opioid-experienced patient groups.OP, opioid; OTC, over-the-counter; Rx NSAID, prescription nonsteroidal anti-inflammatory drug

Figure 2. Paired analysis flow chart of changes from baseline in the use of concurrent pain medications for the 3-month opioid-experienced patient group.OP, opioid; OTC, over-the-counter; Rx NSAID, prescription nonsteroidal anti-inflammatory drug

Figure 3. Paired analysis flow chart of changes from baseline in the use of concurrent pain medications for the 6-month opioid-experienced patient group.OEP, opioid-experienced patient; OP, opioid; OTC, over-the-counter; Rx NSAID, prescription nonsteroidal anti-inflammatory drug

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Figure 5. Paired analysis flow chart of changes from 3 months to 6 months in the use of concurrent pain medications for the baseline subset opioid test group.OP, opioid; OTC, over-the-counter; Rx NSAID, prescription nonsteroidal anti-inflammatory drug

Figure 6. Change from baseline in the BPI-sf overall mean pain severity and interference scores within the (a) 3- and (b) 6-month opioid-experienced patient groups.Figure 6a: n = 121, Figure 6b: n = 27; BPI-sf, Brief Pain Inventory short form; Cl, 95% confidence interval of the difference, Lower-Upper. Error Bars: Standard Deviation.

Figure 4. Paired analysis flow chart of changes from baseline in the use of concurrent pain medications for the 3-month subset opioid test group that alsocompleted the 6-month survey.OP, opioid; OTC, over-the-counter; Rx NSAID, prescription nonsteroidal anti-inflammatory drug

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Baseline brief pain inventory scores

The overall mean pain severity score at baseline was 5.7 forboth the 3- and 6-month OEP groups. Overall mean paininterference score was 6.0 for the 3-month and 5.7 for the6-month OEP groups (Figure 6).

Change from baseline in the mean pain severity andinterference scores

Evaluation of changes in overall mean pain severity andpain interference scores revealed statistically significantdecreases from baseline for both the 3- and 6-month OEPgroups. For the 3-month OEP group, the overall mean painseverity score decreased from 5.7 to 4.7 (CI: 0.7–1.4)(Figure 6). For the 6-month OEP group, the overall meanpain severity score decreased from 5.7 to 4.1 (CI: 0.7–2.4).Statistically significant reductions in pain interferencescores (CI: 1.4–2.2, 1.2–3.5) were also evident for both 3-and 6-month OEP groups. The alternative hypotheses wereconfirmed.

Safety

A minimal number of patients reported side effects associatedwith the topical therapy. For the 3-month OEP group, 1.7% ofpatients reported a skin rash, with no AEs reported for the6-month OEP group. No SAEs were reported by clinicians atthe participating study sites.

Discussion

This analysis examines a subset of OEPs enrolled in the pro-spective OPERA observational study [39]. Patients with chronicpain who were taking opioids at baseline were treated withtopical analgesics and completed 3- and 6-month follow-upassessments. Key findings included de-escalations of opioidusage, cessation of pain medication use after 3 and 6 months,reductions in pain severity and pain interference scores, and inaddition to opioids, de-escalations of other concurrent medi-cations. As with the full population of subjects from theOPERA study [39], this subset of OEPs reported their primarychronic pain complaint as either myofascial, musculoskeletal,neuropathic, arthritic, or radiculopathic, or combinations ofthem. In addition to opioids, these OEPs also noted additionalmedications that they were taking at baseline including OTC

Table 3. OEP groups opiate categories and frequency of use at baseline and 3 months, and baseline and 6 months.

3-month OEP group (n = 121) 6-month OEP group (n = 27)

Opiatecode Opiate category name

Baseline n, %Freq. of use

3 months n, %Freq. of use

Baseline n, % Freq. ofuse

6 months n, % Freq.of use

0 No opioid used 0, 0 59, 48.8 0, 0 15, 55.61 Avinza, Kadian (morphine) 2, 1.7

2/day = 1>3/day = 1

1, 0.8AN = 1

– –

2 Demerol (meperidine) – – – –3 Dilaudid, Exalgo (hydromorphone) 2, 1.7

AN = 13/day = 1

1, 0.8>3/day = 1

1, 3.7AN = 1

–

4 Duragesic, Tentora, Actiq (fentanyl) 1, 0.81/day = 1

– – –

5 Lorcet, Lortab, Norco, Vicodin (hydrocodone) 53, 43.8AN = 291/day = 12/day = 93/day = 7>3/day = 7

25, 20.7AN = 131/day = 12/day = 43/day = 4>3/day = 3

14, 51.9AN = 7

1/day = 12/day = 33/day = 3

6, 22.2AN = 6

6 Opana (oxymorphone) 1, 0.8>3/day = 1

1, 0.82/day = 1

– –

7 Oxycontin, Oxyfast, Percocet, Roxicodone (oxycodone andacetaminophen)

55, 45.5AN = 251/day = 52/day = 113/day = 8>3/day = 6

32, 26.4AN = 101/day = 32/day = 73/day = 10>3/day = 2

10, 37.0AN = 6

2/day = 13/day = 2>3/day = 1

4, 14.8AN = 3

3/day = 1

1, 3, 4, 5,7

Combination A 1, 0.8Each AN = 1

– 1, 3.7Each AN = 1

–

3, 7 Combination B 1, 0.8Each 2/day = 1

– – –

3, 5, 7 Combination C – 1, 0.8>3/day + 3/day +

>3/day

1, 3.7Each 3/day = 1

4, 5 Combination D 2, 1.7Each 3/day = 13/day + >3/

day = 1

– – –

5, 7 Combination E 3, 2.5Each 1/day = 1Each AN = 2

1, 0.81/day + 1/day

1, 3.7Each 1/day

1, 3.73/day + AN

Total 121, 100 121, 100 27, 100 27, 100

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agents, prescription NSAIDs, or in combination. Based uponthe anchors for the BPI-sf pain scores, patients experiencedpain that was of moderate severity.

The prolonged use of opioids can lead to physical depen-dence and addiction [42]. The 3- and 6-month follow-upassessments evaluated in these groups of patients being trea-ted with opioids upon enrollment revealed that topicalanalgesics were effective for pain relief based on BPI andmedication change patterns.

Interestingly, a higher percentage of patients (64.5% and74.1%) in the 3- and 6-month OEP groups reported de-escala-tion of their use of concurrent pain medications compared tothe larger corresponding study population of 631 and 158patients (53.6% and 60%) [39]. The ‘Frequency of Opioid Use’analysis (Table 3) affirms the results of de-escalation asreported. This may suggest that those patients who are opioidexperienced have reached a tolerance level on their currentopioid therapy where the addition and supplement of opioid-sparing topical formulations provide an analgesic effect thatprovides for adequate pain relief to allow the patients to reduceor stop their prescribed opioid medication. Also, in the 3-monthoverall matched control group from OPERA (those who werenot on topical analgesic therapy), patients increased their use ofconcurrent medications, including opioids, by 49.3%. After6months, the increase was 53.1% [39]. The finding that approxi-mately 30% of patients completely discontinued all analgesicsafter 3 or 6 months of using topical treatment was of interest.This findingmay support that there is an associated time courseand natural progression of healing with some sub-acute painfulconditions. Further, although not measured, another explana-tion may be that the OEPs were more motivated to discontinuetheir opioid medication(s) and less motivated to strive for morepain relief. More study on this topic is encouraged. In additionto the responses from patients using the validated tools, furtherrandomized control studies may benefit from calculation ofMorphine Milligram Equivalent as well as verification of pre-scription use via a urine toxicology screen or other verificationtests.

There were 14.8% (21/142) of patients who were treatedwith topical analgesics and who completed the baseline assess-ment but did not complete the 3-month assessment. In addi-tion to normal study attrition and withdrawal, the dropoutsmay be reflective of the medication providing adequate painrelief or, consequently, not providing adequate pain relief. Thenumber of patients completing the 6-month assessment (27)was lower than the number of patients who completed the 3-month assessment (121). Data on patients who submitted anincomplete assessment were removed as well as those patientswho no longer met the study’s inclusion criteria, includinghaving insurance coverage for the topical medication.Another explanation that may have contributed to thedecrease, but was not evaluated, is that the topical analgesicwas not providing adequate pain relief. It should be notedhowever that trials studying chronic pain patients routinelyexperience retention issues with their patient population. Forexample, in a routine 3-month, fixed-dose, placebo-controlledtrial, a dropout rate of 20–50% is to be expected [43]. Due to the6-month OEP sample size of 27, any interpretation and conclu-sions drawn for the 6-month data group as to the impact and

efficacy of topical analgesics on a patient’s opioid use should betaken into consideration. A larger sample size and a formal RCTare suggested to determine the potential efficacy and impact ofthe topical analgesic in this group of patients.

Another aspect of the addressing the current opioid epidemicis understanding the financial cost and downstream impact ofprolonged prescription opioid use. This cost is absorbed not justby payors but all of society including families, law enforcementand first responders, employers, and others [44]. Identifying safeand effective opioid-sparing treatments, such as topical analge-sics, provides an opportunity to shorten the amount of time thatpatients are treated with opioids, ultimately reducing down-stream health-care cost and societal impact. There is a need toprovide access to patients and reasonable coverage for thesealternative opioid-sparing therapies, recognizing that they areonly one component of the strategy.

In July 2017, the National Academies of Science,Engineering, and Medicine (NASEM) reviewed the history andevolving role of opioids to identify actions that clinicians andothers can incorporate to respond to the opioid epidemic [45].They found that research on pain was poorly resourced andsuggested that in order to get practical information, thatresearch include studies that emphasize available treatment,including topical analgesic creams, delivered under real-worldscenarios rather than formalized and idealized conditions [45].This further confirms the value of this type of observationalanalysis in addition to the standard methodology of rando-mized clinical trials. Another finding the NASEM committeeput forth is identification of misaligned incentives that currentpayors have that effectively limit non-opioid strategies andapproaches to pain management. They recommend that pub-lic and private payors develop reimbursement models forcomprehensive pain management that increase coverage toencompass these alternative pharmacologic and other non-pharmacologic approaches [45].

Compared to the total population 3- and 6-month OPERAoverall test groups [39], the decreases in pain severity andinterference scores in the 3- and 6-month OEP groups weresimilar. Notedly however, the starting pain severity and inter-ference score levels were higher for the 3- and 6-month OEPgroups. This would not necessarily be unexpected as thosewho are on opioid therapy may have reached a tolerance totheir opioid treatment and it was not adequately addressingtheir pain levels. The results showed that the topical analge-sics provided significant reductions to their pain relief levelsover the course of 3 and 6 months.

There is lack of consensus among health-care providersabout defining opioid-treated patients as naïve, experienced,or tolerant [46]. The FDA has defined opioid tolerance aspatients who have been on an opioid for at least 1 weekwho have been prescribed a certain threshold dose of opioids,which is routinely a higher dose than is prescribed for acutepain. This ‘FDA-endorsed’ definition of opioid tolerance is alsofound in many of the new REMS documents and FDA-approved Medication Guides for new opioids [47]. We definedpatients as opioid-experienced instead of opioid-tolerant aswe did not request the duration of time the patient was onopioid therapy prior to enrolling in the study. That said, some

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researchers and entities have indicated that patients areopioid-naïve despite having been prescribed and treatedwith opioid therapy [46,48]. There is a need for consensusamong health-care providers in order to limit the misunder-standing of the multiple definitions of those treated withopioid therapy. Evaluating the impact of opioid rotation inpatients when determining consensus is also encouraged.Outcomes from this subset of OEPs from the observationalOPERA study suggest that topical analgesics provide an effec-tive and safe treatment alternative to opioids and may assist inshortening the length of time patients who are prescribedopioids for chronic pain are treated with prescribed opioids.

Although opioid prescribing has decreased slightly in thepast few years, the opioids that have been prescribed havebeen for a longer period of time [19], providing one possi-ble explanation of why prescriptions have decreased. Morestudies, including randomized, controlled trials, are encour-aged to evaluate the impact of the National Pain Strategies,including REMS, on financial and societal burden associatedwith prescription opioid use and to confirm the efficacy andsafety results reported here.

Limitations

This analysis included patients from diverse clinical settingsfor the treatment of chronic pain who consented to partici-pate. The primary purpose of this study was not to identifythe optimal agent or compare specific topical analgesics orcombinations of same. Additionally, data were not collectedabout duration or dose of opioid use at baseline assess-ment. These findings are representative of patients whoconsulted a health-care professional for their chronic painand thus may not be representative of the larger generalpopulation who have not sought treatment for their pain.However, to increase the likelihood of a representativeexample of the general population, strict inclusion criteriawere avoided.

The number of patients in the 3- and 6-month OEPgroups made up a smaller sample size than that of thelarger OPERA study [39], and unlike the larger OPERA studyresults, this analysis did not include a control group ana-lysis. A larger sample size in the 3- and 6-month OEPgroups would inform and strengthen the reported results.However, the statistical comparison of the larger studypopulation and this subset of patients yielded results thatwere similar to those reported in the original analysis. Thisfinding suggests that these results accurately representchanges from baseline in overall pain severity and inter-ference scores and use of concurrent pain medications inboth the 3- and 6-month OEP groups.

An analysis of the data showed a decrease in opioid use.Additional measures to confirm the de-escalation or escalationof opioids or other concurrent medications in future clinical trialsstudies are encouraged to confirm these findings. The approachused to analyze changes in concomitant opioid use may not fullytake into consideration all variables to determine with certaintythe effect of topical analgesics on these OEPs. Completer ana-lyses may overestimate the efficacy of a particular treatment.

The follow-up assessment did not require patients to indi-cate why they dropped out of the study. Other than no longermeeting the study’s inclusion criteria or not having matcheddata, this information would have identified other reasons ofwhy patients discontinued the topical medication anddropped out of the study.

Less than 2% of patients reported an AE (e.g. rash) whilethey were taking the topical analgesic. Earlier studies eval-uating topical analgesics show a higher rate of AEs forchronic pain which were then reported in the 3- or 6-month OEP groups [49,50].

Conclusions

These results suggest that the topical analgesics used in thestudy are effective in reducing opioid consumption in someOEPs. They were shown to be safe for the relief of moderate-to-severe chronic pain and patients were satisfied with thetopical route of administration. In addition to the reductions inopioid use and other concurrent pain medications, significantdecreases in pain severity and interference scores were alsoshown. These are encouraging results for the role of topicalanalgesics in the treatment of chronic pain in OEPs.

Acknowledgments

Carole Alison Chrvala, PhD, Health Matters Inc. assisted in editing themanuscript.

Funding

This manuscript was funded by Annie’s Apothecary, Boothwyn Pharmacy,Cypress Compounding Pharmacy and Safe Harbor Compliance and ClinicalServices.

Declaration of interest

JAG and MJB received funds for their roles as Principal Investigatorsand additional protocol-required services. EDH and PLH are employeesof Clarity Science. DTD received funds for statistical analysis. JDS is theCEO of Safe Harbor compliance and Clinical Services. Peer reviewers onthis manuscript have received an honorarium from PGM for theirreview work, but have no other relevant financial relationships todisclose.

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