Abstract
Importance
Polyneuropathy is one of the most common painful conditions managed within general and specialty clinics. Neuropathic pain frequently leads to decisions about using long-term opioid therapy. Understanding the association of long-term opioid use with functional status, adverse outcomes, and mortality among patients with polyneuropathy could influence disease-specific decisions about opioid treatment.
Objectives
To quantify the prevalence of long-term opioid use among patients with polyneuropathy and to assess the association of long-term opioid use with functional status, adverse outcomes, and mortality.
Design, Setting, and Participants
A retrospective population-based cohort study was conducted of prescriptions given to patients with polyneuropathy and to controls in ambulatory practice between January 1, 2006, and December 31, 2010, to determine exposure to long-term opioid use as well as other outcomes. The latest follow-up was conducted through November 25, 2016.
Exposures
Long-term opioid therapy, defined by 1 or multiple consecutive opioid prescriptions resulting in 90 continuous days or more of opioid use.
Main Outcomes and Measures
Prevalence of long-term opioid therapy among patients with polyneuropathy and controls. Patient-reported functional status, documented adverse outcomes, and mortality were compared between patients with polyneuropathy receiving long-term opioid therapy (≥90 days) and patients with polyneuropathy receiving shorter durations of opioid therapy.
Results
Among the 2892 patients with polyneuropathy (1364 women and 1528 men; mean [SD] age, 67.5 [16.6] years) and the 14 435 controls (6827 women and 7608 men; mean [SD] age, 67.5 [16.5] years), patients with polyneuropathy received long-term opioids more often than did controls (545 [18.8%] vs 780 [5.4%]). Patients with polyneuropathy who were receiving long-term opioids had multiple functional status markers that were modestly poorer even after adjusting for medical comorbidity, including increased reliance on gait aids (adjusted odds ratio, 1.9; 95% CI, 1.4-2.6); no functional status markers were improved by long-term use of opioids. Adverse outcomes were more common among patients with polyneuropathy receiving long-term opioids, including depression (adjusted hazard ratio, 1.53; 95% CI, 1.29-1.82), opioid dependence (adjusted hazard ratio, 2.85; 95% CI, 1.54-5.47), and opioid overdose (adjusted hazard ratio, 5.12; 95% CI, 1.63-19.62).
Conclusions and Relevance
Polyneuropathy increased the likelihood of long-term opioid therapy. Chronic pain itself cannot be ruled out as a source of worsened functional status among patients receiving long-term opioid therapy. However, long-term opioid therapy did not improve functional status but rather was associated with a higher risk of subsequent opioid dependency and overdose.
This population-based cohort study quantifies the prevalence of long-term opioid use among patients with polyneuropathy and assesses the association of long-term opioid use with functional status, adverse outcomes, and mortality.
Key Points
Question
What is the association of long-term opioid therapy with functional status, adverse outcomes, and mortality among patients with polyneuropathy?
Findings
In this population-based cohort study that included data from 1993 patients with polyneuropathy who were receiving opioid therapy, those receiving long-term opioid therapy (≥90 days) were significantly more likely to be diagnosed with depression, opioid dependence, or opioid overdose than those receiving shorter durations of opioid therapy. Self-reported functional status measures were either unimproved or poorer among those receiving long-term opioid therapy.
Meaning
Long-term opioid therapy among patients with polyneuropathy appears to increase the risk of adverse outcomes without benefiting functional status.
Introduction
Opioids appear to be effective for the treatment of noncancer pain in short-duration trials, but the evidence for long-term efficacy is less convincing. Opioid therapy longer than 90 days is associated with a greater likelihood of long-term opioid use, which is linked with higher rates of opioid use disorders. Opioid prescription for chronic noncancer pain continues to be the focus of efforts to curb the opioid-related morbidity pandemic. Certain patient populations in legitimate need of pain relief may be more likely to receive opioid therapy for 90 days or more; long-term outcomes among such populations should be of interest.
Polyneuropathy is a common condition, especially among the elderly, with well-described impairments in functional status. Primary care physicians are involved not only in managing the underlying etiologic factors of polyneuropathy for their patients (eg, diabetes) but also in managing one of its most common symptoms, neuropathic pain. Opioids are listed by several guidelines as second-line options for the treatment of neuropathic pain, and primary care physicians issue most opioid prescriptions. Understanding the benefits and limitations of opioids can allow patients with polyneuropathy and their physicians to make more informed decisions. A previous study characterized a population-based cohort of patients with polyneuropathy. In the present study, we used this longitudinally followed cohort with comprehensive access to prescriptions to determine the prevalence of long-term opioid therapy among patients with polyneuropathy compared with matched controls, and to examine the association between duration of opioid therapy and functional status, adverse outcome rates, and mortality among patients with polyneuropathy.
Methods
Health care visit dates are linked to addresses within the Rochester Epidemiology Project (REP) database; this information has been used to define who resided in Olmsted County, Minnesota (REP Census) at any time since 1966. The population counts obtained by the REP Census exceed those obtained by the US Census, indicating that virtually the entire population of the county is captured by the system. We used the REP Census to identify all individuals who resided in Olmsted County from January 1, 2006, through December 31, 2010. Patients and controls in this study have been reported previously. The Mayo Clinic and Olmsted Medical Center institutional review boards approved the study. Participants provided written consent.
A comprehensive prescription database from all ambulatory practice professionals in the county is available starting with prescriptions issued on January 1, 2006. This database was queried for opioid prescriptions (ie, codeine sulfate, fentanyl citrate, hydrocodone bitartrate, hydromorphone hydrochloride, meperidine hydrochloride, methadone hydrochloride, morphine sulfate, oxycodone hydrochloride, oxymorphone hydrochloride, propoxyphene hydrochloride or napsylate, tapentadol hydrochloride, and tramadol hydrochloride) issued during the study period. Data fields included the following: date prescribed, medication, strength, form, route, instructions (which included dose, frequency, and “as needed”), amount dispensed (eg, number of tablets or dose in milliliters), number of refills (if applicable), and intended duration (in days). Whether or not each patient had been prescribed a nonopioid analgesic (α2Δ antagonist, tricyclic antidepressant, serotonin norepinephrine reuptake inhibitor, or topical analgesic) during the study period was also determined, as previously described. Indication for opioid prescriptions and the prescribing clinician’s specialty among those receiving 90 or more consecutive days of opioid therapy were obtained by reviewing clinical documentation around the time that the prescription was issued. Administrative code and patient survey data were retrieved from an electronic database as previously described. Depression, substance abuse, overdose, and chemical dependence were determined by International Classification of Diseases, Ninth Revision, Clinical Modification, codes from 2006 to 2014 (eTable 1 in the Supplement).
All data fields were not available for every opioid prescription. If an intended duration was specified, no expected duration was calculated. For calculating the expected duration, it was assumed that every as-needed dose was taken and dosing frequency was converted to doses per day. This conservatively underestimates the total duration of opioid exposure. Expected duration for each prescription (in days) was calculated as:
| Duration = {[Amount Dispensed × (1 + Number of Refills)]/(Dose)}/Doses per Day. |
Extraction of data about prescriptions and calculated duration were done with automated algorithms and formulas to ensure uniform assessment. Data on duration were not available for all prescriptions. Because it was our goal to identify duration of continuous opioid exposure, we excluded prescriptions without sufficient data to identify duration.
Intervals of continuous opioid exposure were defined as either the duration of a single prescription or the summed durations of multiple prescriptions when there was less than or equal to 10 days between the expected end date of 1 prescription and the start date of the next prescription. Long-term opioid therapy was defined as greater than or equal to 90 continuous days based on the length of use to treat chronic instead of acute pain as defined by the International Association for the Study of Pain.
Statistical Analysis
All analyses were performed with JMP Pro, version 11.2.1, software (SAS Institute Inc). Odds ratios (ORs) with 95% CIs were calculated to compare differences in the rate of long-term opioid therapy between cases and controls, as well as self-reported markers of functional status between patients with polyneuropathy receiving 90 days or more vs fewer than 90 days of opioids. Hazard ratios (HRs) with 95% CIs were used to compare latencies of adverse outcomes (including mortality) after initiation of long-term opioid therapy. Multivariate models were used to adjust ORs and HRs for the potentially confounding effects of Charlson Comorbidity Index comorbidities, sex, and use of nonopioid analgesics, when applicable. P < .05 was considered significant.
Results
Patients With Polyneuropathy and Long-term Opioid Therapy
A total of 48 807 opioid prescriptions with complete data available were issued to 7906 of the 17 327 patients comprising cases and controls from a previously published cohort. The expected duration of opioid use had to be calculated for 42 564 of the prescriptions (87.2%); in the remainder, the prescriber’s intended duration was available in the REP database. Among the 2892 patients with polyneuropathy, 1464 (50.6%) received opioids for fewer than 90 days, while 545 (18.8%) received long-term opioid therapy (Table 1). This finding was significantly higher than the 780 of 14 435 controls (5.4%) who received long-term opioid therapy (OR, 2.4; 95% CI, 2.2-2.8), even after adjusting for Charlson Cormorbidity Index medical comorbidities (OR, 1.7; 95% CI, 1.5-2.0). Oxycodone was the most common opioid prescribed during the study period, accounting for 9333 of the 20 333 opioid prescriptions (45.9%) to patients with polyneuropathy (Table 1). Prescribing trends (in order from most to least common) were fairly similar for patients with polyneuropathy and controls, with some exceptions.
Table 1. Data on Opioids Prescribed to Patients With Polyneuropathy and Matched Controls.
| Data | No. (%) | |
|---|---|---|
| Patients With Polyneuropathy (n = 2892) |
Matched Controls (n = 14 435) |
|
| Duration of opioid therapy, d | ||
| <90 | 1464 (50.6) | 5117 (35.4) |
| ≥90 | 545 (18.8) | 780 (5.4) |
| Prescriptions | (n = 20 333) | (n = 28 474) |
| Oxycodone hydrochloride | 9333 (45.9) | 11 882 (41.7) |
| Hydrocodone bitartrate | 3332 (16.4) | 5912 (20.8) |
| Tramadol hydrochloride | 2912 (14.3) | 4765 (16.7) |
| Fentanyl citrate | 1042 (5.1) | 1048 (3.7) |
| Morphine sulfate | 1015 (5.0) | 904 (3.2) |
| Codeine sulfate | 957 (4.7) | 1883 (6.6) |
| Propoxyphene hydrochloride or napsylate | 846 (4.2) | 1677 (5.9) |
| Hydromorphone hydrochloride | 628 (3.1) | 261 (0.9) |
| Methadone hydrochloride | 263 (1.3) | 111 (0.4) |
| Meperidine hydrochloride | 5 (0.02) | 14 (0.05) |
| Oxymorphone hydrochloride | 0 | 17 (0.06) |
Long-term Opioid Therapy and Comorbidities
Prescription and comorbidity data were available in the REP database for 1993 of 2009 patients with polyneuropathy who were receiving opioids (99.2%) (Table 2). Patients with polyneuropathy receiving long-term opioid therapy were more likely than those receiving opioid therapy for fewer than 90 days to be female (308 of 541 [56.9%] vs 674 of 1452 [46.4%]; P < .001), but there were no significant differences in median age between the 2 groups (70 vs 69 years; P = .13) (Table 2). Those receiving long-term opioid therapy had a significantly higher likelihood of having a Charlson Comorbidity Index medical comorbidity, with the exception of paralysis, cancer, and AIDS (Table 2). Excluding ulcers, we found that the rates of lower limb complications were comparable between the 2 groups. Nonopioid analgesics were used more often among patients with polyneuropathy receiving long-term opioids; however, 111 of 541 patients with polyneuropathy receiving long-term opioid therapy (20.5%) did not receive any of the nonopioid analgesics prescribed during the study period.
Table 2. Characteristics of Patients With Polyneuropathy Based on Duration of Opioid Use.
| Characteristic | Duration of Opioid Use | P Valuea | |
|---|---|---|---|
| <90 d (n = 1452) |
≥90 d (n = 541) |
||
| Duration of consecutive opioids, median (IQR), d | 17 (8-34) | 228 (133-392) | <.001b |
| Age, median (range), y | 69 (3-101) | 70 (26-98) | .13b |
| Female sex, No. (%) | 674 (46.4) | 308 (56.9) | <.001 |
| Nonopioid analgesic prescriptions, No. (%) | |||
| α2Δ antagonist | 456 (31.4) | 335 (61.9) | <.001 |
| Serotonin norepinephrine reuptake inhibitor | 161 (11.1) | 129 (23.8) | <.001 |
| Tricyclic antidepressant | 218 (15.0) | 162 (29.9) | <.001 |
| Topical analgesics | 156 (10.7) | 148 (27.4) | <.001 |
| Any nonopioid analgesic | 670 (46.1) | 430 (79.5) | <.001 |
| Charlson Cormorbidity Index comorbidities, No. (%) | |||
| Myocardial infarction | 339 (23.3) | 173 (32.0) | <.001 |
| Congestive heart failure | 469 (32.3) | 258 (47.7) | <.001 |
| Peripheral vascular disease | 741 (51.0) | 336 (62.1) | <.001 |
| Cerebrovascular disease | 525 (36.2) | 241 (44.5) | <.001 |
| Dementia | 265 (18.3) | 123 (22.7) | .03 |
| Chronic pulmonary disease | 871 (60.0) | 374 (69.1) | <.001 |
| Peptic ulcer disease | 260 (17.9) | 160 (29.6) | <.001 |
| Mild liver disease | 359 (24.7) | 162 (29.9) | .02 |
| Types 1 and 2 diabetes | 795 (54.8) | 367 (67.8) | <.001 |
| Types 1 and 2 diabetes with end-organ complications | 642 (44.2) | 300 (55.5) | <.001 |
| Paralysis | 131 (9.0) | 49 (9.1) | .98 |
| Renal disease | 501 (34.5) | 268 (49.5) | <.001 |
| Severe liver disease | 70 (4.8) | 41 (7.6) | .02 |
| Metastatic cancer | 191 (13.2) | 66 (12.2) | .57 |
| AIDS | 4 (0.3) | 1 (0.2) | .71 |
| Rheumatologic disease | 174 (12.0) | 105 (19.4) | <.001 |
| Nonmetastatic cancer, No. (%) | 684 (47.1) | 251 (46.4) | .77 |
| Lower limb complications, No. (%) | |||
| Ulcers | 300 (20.7) | 151 (27.9) | <.001 |
| Amputations | 73 (5.0) | 29 (5.4) | .77 |
| Neuroma, bunion, and toe deformity | 46 (3.2) | 19 (3.5) | .70 |
| Ankle fusions | 10 (0.7) | 5 (0.9) | .60 |
Abbreviation: IQR, interquartile range.
Determined by use of the χ2 test.
Determined by use of the Wilcoxon rank sum test.
Main Prescribers of and Indications for Long-term Opioid Therapy
Abstraction of medical records identified the specialty of the prescribing clinician and indication for 537 of the patients with polyneuropathy receiving long-term opioid therapy (99.2%) (eTable 2 in the Supplement). Internal medicine (373 [69.5%]) and family medicine (71 [13.2%]) were the most likely prescribers of long-term opioid therapy for patients with polyneuropathy and controls, accounting for 444 of 537 of all opioid prescriptions (82.7%). Pain specialists had clinical notes in the medical charts of 141 of 537 patients with polyneuropathy receiving long-term opioid therapy (26.3%). However, only 20 patients with polyneuropathy (3.7%) received their prescriptions for long-term opioid therapy from pain physicians. The majority of patients with polyneuropathy (282 [52.5%]) were prescribed opioids for musculoskeletal pain, as indicated by the clinical documentation, whereas polyneuropathy was the indication for only 129 patients with polyneuropathy (24.0%). Other indications collectively made up less than one-fourth of long-term opioid therapy prescribed during the study period.
Long-term Opioid Therapy and Worsening Functional Status
Patients with polyneuropathy receiving long-term opioid therapy were more likely to report having pain at the end of the study period than were patients with polyneuropathy who received a shorter duration of opioid therapy (adjusted OR, 2.5; 95% CI, 1.9-3.4) (Table 3). The temporal relationship between the pain rating and multiple opioid prescriptions over time could not be assessed owing to a lack of multiple data points over time. Near the end of the study period, patients with polyneuropathy receiving long-term opioid therapy also had greater difficulty performing some of their activities of daily living and self-reported more functional limitations such as difficulty climbing stairs (adjusted OR, 1.7; 95% CI, 1.2-2.4), needing an assistive device (adjusted OR, 1.9; 95% CI, 1.4-2.6), or being unable to work (adjusted OR, 1.3; 95% CI, 0.8-2.0). These findings were significant even when accounting for differences in sex, medical comorbidities, and use of nonopioid analgesics. Although not all of the activities of daily living or other markers of functional status were worse among patients with polyneuropathy receiving long-term opioid therapy, none of the functional status indicators were better among those receiving long-term opioid therapy (ie, OR < 1.0 with 95% CI).
Table 3. Self-reported Markers of Functional Status Among Patients With Polyneuropathy Receiving Opioids.
| Surrogate Marker of Functional Status | Patients With Data, No./Total No. (%) | OR (95% CI) | Adjusted OR (95% CI) | |
|---|---|---|---|---|
| <90 d of Therapy | ≥90 d of Therapy | |||
| Preparing meals | 167/1113 (15.0) | 90/414 (21.7) | 1.6 (1.2-2.1) | 1.2 (0.9-1.7) |
| Feeding yourself | 23/1113 (2.1) | 16/414 (3.9) | 1.9 (1.0-3.6) | 1.9 (0.9-3.9) |
| Dressing | 115/1113 (10.3) | 77/414 (18.6) | 2.0 (1.4-2.7) | 1.7 (1.2-2.4) |
| Using the toilet | 72/1113 (6.5) | 42/414 (10.1) | 1.6 (1.1-2.4) | 1.4 (0.9-2.2) |
| Housekeeping | 220/1113 (19.8) | 144/414 (34.8) | 2.2 (1.7-2.8) | 1.6 (1.2-2.2) |
| Bathing | 135/1113 (12.1) | 90/414 (21.7) | 2.0 (1.5-2.7) | 1.6 (1.1-2.2) |
| Walking | 258/1113 (23.2) | 151/414 (36.5) | 1.9 (1.5-2.4) | 1.5 (1.1-1.9) |
| Using transportation | 142/1113 (12.8) | 75/414 (18.1) | 1.5 (1.1-2.0) | 1.2 (0.9-1.7) |
| Getting in and out of bed | 88/1113 (7.9) | 56/414 (13.5) | 1.8 (1.3-2.6) | 1.4 (1.0-2.1) |
| Limb weakness | 207/1113 (18.6) | 110/414 (26.6) | 1.6 (1.2-2.1) | 1.3 (0.9-1.7) |
| Limb numbness/shooting pain | 258/1113 (23.2) | 127/414 (30.7) | 1.5 (1.1-1.9) | 1.3 (1.0-1.7) |
| Fall tendency | 129/1113 (11.6) | 69/414 (16.7) | 1.5 (1.1-2.1) | 1.2 (0.9-1.2) |
| Any pain (yes or no) | 381/901 (42.3) | 241/337 (71.5) | 3.4 (2.6-4.5) | 2.5 (1.9-3.4) |
| Stair intolerance | 618/980 (63.1) | 291/355 (82.0) | 2.7 (2.0-3.6) | 1.7 (1.2-2.4) |
| Assistive device | 399/1010 (39.5) | 221/361 (61.2) | 2.4 (1.9-3.1) | 1.9 (1.4-2.6) |
| Unable to work | 71/1053 (6.7) | 44/374 (11.8) | 1.8 (1.2-2.7) | 1.3 (0.8-2.0) |
| Assisted living or nursing home | 80/1036 (7.7) | 41/362 (11.3) | 1.5 (1.0-2.3) | 1.3 (0.8-2.1) |
Abbreviation: OR, odds ratio.
Long-term Opioid Therapy and Adverse Outcomes
Long-term opioid use among patients with polyneuropathy was associated with an increased likelihood of all adverse outcomes assessed before adjusting for potential confounding variables (Table 4). The following diagnoses were still significantly more common in the setting of long-term opioid therapy as determined by administrative coding, even after adjusting for sex, medical comorbidity, and use of nonopioid analgesics: depression (adjusted HR, 1.53; 95% CI, 1.29-1.82), opioid overdose (adjusted HR, 5.12; 95% CI, 1.63-19.62), opioid dependence (adjusted HR, 2.85; 95% CI, 1.54-5.47), and other chemical dependence (adjusted HR, 1.73; 95% CI, 1.21-2.49). Given that HRs were used for this analysis, only incident diagnoses occurring after the initial opioid prescription were counted. Long-term opioid therapy appeared to have a slight association with increasing mortality among patients with polyneuropathy; however, the adjusted HR for mortality was nonsignificant (0.99; 95% CI, 0.84-1.16).
Table 4. Adverse Outcomes and Mortality Among Patients With Polyneuropathy Receiving Opioids.
| Adverse Outcome | Opioid Treatment, No. (%) | HR (95% CI) | Adjusted HR (95% CI) | |
|---|---|---|---|---|
| <90 d (n = 1452) |
≥90 d (n = 541) |
|||
| Depression | 633 (43.6) | 341 (63.0) | 1.97 (1.68-2.30) | 1.53 (1.29-1.82) |
| Abuse | ||||
| Alcohol | 109 (7.5) | 54 (10.0) | 1.63 (1.10-2.39) | 1.38 (0.90-2.11) |
| Opioid | 2 (0.1) | 9 (1.7) | 10.66 (2.71-70.27) | 3.97 (0.87-28.9) |
| Other substance | 27 (1.9) | 25 (4.6) | 2.37 (1.29-4.36) | 1.81 (0.92-3.58) |
| Overdose | ||||
| Opioid | 4 (0.3) | 14 (2.6) | 8.29 (2.93-29.44) | 5.12 (1.63-19.62) |
| Other substance | 24 (1.7) | 22 (4.1) | 2.53 (1.37-4.65) | 1.82 (0.92-3.6) |
| Dependence | ||||
| Opioid | 20 (1.4) | 39 (7.2) | 5.59 (3.20-10.18) | 2.85 (1.54-5.47) |
| Other substance | 129 (8.9) | 95 (17.6) | 2.41 (1.73-3.34) | 1.73 (1.21-2.49) |
| Deceased by 11/25/16 | 530 (36.5) | 256 (47.3) | 1.22 (1.05-1.41) | 0.99 (0.84-1.16) |
Abbreviation: HR, hazard ratio.
Discussion
To our knowledge, this is the first population-based study on the prevalence of long-term opioid therapy among patients with polyneuropathy and its association with functional status, adverse outcomes, and mortality. We found that diagnosis of polyneuropathy increases the risk of long-term opioid therapy even when polyneuropathy is not mentioned in the medical record as the primary indication to start opioid therapy, long-term opioid therapy may be associated with a worsened functional status beyond that of polyneuropathy, and adverse outcomes commonly linked to opioid use occurred more often among patients with polyneuropathy receiving long-term opioid therapy. An unanswered and potentially confounding issue is whether the differing severity of pain between those receiving long-term opioid therapy and those receiving shorter-duration opioid therapy might be driving worsened functional status and more adverse outcomes.
Although polyneuropathy was associated with a greater likelihood of long-term opioid therapy, it was the indication for a minority of long-term opioid prescriptions, based on clinician documentation. Musculoskeletal pain was the most common documented indication for starting long-term opioid therapy. It is possible that peripheral and central sensitization occurring in polyneuropathy decreases the pain threshold and patients’ abilities to tolerate nonneuropathic (nociceptive) pain, thus leading to increased rates of long-term opioid prescriptions for nociceptive musculoskeletal pain among patients with polyneuropathy. In another study, more than 40% of patients with polyneuropathy had nonneuropathic or mixed-type pain, while only 20% had strictly neuropathic pain. Pain without typical neuropathic qualities may, therefore, still be associated with the underlying polyneuropathy, making it indirectly the indication for opioid therapy.
Neurologists are often involved in the diagnosis and management of polyneuropathy, but they were unlikely to be the prescribers of long-term opioid therapy in this study. Furthermore, pain physicians saw one-fourth of patients with polyneuropathy receiving long-term opioid therapy during the study period, but they were the prescribers of long-term opioid therapy for only 3.7% of such patients. These data are consistent with national trends. Therefore, it is likely that discussing potential benefits, as well as adverse outcomes, of long-term opioid therapy will fall to the primary care clinician.
Reducing pain and improving functional status are commonly purported as the goals of analgesia such as long-term opioid therapy. The data available in the present study were better suited to addressing the latter and showed that long-term opioid therapy was not associated with improved functional status among patients with polyneuropathy. In fact, long-term opioid therapy made several markers of functional status worse, including inability to work. This finding is not dissimilar to the finding that long-term opioid use is associated with disability among those with chronic back pain and other forms of chronic noncancer pain.
Based on the marked difference in duration of opioid therapy between those receiving short-term vs long-term opioid therapy (median duration, 17 vs 228 days) and the percentage of responders reporting pain (381 of 901 [42.3%] vs 241 of 337 [71.5%]; Table 3), these appear to be 2 potentially different populations with regard to baseline pain and patterns of opioid use. Pain was neither qualitatively described nor quantitatively graded in severity in the survey instrument used. The lack of a validated pain instrument administered over time prevented differentiation of those with painful vs nonpainful neuropathy and assessment of the efficacy of opioid analgesia. Therefore, pain reporting may be reflective of inadequate analgesia or simply that some analgesia occurred but the patient was not made pain free (ie, self-rating of pain decreased from 8 to 3 on a scale of 10, where 0 is no pain and 10 is the worst possible pain). It remains a possibility that impaired functional status may be associated with the higher baseline pain itself and not the long-term opioid therapy. However, even if pain was driving functional impairment, the findings did not support improved functional status with long-term opioid use.
As a chronic condition with an already notable amount of impairment including pain, it is important for health care professionals to avoid iatrogenically causing morbidity and provide the safest and most effective means of analgesia to patients with polyneuropathy. In addition to functional limitations, we found that other adverse outcomes linked to opioid use were also more likely in patients with polyneuropathy receiving long-term opioid therapy. A diagnosis of opioid abuse among patients with polyneuropathy prescribed opioids for any duration was very rare (≤2% of patients); however, the rate of opioid dependence was 7.2%, and the rate of opioid overdose was 2.6%. Although this finding may represent underrecognized opioid abuse from inadequate screening and detection, it underscores that abuse and dependence are not synonymous. Despite this increased association with opioid dependence and even overdose, there was no significant association with overall mortality after adjusting for confounders. Thus, our results agree with those of prior studies citing that opioid use disorders are more prevalent among those receiving long-term opioid therapy, but we did not find that long-term opioid therapy significantly increases mortality among patients with polyneuropathy as it does among broader populations of patients reported elsewhere.
Because of the unclear benefit and the risk of adverse effects from the use of opioids for chronic noncancer pain, in 2016, the Centers for Disease Control and Prevention declared that “nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain.”(p16) However, this recommendation is in the setting of the International Association for the Study of Pain, the European Federation of Neurological Societies, and the American Academy of Neurology guidelines indicating that opioids are acceptable, albeit perhaps not preferred, agents for neuropathic pain. In the present study, nonopioid neuropathic pain medications were used by 46.1% of all patients with polyneuropathy receiving short-duration opioids and even more (79.5%) by the subset of patients receiving long-term opioid therapy. More important, however, 111 patients with polyneuropathy receiving long-term opioid therapy (20.5%) and 782 patients receiving shorter durations of opioids (53.9%) were not prescribed any nonopioid analgesic during the study period. Thus, there are still some patients who could have potentially benefited from trials of 1 or more nonopioid analgesics. One potential limitation of this conclusion is that prescriptions prior to 2006 were not available in the database, to ensure against the use of nonopioid analgesics before the study period. It is also unknown how many patients in the present study used nonpharmacologic methods of treating pain, as recommended by the Centers for Disease Control and Prevention.
Twenty years ago, prescribing opioids in the United States for 3 months or longer was essentially prohibited by statutes and regulations. Lobbying efforts effectively lifted limits on dose, amount dispensed, and frequency prescribed. Eventually, even the Joint Commission on Accreditation of Healthcare Organizations adopted pain as the fifth vital sign. These changes led to increased opioid prescribing rates in subsequent years. When claims data from more than half a million patients with new chronic noncancer pain between 2000 and 2005 were examined, the liberalized opioid prescribing trends had appeared to increase the prevalence of opioid use disorders among patients receiving long-term opioid therapy compared with patients receiving opioids for shorter durations.
Patient-centered outcomes data of specific populations receiving long-term opioid therapy (ie, for polyneuropathy), such as those reported here, can allow patients and clinicians considering long-term opioid therapy to make informed decisions. Our results, even when interpreted conservatively, suggest unintended consequences of long-term opioid therapy when it is used for or in the setting of polyneuropathy. This finding should be considered by physicians counseling patients with neuropathic pain who are considering opioid analgesic therapy, as well as by authors of guidelines, policy, and consensus statements.
Strengths and Limitations
The strengths of this study included that it was a population-based cohort including approximately 98% of the population under study instead of relying on a sample from that population. It was also coupled with detailed results of standardized questionnaires containing patient-reported functional status outcomes for more than 66% of patients in the study (the survey item with the lowest number of respondents was stair intolerance, answered by 355 of 541 patients [65.6%] and 980 of 1452 controls [67.5%]). The population of Olmsted County has documented generalizability to the rest of the United States for demographics and prevalence of chronic disease.
The limitations of this study include that it is retrospective and that it used administrative codes for both the ascertainment of polyneuropathy and the adverse outcomes associated with use of opioids. This study was also based on prescription data without confirmation that prescriptions were filled and taken as intended. Prescription duration was calculated in most cases presuming patients took each as-needed dosage. Daily morphine equivalents were not estimated, which prevented determination of a dose effect.
Conclusions
The importance of effective and safe use of opioids has been stressed, and policy changes have even been suggested to limit and improve oversight of opioid prescribing. This population-based study examined how opioids were used by patients with polyneuropathy, a common chronic condition in which more than two-thirds of patients may receive opioid therapy. By showing that polyneuropathy increases the risk of long-term opioid therapy and that long-term opioid therapy is not associated with improved functional status but is associated with adverse outcomes, this study provides useful information to counsel patients with polyneuropathy who are considering or are already receiving opioid therapy. Furthermore, it provides evidence that could influence treatment guidelines and health policy.
eTable 1. ICD-9-CM Codes Used to Assess Morbidity
eTable 2. Prescribing Indication and Provider for Chronic Opioid Therapy
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Associated Data
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Supplementary Materials
eTable 1. ICD-9-CM Codes Used to Assess Morbidity
eTable 2. Prescribing Indication and Provider for Chronic Opioid Therapy