Peripheral neuropathy incidence is more than 70 per 100,000 person-years and rises with age and diabetes.10,18,19 The prevalence of pain in those with diabetic peripheral neuropathy is approximately 35%.6 Limited disease-modifying treatments exist, thus management typically focuses on treatment of neuropathic pain.4 Systematic reviews from the American Academy of Neurology (AAN), the European Federation of Neurological Societies (EFNS), the Agency for Healthcare Research and Quality (AHRQ), and others report a consensus that the medications with the best evidence to reduce pain in diabetic peripheral neuropathy are serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and gabapentinoids.1,2,9,12,20 Although opioid medications have also demonstrated short-term benefit in the treatment of this disabling condition, the risks include overdose, dependency, addiction, and death.11 These risks have led the AAN and the Centers for Disease Control and Prevention (CDC) to recommend against the treatment of chronic noncancer pain, such as painful peripheral neuropathy, with opioid medications.8,11 Thus, peripheral neuropathy is unique amongst prevalent painful conditions in that multiple nonopioid evidence-based medications exist, and recommendations explicitly prioritize these medications above opioids.
A recent regional study demonstrated that 69.4% of peripheral neuropathy patients receive opioid medications with 18.8% receiving chronic opioid therapy, although other chronic pain conditions were not excluded.14 Furthermore, opioid medications were associated with increased depression, overdose, and dependence without improved in functional status.14 On the other hand, previous studies demonstrate that painful peripheral neuropathy is likely undertreated.6 Patients do not always discuss their neuropathic pain with their physicians, and even when they do, their physicians often do not prescribe guideline-recommended medications.6 To optimize treatment of painful peripheral neuropathy, information on the current prescription practice patterns of neuropathic pain medications is needed.
We aimed to investigate the longitudinal pattern of neuropathic pain medication utilization in patients with peripheral neuropathy with a focus on opioids and guideline-recommended medications. We also determined the patient-related factors associated with neuropathic pain medication use and pain specialist visits.
We used the deidentified Clinformatics Datamart (OptumInsight, Eden Prairie, MN) database, which consists of detailed medical claims data, including pharmaceutical claims, on more than 59.7 million unique individuals insured by United Healthcare from 2001 to 2014. United Healthcare is the largest private insurer in the country, and the population demographics closely match those of the individuals younger than 65 years and privately insured population within the United States. We identified individuals with peripheral neuropathy using a validated ICD-9 code claims definition (356.x, 357.1-8, 357.82, 357.89, and 357.9),13 but we excluded ICD-9 autonomic neuropathy diagnoses (337.0 and 337.1). Patients were required to be18 years and older and have 4 years of continuous insurance enrollment with at least one year before and 3 years after the incident peripheral neuropathy diagnosis. Importantly, claims data are unable to distinguish whether patients had neuropathic pain. Therefore, to focus on peripheral neuropathy as the main indication for pain treatment, we excluded patients who had other diagnoses that result in chronic pain (eg, low-back pain, osteoarthritis, fibromyalgia, lumbar and cervical radiculopathy, rheumatoid arthritis, and irritable bowel syndrome) at or before their peripheral neuropathy diagnosis as previously described.7
2.2. Exposures (patient characteristics)
The database contains patient demographic information including age, sex, race, education, and household income. Using ICD-9 codes from visits before the initial neuropathy diagnosis, we defined diabetes as (249.xx, 250.xx, 362.01-362.03, 357.2), depression as (311.00, 296.30-296.36, 296.2x), and anxiety as (300.0x). Charlson comorbidity index was used to estimate patient comorbidities as previously described with removal of the diabetes components to avoid double-counting this comorbidity.17
2.3. Main outcomes and measures
Opioid medications were defined using the American Hospital Formulary Service (AHFS) class (opiate antagonists: 281000, opiate partial agonists: 280812, and opiate agonists: 280808). Chronic opioid use was defined by having 90 continuous days of opioid prescription, allowing for less than 10 days between prescriptions. This is the same definition previously used by Hoffman et al.,14 which is based on the treatment duration of chronic pain as defined by the International Association for the study of pain (greater than or equal to 90 continuous days).5 Guideline-recommended medications included TCAs (eg, amitriptyline and nortriptyline), SNRIs (eg, venlafaxine and duloxetine), and gabapentinoids (gabapentin and pregabalin).1,2,9,12,20 Visits to pain specialists were considered office visits (CPT codes 99201-99205, 99211-99215, and 99241-99245) with provider category codes for neurologists, physiatrists, and anesthesiologists on or after the index diagnosis.
2.4. Statistical analysis
Descriptive statistics were used to characterize the peripheral neuropathy population in terms of patient sociodemographic (age, sex, race, education, household income, and insurance-type geographic location) and clinical characteristics (Charlson Comorbidity Index, presence of diabetes, depression, and/or anxiety, visits to anesthesiologists, neurologists, and physiatrists).
2.4.1. Current practice patterns
To describe longitudinal patterns of neuropathic pain medication use, we examined patient's prescription states over time. First, we defined the following 8 discrete prescription states: no neuropathic pain medication use, any chronic opioid use (consuming state), and 6 different states for the number of guideline-recommended medications prescribed (#1-6). At the time of any new prescription, a patient would change states and we tabulated the probabilities of each state transition.
2.4.2. Trends in utilization of neuropathic pain medications
To evaluate the change in the frequency of neuropathic pain prescriptions over time, we plotted the number of prescriptions adjusted for the number of patient-days (number of patients with peripheral neuropathy multiplied by the amount of time continuously enrolled in insurance plan for that year) for opioid medications and for each guideline-recommended medication for each year (2002-2014).
2.4.3. Association of patient-level factors with neuropathic pain medication use and pain specialists
Separate multivariable logistic regression models were used to evaluate the association between patient-level variables and the dependent variables of opioid medication use, guideline-recommended medication use, and pain-specialist visits (neurologists, physiatrists, or anesthesiologists) after the incident peripheral neuropathy diagnosis. For opioid medication use, we used 2 different logistic regression models to predict factors associated with any opioid medication use and to predict chronic opioid medication use amongst those patients who received any opioid medications. Given that little is known about the patient-level variables that are associated with these outcomes in patients with peripheral neuropathy, we included all the patient sociodemographic and clinical characteristics (see above) in our models. As a sensitivity analysis, we excluded tramadol from the models evaluating opioid medication use.
All analysis was performed with SAS, version 9.4 (SAS Institute Inc). Figure 2 was created using the ggplot2 package in R v3.4.2.
2.5. Standard protocol approvals, registrations, and patient consents
The University of Michigan IRB determined that this study was exempt.
Patients were followed for a mean (SD) of 3.1 (1.7) years before and 4.5 (1.4) years after the incident peripheral neuropathy diagnosis. Mean (SD) age was 43.1 years (2.8) and 52.4% were men (Table 1). Of the 14,426 patients with peripheral neuropathy, 11.5% were African American, 10.4% Hispanic, 2.5% Asian, and 75.6% non-Hispanic white. In this population, 46.5% had diabetes, 7.8% anxiety, and 4.2% depression.
Opioid medications were prescribed to 65.9% of patients and 8.8% received chronic opioid therapy. Excluding tramadol, opioid medications were prescribed to 62.4% of patients and 6.9% received chronic opioid therapy. At least one guideline-recommended medication was prescribed to 35.7% of the population, 12.4% received 2 or more, 3.8% received 3 or more, and 1.0% received 4 or more of these medications. In those with diabetes, opioid medications were prescribed to 68.5% of patients, 10.2% received chronic opioid therapy, and 39.2% received at least one guideline-recommended medication. The most common guideline-recommended medications were gabapentin (24.7%), pregabalin (8.3%), amitriptyline (6.7%), and duloxetine (5.7%). Pain specialists were involved in the care of 35.9% of these patients, of which, 27.8% saw a neurologist, 8.7% a physiatrist, and 6.4% an anesthesiologist.
3.1. Current practice patterns
Of the 14,426 peripheral neuropathy patients, 8953 (62.1%) never received a guideline-recommended medication and never received chronic opioid therapy (Fig. 1). Before receiving any guideline-recommended medications, 6.5% received chronic opioid therapy. Of those receiving chronic opioid therapy (n = 1266), 26.4% received at least one guideline-recommended medication before chronic opioid status, 6.4% at least 2 medications, 1.6% at least 3 medications, and 0.2% at least 4 different medications. Of the 5473 patients who received neuropathic pain medications, 83% received a guideline-recommended medication, whereas 17% received chronic opioid therapy before receiving any guideline-recommended medications. Of those receiving at least one guideline-recommended medication and receiving more neuropathic pain medications, 84% received a second guideline medication and 16% received chronic opioid therapy before receiving any additional guideline-recommended medications. Similar proportions were seen for those receiving at least 2 and 3 guideline-recommended medication and receiving more neuropathic pain medications.
3.2. Trends in utilization of neuropathic pain medications
From 2002 to 2014, the frequency of opioid prescriptions increased faster than all other guideline-recommended medications (Fig. 2). Amongst guideline-recommended medications, gabapentin had the largest increase.
3.3. Association of patient-level factors with neuropathic pain medication use
No patient-level factors were associated with both high opioid utilization (initiation and chronic use) and low guideline-recommended medication utilization. Older patients and Asians had significantly less initiation of opioid therapy and less guideline-recommended medication (Table 2). Men and Hispanics had significantly less initiation of opioids, less transition to chronic opioid therapy, and less guideline-recommended medications. Diabetes, depression, Charlson score, and pain specialists were all significantly associated with more initiation of opioid therapy, more transition to chronic opioid therapy, and more guideline-recommended medication. Anxiety was significantly associated with more transition to chronic opioid therapy and more guideline-recommended medication. Higher household income was significantly associated with more transition to chronic opioid therapy. Excluding tramadol had minimal effects on the odds ratios for our models investigating initiation of opioids and transition to chronic opioids.
3.4. Association of patient-level factors with pain specialists
Older patients and Hispanics had less visits to pain specialists (Table 3). Asians also had less visits to pain specialists, but this was only significant for anesthesiologists. Seeing other pain specialists is significantly associated with more involvement of the other pain specialists. Higher household income and higher Charlson scores were significantly associated with more involvement of neurologists and physiatrists. Diabetes was significantly associated with less involvement of neurologists and physiatrists. Depression and anxiety were significantly associated with more involvement of neurologists. Higher educational level was associated with less involvement of anesthesiologists.
In a large, national, privately insured population, we found that almost two-thirds of peripheral neuropathy patients receive at least one opioid prescription with nearly 9% eventually receiving chronic opioid therapy even after excluding patients with other diagnoses that result in chronic pain. By contrast, approximately one-third of patients receive at least one guideline-recommended medication for peripheral neuropathy. Importantly, a substantial proportion of patients receive chronic opioid therapy before trying even one guideline-recommended medications for peripheral neuropathy. Very few patients receive more than one guideline-recommended medication with a substantial proportion receiving chronic opioid therapy instead of trying additional evidence-based medications. Furthermore, opioid prescriptions are increasing faster in this population than any of the guideline-recommended medications.
These results illustrate 3 main problems with the current practice of treating painful peripheral neuropathy. One, most patients with peripheral neuropathy are exposed to opioid therapy at some point after diagnosis, which is consistent with 2 previous studies in patients with peripheral neuropathy.14,16 Given the magnitude of this issue, efforts to curb initiation of opioids in this population would likely help reduce the large numbers of patients who eventually transition to chronic opioid therapy. In fact, the peripheral neuropathy population may be an ideal group to study opioid-reducing interventions because of the high prevalence of both initiation and transition to chronic opioid therapy. Two, chronic opioid therapy is common, although AAN and CDC recommendations advise against their use for chronic noncancer pain.8,11 As successful interventions are developed to taper patients off chronic opioid therapy, the enriched peripheral neuropathy population should be targeted. Three, patients with painful peripheral neuropathy often transition to chronic opioid therapy without trying other medications that are known to be effective. No previous studies have focused on the sequence of neuropathic pain medications given to peripheral neuropathy patients. Given that the best evidence supports the use of nonopioids, optimal treatment algorithms may require that a patient fail at least 3 guideline-recommended medications, one in each of the 3 effective classes (SNRIs, TCAs, and gabapentinoids) before trying alternative therapies.1,2,9,12,20 Perhaps even better would be failure of at least 2 medications in each class, including their combinations, before consideration of opioid therapy. However, our data show that only 2.8% of the patients tried 3 guideline-recommended medications and only 0.02% tries 6 or more medications. Improving guideline-concordant care has the potential to not only improve pain control in this population, but also simultaneously decrease both opioid initiation and chronic opioid therapy and should be the focus of implementation efforts.
Besides decreasing opioid medications and increasing guideline-recommended medications for neuropathic pain, improvement of neuropathic pain treatment would also be facilitated with better data on how to treat painful peripheral neuropathy. We currently do not know which guideline-recommended medications are most efficacious because comparative effectiveness data are lacking.2 We also do not know the likelihood of response to additional medications if an initial guideline-recommended medication fails, which would inform how many medications to try. We have little information on the benefits of trying a second medication in the same therapeutic class if the first one fails, although pregabalin treatment after gabapentin failure is a common prescription practice pattern. We also do not know what interventions to try if the guideline-recommended medications all fail. Similarly, where nonpharmacologic approaches to pain treatment fit into the algorithm are unclear. Finally, whether there is any role for opioid therapy in this population is unknown. Future studies should answer these questions, so that clinicians are armed with the necessary data to optimally treat neuropathic pain.
Importantly, no patient-level factors were associated with high opioid use and low guideline-recommended medication use because all variables studied had similar associations with both types of medications. Therefore, the specific population that should be the focus of interventions to improve neuropathic pain treatment practices is unclear. However, patient-level factors associated with both low guideline-recommended medications and low opioid use may require interventions to increase guideline-recommended medications without the unintended consequence of increasing opioid medications as well. Conversely, patient-level factors associated with both high guideline-recommended medications and high opioid use may require interventions to lower opioid use without the unintended consequence of decreasing guideline-recommended medications as well.
We found that older age, male sex, Hispanics, and Asians were associated with less guideline-recommended medications and either less initiation of opioids or transition to chronic opioid therapy. According to a 2012 National Health Interview Survey, Asians and men self-report less severe pain in general compared with other races and women.15 Whether this is true of peripheral neuropathy patients is unknown, and we also do not know whether this is the sole reason for differences in utilization. However, Hispanics report the same proportion of severe pain, and older patients report more severe pain compared with other races and younger patients.15 Physicians may be concerned about the side effects of pain medications in older patients, but both of these observations require further study. Diabetes, anxiety, depression, higher charlson scores, and seeing pain specialists were all associated with higher utilization of opioid and guideline-recommended medications. Patients with more medical problems and comorbid psychiatric diagnoses would be expected to have more pain and higher pain medication utilization.15 Interestingly, high household income was associated with a higher transition to chronic opioid therapy. The implication of this result is that the prescription opioid epidemic in peripheral neuropathy patients does not preferentially affect the poor.
Pain specialists were not associated with less opioid therapy, although this is likely at least partly explained by differences in unmeasured patient characteristics.3 However, the magnitude of the associations makes interventions to increase pain specialist referrals unlikely to succeed in reducing opioid prescriptions. Older age, Hispanic ethnicity, and Asian race were all associated with lower utilization of pain specialists. For older patients and Hispanics, this is likely not secondary to less severe pain as previously stated. However, given that pain specialists are associated with both more guideline-recommended and opioid medications, these differences are unlikely to lead to meaningful changes in long-term pain management given the downsides of chronic opioid therapy. Targeting interventions to pain specialists may be promising given the potential for their practice patterns to influence other physicians.
Limitations include the use of claims data to diagnose peripheral neuropathy, which may lead to misclassification bias. However, a previous study revealed that 93.4% of patients meeting this definition had peripheral neuropathy after medical record review and only 5.1% of controls not meeting this definition had peripheral neuropathy.13 Moreover, we are unable to link the medications specifically as treatments for peripheral neuropathy, but we were able to exclude patients with other indications for chronic pain. Claims data do not have detailed clinical information to allow for judgment of appropriate clinical decision making in individual patients. However, these data can provide important information on the typical prescribing practice patterns in peripheral neuropathy patients to identify areas of potential improvement. Furthermore, the guideline-recommended medications have other indications such as epilepsy and anxiety/depression, but exclusion of treatment for these conditions would only have accentuated the finding of opioid medication use early and often for peripheral neuropathy before these medications. The findings pertaining to pain specialists need to be interpreted with caution given that patients who see pain specialists are likely different than those that do not based on unmeasured variables. For our analyses pertaining to opioid therapy, we could not exclude patients with acute or chronic post-traumatic pain, but we were able to exclude many chronic pain conditions.7 Current analyses focused on logistic regression models. Future studies could take advantage of the longitudinal data available.
Peripheral neuropathy patients receive opioids early and often in the treatment of their pain. Few patients try multiple guideline-recommended medications despite the large proportion that end up on chronic opioid therapy. Decreasing opioid prescriptions and increasing guideline-recommended medications should be the focus of future intervention efforts. Without interventions, opioid prescriptions in the peripheral neuropathy population are likely to continue to rise.
Conflict of interest statement
B.C. Callaghan receives research support from Impeto Medical Inc. He performs medical consultations for Advance Medical, consults for a PCORI grant, consults for the immune tolerance network, and performs medical legal consultations. L.E. Skolarus has received compensation from Bracket Global. J.F. Burke has received compensation from Astra Zeneca for his role on the adjudication committee of the SOCRATES trial. The remaining authors have no conflicts of interest to declare.
B.C. Callaghan is supported by a NIH K23 grant (NS079417) and a VA CSRD Merit (CX001504). K.A. Kerber is supported by NIH/NCRR K23 RR024009, AHRQ R18 HS017690, NIH/NIDCD R01DC012760, and AHRQ R18HS022258. L.E. Skolarus is supported by NIH/NIMHD R01MD00887, NIH/NIMHD R01MD011516, and NIH/NMHD U01MD010579. J.F. Burke is supported by NINDS K08 NS082597 and NIH/NIMHD R01MD00887.
Author contributions: B.C. Callaghan, E. Reynolds, M. Banerjee, and J.F. Burke were involved in the study design, interpretation of the statistical analysis, and critical revisions of the manuscript. B.C. Callaghan also wrote the manuscript. E. Reynolds also performed the statistical analyses. K.A. Kerber and L.E. Skolarus were involved in the interpretation of the statistical analysis, and critical revisions of the manuscript.
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Keywords:© 2019 International Association for the Study of Pain
Pain; Peripheral neuropathy; Guideline recommended medications; Opioids; Epidemiology