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Home , Diabetic neuropathy, Peripheral neuropathy

At a Glance Original Research Practical Implications e104 Author Information e119 Web Exclusive www.ajpblive.com

Patterns and Predictors of Initiation in Diabetic

chris M. Kozma, PhD; terra l. Slaton, MS; Wing chow, PharmD, MPH; and Marcia f. t. Rupnow, PhD

f the more than 25 million Americans with dia- 1,2 betes, up to 25% will develop painful diabetic ABSTRACT 3,4 O peripheral neuropathy (DPN). Patients with DPN Objectives: To investigate patterns and predictors of medication are generally in poorer health and incur higher healthcare initiation and type of medication initiated in patients with newly resource utilization and costs than similar patients without diagnosed diabetic peripheral neuropathy (DPN). DPN.5 Moreover, these patients are more likely to have Study Design: Retrospective analysis of a nationwide administra- greater numbers of comorbidities including musculoskeletal tive claims database. and other neuropathic –related conditions,6,7 increasing Methods: Adults with a new principal DPN diagnosis were categorized as initially untreated if they had no newly initiated DPN- the likelihood that they will be prescribed pain . related medication within the fi rst 14 days after diagnosis. Bivariate Given the clinical and economic burden associated with logistic regression evaluated predictors for newly initiating medica- painful DPN, deeper understanding of factors that lead to tion versus being initially untreated. Multinomial logistic regression medication initiation and medication choice is necessary for evaluated predictors for each medication category (antidepres- optimization of patient outcomes. sants, , or multiple medications versus ). Painful DPN is a challenging chronic condition to man- Results: Of 53,753 patients with DPN, 46,335 (86%) were age and often requires a multimodal approach, in parallel initially untreated and 7418 (14%) newly initiated an anticon- vulsant (48%), (28%), (18%), or multiple or sequentially. Guidelines recommend or medications (6%). Having a preindex claim for an , anticonvulsants as fi rst-line treatments in the management of antidepressant, or weak opioid predicted newly initiating another painful DPN.8-10 Of the antidepressants and anticonvulsants DPN-related medication. A weak opioid preindex predicted switch- available in the United States, only (an antide- ing to another medication category after diagnosis and a strong pressant) and (an anticonvulsant) are indicated opioid preindex predicted switching to an antidepressant or multiple medications. A preindex anticonvulsant predicted switch- for the management of painful DPN.11,12 However, a meta- ing to an opioid. A preindex antidepressant was not predictive of analysis of the available data suggested that other antidepres- switching. Of the patients who newly initiated medication, 28% had sants (tricyclic antidepressants, selective serotonin reuptake received an opioid preindex and 43% to 74% received an opioid inhibitors) and anticonvulsants (, sodium-channel between 14 and 180 days postindex. blockers, membrane-stabilizing agents) also reduce chronic Conclusions: Prior medication use is the most signifi cant predic- more effectively than .13 tor of whether patients initiate a new medication at the time of When antidepressants or anticonvulsants provide insuf- a new DPN diagnosis, as well as what type of medication they receive. Opioid use is common before and after starting a new fi cient pain relief, guidelines for the management of pain- medication for DPN. ful DPN recommend opioid therapy.8-10 Limited literature Am J Pharm Benefi ts. 2013;5(5):e111-e121 examining treatment patterns within patients with painful DPN has suggested that opioids are a commonly used class of medications,7,13 but the reasons and timing for introduc- ing an opioid regimen are not well documented. Given the chronic nature of DPN, treatment with a long-acting opioid (sustained-release, extended-release, or controlled-release formulations) is a recommended component of multimodal management strategies.14 Currently, only 1 opioid is indicated

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The index date was the date of the fi rst principal PRActIcAl IMPlIcAtIONS diagnosis of DPN in the identifi cation window Improved understanding of pain progression and consideration of what constitutes (January 1, 2006, to June 30, 2009), which was optimal are needed in planning for diabetic peripheral neuropathy selected to allow for analysis of claims data for (DPN) medication pharmacy benefi ts. 360 days preindex through 180 days postindex. I At DPN diagnosis, 14% of patients initiated a DPN-related medication, mostly an To be eligible for inclusion, patients were re- anticonvulsant or antidepressant (66%), followed by opioids (28%) and combina- quired to be at least 18 years of age at the in- tion treatment (6%). dex date and continuously eligible for insurance I Having a DPN-related medication claim before DPN diagnosis predicted initiating plan and pharmacy coverage throughout their another DPN-related medication at diagnosis, illustrating the diffi culties in fi nding optimal regimens. preindex and postindex periods. Patients were excluded if they had a diagnosis of DPN in the I Many patients received opioids before or after their diagnosis. 360-day preindex period (ie, only “newly” diag- nosed patients were analyzed). Patients were divided into 2 cohorts: the new- ly initiated medication group and the initially un- for the management of painful DPN in the United States treated group. Because prescriptions were not linked to a ( extended release).15 Nonetheless, patients specifi c diagnosis, rules were defi ned to identify patients with DPN are up to 10 times more likely to receive a who received medications for the DPN diagnoses. The short-acting opioid than a long-acting opioid.2,7,16-20 To goal of the rules was to create a high degree of confi dence our knowledge, predictors for the use of long-acting or that the new medication therapy was related to the DPN short-acting opioids in the management of painful DPN diagnosis. The newly initiated medication group included have not been explored previously. patients who received a new prescription for a DPN-re- The primary objective of this analysis was to investi- lated medication (Appendix) within 14 days postindex. gate predictors of medication initiation and type of medi- The 14-day window was selected to identify medications cation initiated in newly diagnosed DPN patients. that were likely to have been initiated for the new DPN diagnosis; it was long enough to allow patients up to 2 MetHODS weeks to fi ll their new prescription after the DPN diagno- Data Source sis, but short enough to exclude DPN-related medications The data source for this analysis was employer-based that were prescribed for subsequent diagnoses. Patients claims from the MarketScan Research Database.21 The an- in the newly initiated medication group could have used nual medical databases include private-sector health data other medications (including another medication from the from approximately 100 payers and more than 500 million same category) previously, but they were excluded from claim records. The database represents the medical experi- the analysis if they had another claim in the 360-day pre- ence of insured employees and their dependents for active index period for the same medication (eg, generic level) employees, early retirees, those who continue on COBRA, that they received within 14 days postindex. and Medicare-eligible retirees with employer-provided To increase certainty that patients were using medica- Medicare Supplemental plans. The database includes in- tions related to DPN and not for other purposes, patients tegrated patient-level data for inpatient, outpatient, and in the newly initiated medication group were excluded drug claims, as well as insurance eligibility. The database from the analysis if they had any of the following diagno- is de-identifi ed and compliant with the Health Insurance ses between the DPN diagnosis and the newly initiated Portability and Accountability Act of 1996. As such, no in- medication: a newly initiated antidepressant and a men- stitutional review board approval was necessary. tal health diagnosis (ICD-9-CM codes 290.xx-319.xx); a newly initiated anticonvulsant and a diagnosis of epilepsy Study Design and recurrent seizures or convulsions (ICD-9-CM codes This retrospective analysis included claims from Janu- 345.xx or 780.3); a newly initiated antidementia agent ary 1, 2005, through December 31, 2009 (Figure 1). A and a diagnosis of a mental disorder or of the diagnosis of DPN was identifi ed from International Clas- nervous and sense organs (ICD-9-CM codes 290.xx-319. sifi cation of , 9th Revision, Clinical Modifi cation xx or 320.xx-389.xx); or a newly initiated antihyperten- (ICD-9-CM) codes 250.6X ( with neurologic sive or antiarrhythmic agent and disease of the circulatory manifestations) or 357.2X ( in diabetes). system (ICD-9-CM codes 309.xx-459.xx).

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Figure 1. Study Timeline

ID window starts ID window ends 1/1/2006 6/30/2009

New Rx treatment within 14 days

Identify new DPN Data availability start Data availability end diagnosis in ID window 1/1/2005 12/31/2009

DPN indicates diabetic peripheral neuropathy; ID, identification; Rx, prescription.

The newly initiated medication group was divided version 9.2 (SAS Institute Inc, Cary, North Carolina). For into subgroups by the category of medication received: descriptive analyses, categorical variables were summa- antidepressant, anticonvulsant, opioid, or multiple medi- rized using frequencies and percentages, and continuous cations. The analysis was originally designed to include variables were summarized with means and standard de- antiarrhythmics, antidementia agents, antihypertensives, viations. Two independent logistic regressions were con- or topical anesthetics, but these categories occurred too ducted in which the possible predictors were age, sex, infrequently (<0.23% of the total population) for mean- wage status, Medicare indicator, resource use, comorbidi- ingful interpretation; therefore, patients who were newly ties, and drug use variables. The World Health Organi- initiated on these medications were excluded. zation (WHO) analgesic ladder was used to categorize The initially untreated group included patients who did drug use variables as nonopioids (WHO-1), weak opioids not receive a new DPN-related medication within the first (WHO-2), and strong opioids (WHO-3). The bivariate lo- 14 days postindex. Patients were excluded from the ini- gistic regression predicted whether patients newly initiated tially untreated group if they had received a DPN-related medication or were initially untreated. Odds ratios (ORs) medication during the 60 days leading up to the index and 95% confidence intervals (CIs) were determined for date or if they received their first DPN-related medication each predictor, and goodness of fit was examined with a between postindex days 14 and 31. The purpose of these Hosmer-Lemeshow test. A multinomial logistic regression exclusion criteria was to reduce ambiguity by removing predicted which DPN-related medication (anticonvulsant, patients whose medications might have been related to opioid, antidepressant, or multiple medications) was new- the new DPN diagnosis but did not satisfy the criteria for ly initiated, with opioids as the reference category. An inclusion in the newly initiated medication group. exploratory analysis used logistic regression to evaluate Patients with any of the following were excluded predictors for long-acting opioids versus short-acting opi- from the study: a documented diagnosis of malignant oids among patients with newly initiated opioids. Another neoplasm (ICD-9-CM codes 140.XX-172.XX, 174.xx- exploratory analysis examined the frequency and per- 209.3X, or 209.7x) during the study period (2005-2009); centage of patients (initially untreated or by newly initi- pregnancy (ICD-9-CM codes 630.XX‑679.XX, or V22.XX); ated medication) with subsequent claims for DPN-related during the preindex or postindex period; negative, zero, medications 14 to 180 days postindex. or missing days of supply or quantity on DPN-related medication claims; or long-term inpatient care, custodial Results care, or hospice (place of service codes 27, 33, and 34, Analyzed Patients respectively) during the study period. Of the 290,449 patients with any diagnosis code for DPN in the study period, a total of 53,753 had a new Statistical Analysis principal DPN diagnosis in the identification period All analyses were performed using SAS for Windows and satisfied all other study inclusion criteria (Figure 2).

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Figure 2. Identification of Study Sample

Patients with DPN diagnosis in identification windowa 290,449

Malignant neoplasm at any time 38,883 Not covered 12 months pre-index to 6 months post index 84,044 Less than 18 years of age 32,831 Any invalid study-related Rx claimb 1794 Incomplete pharmacy coverage 22,474 Pregnancy-related diagnosis during study period 415 Long-term inpatient care or hospice 748 No primary diagnosis for DPN 19,513 Any claim for index DPN-related Rx in prior 360 days 17,850 Potential competing diagnosis for DPN-related Rx 116 First DPN-related Rx 14 to 31 days post indexc 3193 DPN-related Rx categories too small to included 157 No newly initiated Rx, but exposure in prior 60 days 14,678

Study sample 53,753 Initially untreated 46,335 Newly initiated medication 7418 Anticonvulsant 3589 Opioid 2068 Antidepressant 1316 Multiple medications 445

DPN indicates diabetic peripheral neuropathy; Rx, prescription. aPatients with a diagnosis of DPN between January 1, 2006, and June 30, 2009. bSuch as claims with negative, zero, or missing days of supply. cPatients who received their first DPN-related medication between 14 and 31 days postindex were considered ambiguous and were not included in the analysis. dIncluded anesthetics, antihypertensives, and antidementia medications.

There were 46,335 (86%) initially untreated patients with Predictors for Newly Initiating a DPN Medication no newly initiated medication and no prior exposure Results of the bivariate logistic regression are provided in to DPN-related medications within 60 days before the Figure 3. The most predictive variables, based on ORs, for DPN diagnosis. Of the 7418 patients who newly initiated newly initiating medication were previous claims for an an- medication, 3589 (48%) received an anticonvulsant, 2068 ticonvulsant (OR = 5.99; 95% CI, 5.51-6.52), an antidepres- (28%) received an opioid, 1316 (18%) received an anti- sant (OR = 6.06; 95% CI, 5.57-6.59), and a weak opioid (OR depressant, and 445 (6%) received multiple medications. = 2.33; 95% CI, 2.19-2.48). Patients had lower odds of newly Patient baseline characteristics are provided in Table initiating medication if they were male (OR = 0.87; 95% CI, 1. During the 360-day preindex period, the percentage of 0.82-0.92), saw a podiatrist in the preindex period (OR = patients who received an anticonvulsant, opioid, or anti- 0.62; 95% CI, 0.58-0.67), or saw an internist in the preindex depressant (other than their index DPN-related medica- period (OR = 0.86; 95% CI, 0.81-0.91). The only variables in tion) was 27%, 53%, and 28%, respectively, in the newly the model that were not statistically significant predictors for initiated medication group, and 3%, 22%, and 3%, respec- newly initiated medication versus being initially untreated tively, in the initially untreated group. Patients in the newly were a diagnosis of anxiety (P = .961) or depression (P = initiated medication group had higher rates than initially .413). Goodness of fit as assessed by the Hosmer-Lemeshow untreated patients for preindex emergency department statistic was adequate (P = .374). Concordance was 78% and visits (35% vs 24%) and inpatient hospitalizations (23% vs the C statistic was 78%. 15%). The newly initiated medication group also incurred higher costs (mean = $16,699; standard deviation [SD] = Predictors for Which Medication Was Initiated $31,751) during the preindex period than the initially un- A multinomial logistic model was used to identify treated group (mean = $11,237; SD = $24,098). predictors for newly initiating an opioid (the reference

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Table 1. Baseline Patient Characteristics Newly Initiated Medication Initially Untreated Characteristics (n = 7418) (n = 46,335) Age, y, mean (SD) 61.3 (12.3) 63.2 (13.2) Sex, female, n (%) 3974 (53.6) 20,325 (43.9) Region, n (%) Northeast 512 (6.9) 5455 (11.8) North Central 2302 (31.0) 13,607 (29.4) South 3229 (43.5) 18,693 (40.3) West 1355 (18.3) 8461 (18.3) Employee classification, n (%) Hourly 2925 (39.4) 16,120 (34.8) Salary 1128 (15.2) 8183 (17.7) Other/unknown 3365 (45.4) 22,032 (47.5) Health plan, n (%) Medicare 2688 (36.2) 20,006 (43.2) Preferred provider organization 2515 (33.9) 14,302 (30.9) Health maintenance organization 1045 (14.1) 5450 (11.8) Point of service (noncapitated) 549 (7.4) 3249 (7.0) Comprehensive 401 (5.4) 1796 (3.9) Point of service (capitated) 39 (0.5) 311 (0.7) Consumer-driven health plan 71 (1.0) 517 (1.1) Missing/unknown 70 (0.9) 481 (1.0) Exclusive provider 40 (0.5) 223 (0.5) Comorbidities, n (%) Any neuropathic pain conditiona 1409 (19.0) 4124 (8.9) Any musculoskeletal pain condition 4535 (61.1) 20,828 (45.0) Arthritis and other arthropathies 2168 (29.2) 9130 (19.7) Back and neck painb 1264 (17.0) 4290 (9.3) Lumbago 1049 (14.1) 2982 (6.4) Low back pain 1021 (13.8) 2458 (5.3) Osteoarthritis 1217 (16.4) 4998 (10.8) Cardiovascular disorders 5167 (69.7) 31,397 (67.8) Sleep disorders 704 (9.5) 3196 (6.9) Mental disorders 696 (9.4) 1732 (3.7) Anxiety 156 (2.1) 383 (0.8) Depression 514 (6.9) 1159 (2.5) Preindex DPN medications, n (%)c Anticonvulsant 1993 (26.9) 1514 (3.3) Antidepressant 2042 (27.5) 1562 (3.4) Mild analgesic (WHO-1) 2416 (32.6) 8636 (18.6) Weak opioid (WHO-2) 3625 (48.9) 9233 (19.9) Strong opioid (WHO-3) 1135 (15.3) 1821 (3.9) Preindex healthcare utilization Emergency department visit, n (%) 2616 (35.3) 11,351 (24.5) Inpatient hospitalization, n (%) 1715 (23.1) 6931 (15.0) Number of outpatient visits, mean (SD) 23.0 (19.8) 18.9 (17.6) DPN indicates diabetic peripheral neuropathy; SD, standard deviation; WHO-1, World Health Organization nonopioids; WHO-2, World Health Organization weak opioids; WHO-3, World Health Organization strong opioids. aOther than DPN. bExcluding low back pain. cPatients could receive DPN medications from more than 1 category preindex (from 360 to 60 days before diagnosis).

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Figure 3. Odds Ratio and Confidence Intervalss for Predicting Initiation of a DPN Medication From Bivariate Logistic Regression

Model Term Odds Ratio 95% Confidence Interval Age 0.994 (0.990-0.998) Male (vs female) 0.871 (0.824-0.992) Hourly (vs salary/other) 1.180 (1.112-1.251) Medicare (vs all other) 0.778 (0.708-0.854) Podiatrist visit—at least 1 preindex 0.621 (0.579-0.667) Internist visit—at least 1 preindex 0.863 (0.814-0.914) Number of prescriptions preindex 1.009 (1.008-1.010) Anxiety diagnosis preindex 1.006 (0.790-1.281) Depression diagnosis preindex 1.062 (0.920-1.226) Back/neck pain with neuropathic pain 1.552 (1.380-1.746) Musculoskeletal condition 1.326 (1.245-1.412) Preindex availability of anticonvulsants 5.994 (5.513-6.517) Preindex availability of antidepressants 6.060 (5.571-6.591) Preindex availability of a drug in the WHO-1 category 1.317 (1.235-1.405) Preindex availability of a drug in the WHO-2 category 2.330 (2.192-2.476) Emergency department visit preindex 1.074 (1.005-1.148) Inpatient hospitalization preindex 1.355 (1.256-1.461) Number of outpatient visits preindex 0.992 (0.990-0.994)

WHO-1 indicates World Health Organization nonopioids; WHO-2, World Health Organization weak opioids.

Figure 4. Odds Ratios and Confidence Intervals for Significant Predictors for Type of Drug at Initiation From Multinomial Logistic Regression

Anticonvulsants Model Term Odds Ratio 95% Confidence Interval Antidepressants Anticonvulsant Antidepressant Multiple vs Opioid vs Opioid vs Opioid Multiple 1.017 Male (vs female) 0.864 (0.908-1.139) (0.748-0.998) (0.663-0.970) 0.784 0.943 Hourly (vs salary/other) 0.794 (0.836-1.065) (0.678-0.930) (0.803-1.262) 1.007 0.744 Region of West 1.363 (0.579-0.956) (1.002-1.885) (0.755-2.080) 1.253

0.658 Podiatrist indicated on index visit 0.524 (0.568-0.762) (0.426-0.645) (0.337-0.646) 0.466

1.290 Chiropractic visit preindex 1.296 (1.009-1.649) (0.958-1.753) (0.845-2.012) 1.304

0.426 Preindex availability of anticonvulsants 1.065 (0.341-0.531) (0.809-1.403) (0.703-1.567) 1.050

1.508 Preindex availability of a drug in the WHO-2 category 1.595 (1.245-1.826) (1.254-2.028) (1.109-2.207) 1.565

1.003 Preindex availability of a drug in the WHO-3 category 1.265 (0.837-1.203) (1.016-1.576) (1.128-2.058) 1.524

1.160 Anxiety diagnosis preindex 1.960 (0.761-1.770) (1.234-3.111) (0.452-2.035) 0.959

0.889 Musculoskeletal condition diagnosis preindex 0.782 (0.785-1.006) (0.667-0.916) (0.704-1.130) 0.892

0.566 Inpatient hospitalization preindex 0.637 (0.492-0.650) (0.533-0.761) (0.795-1.300) 1.017

WHO-2 indicates World Health Organization weak opioids; WHO-3, World Health Organization strong opioids.

category, including weak and strong opioids) versus an an opioid if they lived in the West (OR = 0.74; 95% CI, anticonvulsant or an antidepressant. Figure 4 presents the 0.58-0.96), saw a podiatrist on the index date of their DPN ORs and CIs for significant predictors. The overall model diagnosis (OR = 0.66; 95% CI, 0.57 -0.76), had received test (likelihood ratio) P value was less than .001. Patients an anticonvulsant during the preindex period (OR = 0.43; had lower odds of newly initiating an anticonvulsant than 95% CI, 0.34- 0.53), or had a preindex hospitalization

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Table 2. DPN-Related Prescriptions Between 14 and 180 Days Postindex Newly Initiated Medication Anticonvulsant Opioid Antidepressant Multiple Prescriptions Initially Untreated (n = 3589) (n = 2068) (n = 1316) (n = 445) (n = 46,335) DPN Medications Between 14 Number Percent Number Percent Number Percent Number Percent Number Percent and 180 Days Postindex Any DPN-related medicationa 3555 99.1 1714 82.9 1314 99.8 442 99.3 8739 18.9 Anticonvulsant 3529 98.3 682 33.0 445 33.8 378 84.9 1831 4.0 Opioid 1552 43.2 1539 74.4 584 44.4 325 73.0 6392 13.8 Antidepressant 958 26.7 509 24.6 1312 99.7 271 60.9 1209 2.6 Antihypertensive 131 3.7 74 3.6 39 3.0 16 3.6 229 0.5 89 2.5 62 3.0 38 2.9 69 15.5 159 0.3 Antidementia medication 22 0.6 14 0.7 5 0.4 4 0.9 68 0.1 Antiarrhythmic 3 0.1 2 0.1 1 0.1 0 0.0 2 0.0 Multiple DPN-related medications 2017 56.2 861 41.6 773 58.7 390 87.6 1041 2.2 DPN indicates diabetic peripheral neuropathy. aSum of rows exceed 100% because patients could receive medications from more than 1 category.

(OR = 0.57; 95% CI, 0.49-0.65). They had greater odds seeing an internist on the index date of the DPN diagnosis, of newly initiating an anticonvulsant versus an opioid if the number of DPN-related medication claims in the pre- they had a preindex chiropractic visit (OR = 1.29; 95% index period, preindex availability of an antidepressant or CI, 1.01-1.65) or a preindex claim for a weak (WHO-2) mild pain reliever (WHO-1), preindex depression diagno- opioid (OR = 1.51; 95% CI, 1.25-1.83). sis, preindex coronary disease diagnosis, or presence Patients had lower odds of newly initiating an antide- of at least 1 claim for an emergency department visit. pressant versus an opioid if they were male (OR = 0.86; 95% CI, 0.75-0.99), were hourly wage earners (OR = 0.79; Long-Acting and Short-Acting Opioids 95% CI, 0.68-0.93), saw a podiatrist on the index date of Of the 2068 patients who received an opioid within 14 their DPN diagnosis (OR = 0.52; 95% CI, 0.43-0.65), had a days of their DPN diagnosis, 109 (5%) received a long- preindex musculoskeletal condition diagnosis (OR = 0.78; acting opioid and 1959 (95%) received a short-acting opi- 95% CI, 0.67-0.92), or had a preindex inpatient hospital- oid. In a logistic regression analysis (data not shown), ization (OR = 0.64; 95% CI, 0.53-0.76). They had greater patients had significantly lower odds of newly initiating a odds of newly initiating an antidepressant than an opioid long-acting opioid than a short-acting opioid if they lived if they lived in the West (OR = 1.36; 95% CI, 1.00-1.86), in the South (OR = 0.43; 95% CI, 0.21-0.91) or visited a had received a preindex weak (WHO-2) opioid (OR = podiatrist at index (OR = 0.46; 95% CI, 0.24-0.88). Pa- 1.60; 95% CI, 1.25-2.03) or strong (WHO-3) opioid (OR = tients had significantly greater odds of newly initiating a 1.27; 95% CI, 1.02-1.58), or had a preindex anxiety diag- long-acting opioid than a short-acting opioid if they had nosis (OR = 1.96; 95% CI, 1.23-3.11). received a weak (WHO-2) opioid (OR = 2.10; 95% CI, Patients had lower odds of newly initiating multiple 1.21-3.65) or a strong (WHO-3) opioid (OR = 4.16; 95% medications versus an opioid alone if they were male CI, 2.62-6.61) in the preindex period. (OR = 0.78; 95% CI, 0.66-0.97) or saw a podiatrist on the index date of their DPN diagnosis (OR = 0.47; 95% Postindex DPN Medications CI, 0.34-0.65). They had greater odds of newly initiating Claims for additional DPN-related medications be- multiple medications versus an opioid alone if they had tween 14 and 180 days postindex are summarized in a preindex claim for a weak (WHO-2) opioid (OR = 1.57; Table 2. Postindex DPN medications (including refills or 95% CI, 1.11-2.21) or strong (WHO-3) opioid (OR = 1.52; new prescriptions for the index medication) were used 95% CI, 1.13-2.06). in 99% of patients who newly initiated an anticonvulsant, The following variables were not significant in the an antidepressant, or multiple medications, 83% of pa- logistic model and are not included in the figure: age, tients who newly initiated an opioid, and 19% of initially Medicare, being in the North Central or Southern regions, untreated patients. Subsequent claims for DPN-related

www.ajpblive.com Vol. 5, No. 5 • The American Journal of Pharmacy Benefits e117 n Kozma • Slaton • Chow • Rupnow medications were most commonly within the same cat- of neuropathic pain, which recommend initial treatment egory as the newly initiated medication: 98%, 74%, and with an anticonvulsant or antidepressant,10 followed by more than 99% of patients who newly initiated DPN an opioid or multiple medications if the initial medication treatment with an anticonvulsant, opioid, or antidepres- provides insufficient pain relief.8-10 It also illustrates the sant, respectively, had another claim for a medication challenges associated with management of pain in this from that same category (same or different medication) complex DPN population. between 14 and 180 days postindex. Nearly half of the Patients who had been hospitalized during the prein- patients who newly initiated DPN treatment with an an- dex period or who saw a podiatrist on the index date of ticonvulsant (43%) or antidepressant (44%) also received their DPN diagnosis were more likely to newly initiate an an opioid 14 to 180 days postindex. A high percentage of opioid than an anticonvulsant or antidepressant. These patients (42% to 56%) who newly initiated treatment with characteristics could have been markers for more severe- an anticonvulsant, opioid, or antidepressant received ly ill patients whose pain was more severe at the time of medications from multiple categories postindex. Subse- DPN diagnosis and thus required opioid treatment. quent use of antihypertensives, topical anesthetics, anti- The presence of comorbid musculoskeletal or neuro- dementia medications, and anti-arrhythmic medications pathic pain conditions was common in this sample, par- was uncommon. ticularly in the newly initiated medication group. Patients in the newly initiated medication group also had greater Discussion preindex healthcare utilization (eg, preindex DPN medi- In this sample of more than 50,000 patients who had cations, emergency department visits, inpatient hospi- a new principal diagnosis of DPN, approximately 1 in talizations, outpatient visits) and higher healthcare costs 7 patients initiated a new medication within the first 14 than untreated patients. Painful DPN has been shown to days after the diagnosis. The most significant predictor be associated with poorer health and more comorbidi- of newly initiating medication, and which category of ties,6 as well as higher healthcare resource utilization and medication was initiated, was prior use of a DPN-related costs.5 medication. Patients who had received an anticonvul- Opioid use was common during the preindex period; sant or antidepressant previously had approximately 6 a weak (WHO-2) opioid was used in 49% of patients with times greater odds of newly initiating any DPN-related newly initiated medications and 20% of initially untreated medication at index. Similarly, patients who had received patients, and a strong (WHO-3) opioid was used in 15% a weak opioid in the prior 360 days were more than and 4% of patients, respectively. Opioid use during days twice as likely to receive newly initiated medication. In 14 to 180 of the postindex period included 43% to 44% of the multinomial logistic regression, prior opioid use pre- patients who newly initiated an anticonvulsant or antide- dicted newly initiated treatment with an anticonvulsant, pressant in the first 14 days and 73% to 74% of patients antidepressant, or multiple medications instead of an opi- who newly initiated an opioid or multiple medications. oid alone. Patients who had received a weak (WHO-2) Opioids were also the most commonly used DPN-relat- opioid prior to the DPN diagnosis had comparable odds ed medication in the postindex period among patients of switching to an antidepressant, an anticonvulsant, or who were untreated at the time of the DPN diagnosis multiple therapy, whereas patients who had received a (14% of these patients subsequently received an opioid). strong (WHO-3) opioid were more likely to switch to These results confirm previous reports that opioids are multiple DPN-related medications than to an anticon- commonly used in conjunction with anticonvulsants or vulsant alone or an antidepressant alone. A possible antidepressants in DPN patients.2,7,16-20,22-24 However, the explanation was that many patients received an opioid analysis was not designed to evaluate either the dura- to manage pain with an undiagnosed cause; when the tion of or the reason for use during the preindex and source was diagnosed as DPN, they initiated treatment postindex periods, so it is possible that patients received with an anticonvulsant or antidepressant. Conversely, pa- short-term opioid therapy either for breakthrough pain of tients who had received an anticonvulsant preindex were DPN or for another painful condition. more likely to switch to another medication category than Patterns of short-acting and long-acting opioid use in they were to receive a new anticonvulsant, and the odds this analysis were consistent with recommended clinical of switching from an anticonvulsant to an antidepressant practice, which involves initial treatment with a short- or to multiple medications were comparable. These find- acting opioid until the therapeutic daily dose is identified ings are consistent with guidelines for the management and then switching to a long-acting opioid as needed.25

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The analysis was designed to identify patients with a diagnosis. Improved understanding of both nociceptive new DPN diagnosis, and few of these patients received and neuropathic pain progression and consideration of a long-acting opioid as their initial medication. Patients what constitutes optimal pain management at various who had received another opioid (weak or strong) prior stages are needed in the complex population of patients to the new DPN diagnosis were more likely to initiate a with painful DPN. long-acting opioid. It is possible that patients initiated Acknowledgments treatment with a short-acting opioid after the new DPN The authors thank Carmela J. Benson for her contributions to the diagnosis, with the plan to subsequently switch to a long- study conception and acquisition of data. Roxanne Meyer of Janssen acting opioid if needed. Additional research would be re- Scientific Affairs, LLC, and Jonathan N. Latham of PharmaScribe, LLC, quired to confirm whether the use of long-acting opioids, assisted in the preparation and submission of the manuscript. Author Affiliations: Consultant, Saint Helena Island (CMK), SC; which has been recommended in patients with chronic Consultant, West Columbia (TLS), SC; Janssen Scientific Affairs, LLC (WC, pain of DPN,14 increases relative to treatment with short- MFTR), Raritan, NJ. acting opioids after the initial diagnosis. Funding Source: Janssen Scientific Affairs, LLC, supported the re- search and the preparation of the manuscript. Opioid treatment was selected as the reference cat- Author Disclosures: Dr Kozma and Ms Slaton report that they have egory for the multinomial logistic regression. This ap- received funds through a research agreement from Janssen Scientific proach was supported clinically because it evaluated Affairs, LLC. Drs Rupnow and Chow report employment with Janssen Scientific Affairs, LLC, and hold stock in Johnson & Johnson. predictors for conventional analgesic treatment relative Authorship Information: Concept and design (CMK, WC, MFTR); to products with other uses. Because it is not possible analysis and interpretation of data (CMK, TLS, WC, MFTR); critical re- to confirm cause and effect in a study of this nature, vision of the manuscript for important intellectual content (CMK, TLS, WC); statistical analysis (CMK, TLS, MFTR); obtaining funding (MFTR); several aspects of the study design were selected to administrative, technical, or logistic support (WC); and supervision enhance the likelihood that the index medication was (CMK, WC, MFTR). Address correspondence to: Chris M. Kozma, PhD, 84 Tomahawk directly related to a new DPN diagnosis. Patients were Trail, St Helena Island, SC 29920. E-mail: [email protected]. excluded if the “newly initiated” DPN-related medica- tion was also used at any time in the 360-day preindex References period. Many other patients were excluded because 1. Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet: National Estimates and General Information on Diabetes And they did not have continuous coverage from 12 months in the United States 2011. Atlanta, GA: US Department of Health and Human Ser- before to 6 months after the first principal diagnosis of vices, Centers for Disease Control and Prevention; http://www.cdc.gov/diabetes/ DPN. Patients with newly diagnosed DPN who then re- pubs/factsheet11.htm. Published 2011. Accessed July 29, 2011. 2. Gore M, Sadosky A, Tai KS, Stacey B. A retrospective evaluation of the use of ceived a newly initiated medication were excluded if gabapentin and pregabalin in patients with postherpetic in usual-care they had another diagnosis in this interim that could settings. 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Appendix. List of Medications Related to Diabetic Peripheral Neuropathy Opioids Nonopioids Aspirin/phenacetin/caffeine/codeine hydrochloride Acetaminophen/aspirin/caffeine/codeine phosphate hydrobromide Acetaminophen/aspirin/codeine phosphate Bupropion hydrochloride Acetaminophen/butalbital/caffeine/ Acetaminophen/butalbital/codeine phosphate Citalopram hydrobromide Acetaminophen/caffeine/dihydrocodeine bitartrate Acetaminophen/codeine phosphate Acetaminophen/hydrocodone bitartrate Clonidine hydrochloride Acetaminophen/meperidine hydrochloride hydrochloride Acetaminophen/ hydrochloride Desvenlafaxine succinate Acetaminophen/pentazocine hydrochloride Divalproex sodium Acetaminophen/propoxyphene hydrochloride Duloxetine hydrochloride Acetaminophen/propoxyphene napsylate Escitalopram oxalate Acetaminophen/ hydrochloride Ethosuximide Acetaminophen/aspirin/caffeine/codeine phosphate/ Felbamate salicylamide Fosphenytoin sodium Acetaminophen/aspirin/caffeine/codeine/salicylamide Gabapentin Acetaminophen/butabarbital sodium/codeine phosphate hydrochloride Acetaminophen/butalbital/caffeine/codeine phosphate Imipramine pamoate Acetaminophen/caffeine/codeine/salicylamide Aspirin/oxycodone HCl/oxycodone terephthalate Aspirin (buffered)/codeine phosphate Lidocaine Aspirin/butalbital/caffeine/codeine phosphate Memantine hydrochloride Aspirin/caffeine/dihydrocodeine bitartrate Mephenytoin Aspirin/caffeine/hydrocodone bitartrate Methsuximide Aspirin/caffeine/propoxyphene hydrochloride hydrochloride Aspirin/carisoprodol/codeine phosphate hydrochloride Aspirin/codeine phosphate hydrochloride Aspirin/ethoheptazine citrate/meprobamate Aspirin/hydrocodone bitartrate hydrochloride Aspirin/oxycodone hydrochloride Paroxetine mesylate Aspirin/pentazocine hydrochloride Aspirin/propoxyphene hydrochloride Phenytoin sodium Aspirin/propoxyphene napsylate Phenytoin sodium, extended Butorphanol tartrate Phenytoin sodium, prompt Codeine/salicylamide/acetaminophen Pregabalin Codeine phosphate Primidone Codeine sulfate Tiagabine hydrochloride Dihydrocodeine/aminophenol/aspirin/caffeine Dihydrocodeine/acetaminophen/salicylamide Trimipramine maleate Dihydrocodeine/acetaminophen/caffeine sodium Valproic acid Fentanyl citrate hydrochloride Hydrocodone bitartrate/ibuprofen Hydrocodone/aspirin/caffeine hydrochloride Ibuprofen/oxycodone hydrochloride Levomethadyl acetate hydrochloride Levorphanol tartrate Meperidine HCl/promethazine HCl Meperidine hydrochloride hydrochloride sulfate Naloxone hydrochloride/pentazocine hydrochloride Oxycodone hydrochloride Oxymorphone hydrochloride Pentazocine lactate Promethazine/codeine/acetaminophen Propoxyphene hydrochloride Propoxyphene napsylate Tapentadol hydrochloride Tramadol hydrochloride www.ajpblive.com Vol. 5, No. 5 • The American Journal of Pharmacy Benefits e121