INTRODUCTION

Epidemic levels of prescription opioid overdose, abuse, addiction, and diversion have followed dramatic increases in opioid prescribing for chronic non-cancer pain (CNCP) in the U.S.1–6 Chronic opioid therapy (COT) guidelines recommend urine drug tests (UDTs) to improve patient safety and reduce diversion.2,7–11 UDTs can help identify drug misuse/abuse (through detection of illicit drug, opioid, or benzodiazepine use unknown to the opioid prescriber) and diversion (a possibility when prescribed opioids are absent). However, little evidence exists regarding UDT use for various patient subgroups.12 Guidelines vary in their recommendations, with two9,13 recommending mandatory testing for all COT patients, one advising testing for patients at risk for substance use disorders (SUDs),8 and two8,14 commenting that screening low-risk populations increases false-positive results and is less cost-effective.11 Knowledge regarding the risk factors for aberrant results could help inform evidence-based recommendations regarding UDTs for COT monitoring.

We reported a substantial increase in UDTs for COT patients at Group Health’s (GH) integrated group practice after implementation of a multifaceted opioid risk reduction initiative.15 Illicit drug detection was rare, raising the question of whether UDTs should be targeted to patient subgroups based on risk for aberrancies. Little research has examined predictors of UDT results in the primary care COT population. In pain clinic and other settings, some studies found illicit drugs (including tetrahydrocannabinol [THC]) to be more common among UDTs of males16 and younger patients.17,18 Among veterans, UDT detection of illicit substances (including THC) was more common for those with SUD diagnoses.19 Studies in diverse settings18,20 found no significant association between opioid regimen characteristics and UDT detection of illicit drugs.

The purpose of this study was to identify primary care COT patient and opioid regimen characteristics associated with aberrant UDT results. In the state of Washington, the setting of this study, use of marijuana is legal for chronic pain. We examined THC separately from illicit drugs. We hypothesized that illicit drug and THC use would be more common among younger patients, males, and patients with SUD history, and that prescribed opioid non-detection would be more common among patients with a history of SUD , on low-dose opioid therapy, and with less-than-daily opioid supply. Other analyses were exploratory.

METHODS

Study Setting and Sample

GH is a large nonprofit healthcare system in the state of Washington. GH patients are covered by individual, Medicare, Medicaid, state and federal employee, and employer-sponsored plans. The GH opioid risk reduction initiative, implemented in September 2010 in its integrated group practice, included COT patient care guidelines with UDT recommendations based on opioid dose and other risks (Text Box 1) as well as a pain management UDT.15,21 We identified all pain management UDTs performed January 2011–December 2012 for patients aged ≥20 years. We obtained UDT, pharmacy, and patient data from GH databases. To limit the sample to UDTs for CNCP patients, we excluded those of patients who, in the one-year period prior to the UDT, had had hospice care, opioid prescriptions from oncologists, or more than one visit for cancer other than non-melanoma skin cancer. To ensure data availability, we excluded UDTs for patients not continuously enrolled at GH for the previous year. We calculated patients’ days’ supply of transdermal and oral opioids (except buprenorphine) covering the 90 days before each UDT. We included only UDTs for patients on COT, defined by GH as ≥70 days’ opioid supply in the prior 90 days. We compared characteristics of patients with UDTs in our sample to those of the overall population of GH COT patients who met study eligibility criteria on 1/1/2012, the study midpoint. This study was approved by the GH Institutional Review Board.

Text Box 1 GH Guideline (December 2011 update*) UDT Recommendations
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Measures

UDT Results

The GH pain management UDT (Text Box 2) includes a screening immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirmatory test. Text Box 3 lists the LC-MS/MS results examined in the study.

Text Box 2 GH Pain Management UDT
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Text Box 3 UDT LC-MS/MS Results Examined
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Predictors

We selected potential predictors based upon prior studies of predictors of UDT results (see Introduction) and prescription opioid misuse/abuse. The latter predictors include younger age,18,22–29 male gender,24,25,27,30 history of alcohol or other substance abuse,22,23,25–29 history of mental health disorder,4,22,25,27,29,31 current smoking,32,33 high opioid dose,28,29 and use of short-acting opioids.28 From GH databases, we obtained patient gender and age at the time of the UDT (and for all GH COT patients at the study midpoint), and International Classification of Diseases, 9th revision, clinical modification (ICD-9-CM)34 patient visit diagnoses within the previous two years. We classified these diagnoses into clinically meaningful categories using Clinical Classifications Software (CCS).35 We identified CCS alcohol and SUD diagnoses, and defined mental health diagnoses as any in the CCS categories of adjustment disorders, anxiety disorders, mood disorders, personality disorders, psychotic disorders, intentional self-inflicted injury, and some miscellaneous disorders (e.g., eating disorders; we excluded sexual and gender identity, somatoform, and sleep disorders). We identified current smokers as patients with electronic health record (EHR) flags indicating current tobacco use or prior-year visits with tobacco use disorder diagnoses (ICD-9-CM code 305.1).36 For descriptive purposes, we used ICD-9-CM codes37 to identify pain diagnoses for past-year visits.

We calculated the mean daily morphine-equivalent dose (MED) and total days’ supply for opioid prescriptions (except buprenorphine) covering the 90-day period before each UDT (or study midpoint).38 For multiple same-date prescriptions, we counted only the highest value of days’ supply. We categorized days’ supply as less than daily (70–83), daily/near daily (84–96), or excessive (≥97). We characterized patients’ opioids over the 90 days as short-acting only, long-acting (recommended usual dosing frequency ≤3 times daily – fentanyl, levorphanol, methadone, and sustained-release formulations of hydromorphone, morphine, oxycodone, oxymorphone, tramadol, and tapentadol39) only, or short-acting and long-acting.

Statistical Analysis

We conducted descriptive analyses, then logistic regression analyses predicting dilute samples and the following LC-MS/MS UDT results (excluding dilute samples): (1) any aberrancy; (2) prescribed opioid non-detection (defined as negative for all opioids prescribed for prior 90 days); (3) THC but no illicit drug; (4) non-prescribed opioid; (5) illicit drug; and (6) non-prescribed benzodiazepine. To better understand the contributions of individual predictors, we entered all predictors in a multivariable model for each outcome that had sufficient counts for reliable results. Regression models were estimated using generalized estimating equations.40,41 We used an independence working correlation matrix and estimated standard errors using the robust sandwich estimator to account for dependence between some observations (multiple UDTs for some patients).42

RESULTS

Patient Characteristics

Among 10,405 pain management UDTs in 2011–2012 for patients aged ≥20 years, we excluded 3,183 because the patient had <70 days’ opioid supply in the prior 90 days, 290 due to cancer exclusions, and 1,512 because the patient was not enrolled at GH for the prior year. The remaining 5,420 UDTs were performed for 3,809 patients. The study patient sample was similar to the overall GH COT patient population, albeit with more males and more patients under the age of 65, on long-acting opioids, and on moderate-high doses (Table 1).

Table 1 Characteristics of All Group Health COT Patients Who Met Study Inclusion Criteria on 1/1/2012 (Study Midpoint) and of Patients with UDTs in the Study Sample
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UDT Results

Aberrancies were observed in 30.6 % of the UDTs, including 12.3 % negative for all prescribed opioids, 11.2 % with THC, 5.3 % with non-prescribed opioids, 0.6 % with illicit drugs, 1.7 % with non-prescribed benzodiazepines, and 4.8 % dilute (Table 2). Examination of UDT results by patient and opioid characteristics indicates different patterns across different types of aberrancies (Table 3).

Table 2 Results of 5,420 UDTs for Patients on COT in 2011–2012
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Table 3 UDT Results for Patient and Opioid Subgroups
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Predictors of UDT Results

In multivariable analyses (Table 4), adjusted odds ratios (AOR) and 95 % confidence intervals (CI) for any aberrant result were higher for males than females (1.24 [1.07–1.43]), patients with versus without prior SUD diagnoses (1.42 [1.17–1.72]), and current smokers versus non-smokers (1.50 [1.30–1.73]). They were lower for patients aged 45–64 (0.77 [0.65, 0.92]) and 65+ (0.40 [0.32, 0.50]) versus patients aged 20–44, those on 40–<120 mg daily MED (0.78 [0.65, 0.95]) versus <40 mg MED, and for patients on long-acting opioids only (0.72 [0.55, 0.95]) or long-acting plus short-acting opioids (0.67 [0.54, 0.83]) versus short-acting opioids only.

Table 4 Results of Regression Models Predicting Aberrant UDT Findings
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Prescribed opioid non-detection was more likely among patients with versus without prior SUD diagnoses (AOR = 1.70; 95 % CI = 1.31, 2.20). It was less likely among patients aged 45+ versus 20–44, on moderate (0.52 [0.39, 0.70]) or high (0.22 [0.11, 0.43]) doses versus low doses, with daily/near-daily opioid supply versus less-than-daily supply (0.78 [0.63, 0.96]), and on long-acting opioids (versus short-acting opioids only).

Adjusted odds of THC were higher for males than females (2.20 [1.76, 2.75]), patients with versus without prior SUD diagnoses (1.62 [1.22, 2.16]), and smokers versus non-smokers (1.97 [1.58, 2.46]). They were lower for patients aged 45–64 (0.71 [0.55, 0.94]) and 65+ (0.15 [0.09, 0.24]) versus 20–44, and for patients with daily/near-daily opioid supply (0.68 [0.54, 0.86]) versus less-than-daily. Non-prescribed opioids were more common among African-Americans than whites (2.07 [1.16, 3.69]) and among patients with excessive (versus less-than-daily) opioid supply (1.59 [1.03, 2.46]), and less common among patients aged 45+ versus 20–44.

The small number of UDTs positive for illicit drugs and non-prescribed benzodiazepines precluded multivariable analyses. In bivariate analyses (Table 4), illicit drugs were more likely among patients with versus without prior SUD diagnoses (OR [95 % CI] = 2.91 [1.36, 6.25]) and smokers versus non-smokers (2.22 [1.04, 4.71]), and less likely among patients aged 45+. Patients with versus without prior mental health disorder diagnoses (1.82 [1.10, 2.99]) and with opioid doses 120+ mg versus <40 mg daily MED (2.26 [1.22, 4.19]) were more likely to have non-prescribed benzodiazepines detected.

Males were less likely than females (AOR = 0.42, 95 % CI = 0.29, 0.59) and African-Americans were less likely than whites (0.18 [0.04–0.73]) to have dilute samples (Table 4). Smokers were more likely than non-smokers to have dilute samples (1.44 [1.07, 1.94]).

DISCUSSION

Among UDTs performed in 2011–2012 for COT management of primary care patients in the integrated group practice of a large nonprofit healthcare system in the state of Washington, aberrant results were common (30.6 %), largely due to non-detection of prescribed opioids (12.3 % of UDTs) and detection of THC (11.2 %). Males, smokers, patients under the age of 45, and patients with prior SUD diagnoses had higher odds of aberrant results. Patients prescribed only short-acting opioids also had higher odds of aberrant results, apparently due to the greater likelihood of prescribed opioid non-detection. Patients on low opioid doses had higher odds of any aberrancy than those on moderate, but not high, doses. This may be explained by the findings that both moderate and high doses were negatively associated with one aberrancy (opioid non-detection), whereas only high dose was associated with another aberrancy, and this association was in the opposite direction (positive association with non-prescribed benzodiazepine).

Cocaine, amphetamine, and methamphetamine were each detected in <0.5 % of the UDTs and consistent with general population estimates of their use.43 No UDT detected ecstasy, PCP, or heroin. The last finding is unsurprising, given heroin’s rapid metabolism and its estimated use by only 0.1 % of the general population.43

This study extends prior knowledge regarding risk factors for aberrant UDTs. Most prior studies focused only on predictors of illicit drug detection and included THC with other illicit drugs.16–19 Our findings confirm the importance of younger age, SUD history, and smoking as risks for aberrancies, and reveal that risk factors vary across aberrancy types. In this setting, male gender predicted only THC detection; furthermore, history of mental health and alcohol use disorders (at least in the past two years) generally did not predict aberrancies.

As hypothesized, younger patients and patients with a history of SUD had greater odds of illicit drug detection. Low frequency of UDT illicit drug detection has also been reported for older patients in pain clinics.17,18 Patients with prior SUD diagnoses had almost three times greater odds of an illicit drug finding. Among Veterans Affairs healthcare network COT patients, the percentage of UDTs positive for illicit substances (including THC) was about three times higher for those with prior-year SUD diagnoses.19 We found that smokers had over twice the odds of an illicit drug result. Little previous research has examined associations between smoking and chronic pain patient UDT results, although smoking is associated with opioid misuse/abuse among chronic pain patients32,33 and with illicit drug abuse in the general population.44 Our hypothesis that males would have more illicit drug results was not confirmed; findings in previous studies were mixed.16,18 Consistent with prior studies,18,20 we found no significant association between opioid regimen characteristics and illicit drugs.

By far, the most common non-opioid substance detected was THC (11.2 % of UDTs), replicating findings in a study of veterans on COT.20 Marijuana is the most commonly used recreational drug.43 An estimated 7.3 % of the U.S. population uses marijuana, with approximately 7.6 million Americans using marijuana daily or almost daily.43 Currently, 20 states (including Washington) plus the District of Columbia allow marijuana for medical use, and two states (including Washington) have legalized its recreational use. Associations have been reported between marijuana use and physical and mental health problems,45 and between UDT detection of THC and opioid misuse,23 but little is known concerning marijuana’s effects on COT patient safety and outcomes. This is an important priority for future research.

As hypothesized, younger patients, males, and patients with a history of SUD had greater odds of THC detection. Adjusting for other characteristics, males and smokers had approximately twice the odds and patients with prior SUD diagnoses had 1.6 times the odds of THC detection. It is unclear why patients with less-than-daily opioid supply also had higher odds; this may reflect patient preference for marijuana as a primary method for managing pain and/or physician reluctance to prescribe opioids daily for marijuana users.

Non-prescribed opioids (detected in 5 % of UDTs) were more common among patients under the age of 45, consistent with previous findings of greater illicit drug use and opioid abuse among younger adults.18,22–29 Excessive days’ supply of prescribed opioids was also a risk factor, suggesting the importance of prescriber attention to total days’ supply of prescribed opioids. The odds of having a non-prescribed opioid detected were over twice as great for African-Americans as for whites; further research is needed to explore possible reasons.

In 12.3 % of UDTs, no opioid prescribed in the prior 90 days was detected. While the detection threshold was quite low, extremely low opioid levels could have been missed. Prescribed opioid non-detection could reflect no opioid use in the time period allowing detection. Indeed, prescribed opioid non-detection was more common among patients with low opioid doses, less-than-daily opioid supply (versus daily/near-daily), and only short-acting opioid prescriptions. The same proportion of UDTs negative for prescribed opioids (12 %) was reported at an urban teaching hospital pain clinic.18 Unlike our study, this result was not associated with opioid type or dose, although their patient sample was smaller and average dose was much higher. Opioid non-detection could also reflect diversion. In our study, prescribed opioid non-detection was more common among patients under the age of 45 or with prior SUD diagnoses – both risk factors for substance abuse. UDTs negative for prescribed opioids require discussion between prescriber and patient to identify reasons and appropriate response.

Benzodiazepines were detected in 12 % of UDTs; 1.7 % of UDTs detected benzodiazepines in patients without recent benzodiazepine prescriptions. Because benzodiazepines are associated with increased risk of opioid overdose,46 UDTs have value for informing opioid prescribers previously unaware of concomitant benzodiazepine use.

Dilute urine samples, present in 4.8 % of tests, were significantly less common among men and African-Americans. Dilute urine may result from multiple causes (e.g., attempts to avoid drug detection, diuretic use, diet, fluid consumption, race, genetics), and requires interpretation by patients’ physicians.47

Regarding study limitations, the smoking and diagnosis information in the EHR may under-represent true rates of smoking and of mental health, alcohol use disorders, and other substance use disorders. The study was conducted in a single healthcare system, and most patients were on low–moderate opioid doses and on short-acting opioids only; results may not generalize to other settings. UDT aberrancies among COT patients are likely to be more common in pain clinics and other settings with a higher prevalence of substance abuse. Some patients may have obtained medications from non-GH pharmacies, but this would have been more expensive, and previous research indicates that GH members obtain nearly all of their prescription medications from GH pharmacies.48 Study strengths include the large primary care population-based sample data on UDTs, patient diagnoses, and prescribed opioids, as well as the use of multivariable models to predict specific types of UDT aberrancies.

Our findings may be useful for making decisions with regard to UDT frequency and protocol for COT patients in settings with a low prevalence of drug abuse. The costs, physician and patient burden, rarity of illicit drug detection, ability of some patients to purposely avoid illicit drug detection, uncertainty regarding responses to aberrant results, and potential harms of UDTs (e.g., incorrectly assuming illicit drug use or diversion) must be weighed against potential benefits in deterrence of diversion or illicit drug use and in providing an objective reference of COT compliance, illicit drug use, and use of medications (e.g., non-prescribed opioids, benzodiazepines) that increase COT risks. Systematic reviews have noted the paucity (especially in primary care settings) and poor quality of studies of clinical outcomes associated with UDTs for COT patients.2,49–51 Clearly, more research is needed concerning the impact of UDTs on patient and public health safety and the cost-effectiveness of specific UDT guidelines in various settings. Different patient population scenarios may need different guidelines.

In the absence of adequate data, a policy of occasional random urine drug testing for all COT patients, with testing frequency based on known safety and abuse risk factors, might be reasonable. Physician prediction of individual patient risk for aberrant results is likely to be imprecise, and a policy of routine urine drug testing may be easier to administer, may mitigate the possible negative impact of selective UDTs on provider-patient relationships, and may discourage drug abusers from seeking COT. Our results suggest that it might be prudent to order UDTs more frequently for patients under the age of 45, smokers, and those with a history of SUD.