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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Pain Med. Author manuscript; available in PMC 2017 April 1.
Published in final edited form as:
Published online 2016 January 28. doi:  10.1111/pme.12900
PMCID: PMC4805511
NIHMSID: NIHMS716566

PROFILES OF URINE DRUG TEST IN CLINICAL PAIN PATIENTS VERSUS PAIN RESEARCH STUDY SUBJECTS

Cheng-ting Lee, BS,2,* Trang T. Vo, BS,1,* Abigail S. Cohen, BS,1 Shihab Ahmed, MD,1 Yi Zhang, MD, PHD,1 Jianren Mao, MD, PHD,1 and Lucy Chen, MD1

Abstract

Objective

To examine similarities and differences in urine drug test (UDT) results in clinical pain patients and pain subjects participating in pain research studies.

Design

An observational study with retrospective chart review and data analysis.

Methods

We analyzed 1,874 urine drug test (UDT) results obtained from 1) clinical pain patients (Clinical Group; n=1,529) and 2) pain subjects consented to participate in pain research studies (Research Group; n=345). Since several medications such as opioids used in pain management are drugs of abuse (DOA) and can result in a positive UDT, we specifically identified those cases of positive UDT due to non-prescribed DOA and designated these cases as positive UDT with DOA (PUD).

Results

We found that 1) there was a higher rate of PUD in clinical pain patients (41.3%) than in pain research study subjects (14.8%); 2) although subjects in the Research Group were informed ahead of time that UDT will be conducted as a screening test, a substantial number (14.8%) of pain research study subjects still showed PUD; 3) there were different types of DOA between clinical pain patients (cannabinoids as the top DOA) and research study subjects (cocaine as the top DOA); and 4) a common factor associated with PUD was opioid therapy in both Clinical Group and Research Group.

Conclusion

These results support previous findings that PUD is a common finding in clinical pain patients, particularly in those prescribed opioid therapy, and we suggest that UDT be used as routine screening testing in pain research studies.

Keywords: Urine drug test, Urine drug screening, Opioid, Illicit drug, Clinical study, Clinical trial, Pain, Pain management, Opioid Therapy

Introduction

Opioid therapy has been increasingly used to treat chronic pain conditions. However, its long-term clinical use can be complicated by misuse, abuse, and aberrant behaviors [1, 2]. Urine drug test (UDT) has been used to evaluate the compliance of opioid therapy and detect illicit drug use in chronic pain management [39]. In a clinical study of nearly one million urine samples, a large number of patients appeared to be non-compliant with their prescribed pain medications. For example, 38% of patients showed negative UDT while they were scheduled to take opioids whereas 29% of patients who were not on prescription drugs showed positive UDT for prescription drugs [10]. In another study, approximately 11% of UDT results indicated negative findings for subjects who were prescribed opioids [11].

Besides its use in clinical pain management as a tool of monitoring compliance, UDT is also used in clinical pain research studies to minimize confounding factors due to illicit drug use. Indeed, a panel of experts has recommended the use of abuse liability measures such as UDT in clinical analgesic trials [12]. To date, however, there is a dearth of information regarding the rate of illicit drug use in study subjects involved in clinical trials. UDT could also be used to help confirm whether study subjects involved in opioid-related clinical trials actually meet study criteria such as the presence or absence of prescription opioid medications.

The Massachusetts General Hospital (MGH) Center for Translational Pain Research (MGHCTPR) investigates new therapies for chronic pain management and opioid-related disorders such as opioid addiction and opioid-induced hyperalgesia. We routinely use UDT to screen for illicit drug use and gather information on opioid medications in our study subjects. We hypothesized that the rate and profile of drugs of abuse (DOA) in a positive UDT would differ between clinical pain patients and subjects participating in pain research studies. In order to compare the similarities and differences in UDT outcomes between clinical pain patients and pain subjects voluntarily participating in research studies, we analyzed 1,874 UDT results obtained during 2003–2011 from both clinical pain patients (MGH Center for Pain Medicine) and study subjects (MGHCTPR). Since UDT in study subjects and clinical pain patients were mandatory (pre-scheduled) and random, respectively, we specifically examined whether the rate of PUD and the type of DOA would be different between these two groups.

Materials and Methods

We retrospectively analyzed the results of UDT conducted between January 1, 2003 and December 31, 2011 in 1) clinical pain patients under treatment at the MGH Center for Pain Medicine (Clinical Group) and 2) pain subjects enrolled in IRB-approved research studies at the MGH Center for Translational Pain Research (Research Group). UDT in the Clinical Group was conducted randomly at the discretion of physicians who treated the patients, whereas UDT in the Research Group was all pre-scheduled and every subject was aware of the exact date of UDT. The study was approved by the Partner’s Institutional Review Board.

All UDTs were performed by the MGH central toxicology lab that also handles daily clinical drug screening. Immunoassay was the method of testing in the toxicology lab and was conducted by instrumented testing. The test panel was the same between the Clinical Group and Research Group. It is possible that the test panel and method in our central toxicology lab may have changed over time (from 2003 to 2011) but the subjects who were tested were not clustered into a specific period. Therefore, any possible change in the test panel and methods would have impacted both groups across a similar time period. The drug screening panel included the following substances: cannabinoids, benzodiazepines, cocaine metabolites, buprenorphine, 6-monoacetylmorphine (heroin metabolite), oxycodone, methadone, amphetamines, barbiturates, phencyclidine, oxymorphone, hydromorphone, morphine. No follow-up plasma samples were obtained from these subjects to verify a positive UDT. Gas chromatography (GC/MS) or liquid chromatography/tandem mass spectrometry (LC/MS/MS) was not part of a routine UDT to confirm the findings on immunoassay in our hospital. For the Clinical Group, UDT data were collected from patients’ medical record using the MGH’s Longitudinal Medical Record (LMR) system. Each subject’s medical record was reviewed for UDT under “chemistry tests” in LMR. For the Research Group, UDT results were obtained when subjects first enrolled into a study at our research center. Each UDT result was recorded in a standard data collection spreadsheet using Microsoft Excel.

Since several drugs including opioids used in pain management are drugs of abuse (DOA) and can result in a positive UDT, we specifically identified those cases of positive UDT due to non-prescribed DOA and designated these cases as positive UDT with DOA (PUD). The type of DOA and the status of opioid therapy, or lack thereof, at the time of UDT were determined for both the Clinical Group and Research Group. It should be noted that the accuracy of the designated DOA in this manuscript is limited by the information obtained using immunoassay. For example, some of the most commonly used benzodiazepines (e.g., 7-aminoclonazepam) are not detected by many immunoassay tests. Investigators in this study met on a weekly basis to review any issues related to the data collection. All decisions related to the study were implemented uniformly to both groups. The Principal Investigator monitored the performance of team members on a monthly basis. As shown in Table 1, a set of strategies were implemented to improve accuracy and minimize inconsistencies in reviewing UDT results including 1) staff training, 2) clear terms of inclusion and exclusion criteria, 3) clear definition of data variables despite the use instrumented testing, and 4) setup of standard data collection sheets.

Table 1
Strategies used to ensure accuracy in data analysis

Since this is a retrospective cross-section observational study, no power analysis was performed. Statistical analyses were performed using two-tailed Fisher exact tests between the Clinical Group and Research Group. Statistical significance was set at P<0.05 for all analyses. Although we also collected a set of clinical information including type of pain, pain duration, marital status and gender, substance abuse history, alcohol abuse history, employment status, disability status, and other comorbidities (depression, anxiety), we were unable to make further meaningful analysis because of the missing information in medical records in the Clinical Group.

Results

Demographic data

The Research Group (n=345) included chronic pain subjects with or without opioid therapy. Each subject had one UDT after consented to participate in a research study. Of 345 chronic pain subjects, 48.7% (168/345) were males and 51.3% (177/345) were females (Table 2). The average age of all chronic pain subjects in the Research Group was 47 years old and there were no significant age differences between healthy subjects and chronic pain subjects. Pain conditions reported by these subjects included neck pain, back pain, and neuropathic pain such as complex regional pain syndrome.

Table 2
Gender and Age differences between Research Group and Clinical Group

For the Clinical Group, we reviewed the MGH Center for Pain Medicine database of 1,529 chronic pain patients. There were 632 (41.3%) male subjects and 897 (58.7%) female subjects in this group (Table 2). The age range of this group was 17–97 years with an average age of 54.5 years (Table 2). Of 1,529 clinic pain patients under review, 358 subjects had at least one random UDT and were included in the final data analysis. Pain conditions reported by these subjects included neck pain, back pain, neuropathic pain, fibromyalgia, and abdominal pain. Overall, there were no statistical differences in pain conditions between pain subjects in the Clinical Group and Research Group.

Rate of positive UDT

Research Group

UDT was conducted on a total of 345 pain subjects in the Research Group and 51 subjects (14.8%) showed PUD (Figure 1).

Figure 1
A flowchart illustrates the results of urine drug test (UDT) in subjects who voluntarily participated in pain research studies (Research Group). DOA: drugs of abuse. PUD: positive UDT due to non-prescribed controlled or illicit drugs.

Clinical Group

Of 358 clinical pain patients, 282 subjects (78.8%) had a positive UDT and 76 subjects (21.2%) had negative UDT. Among 282 subjects with a positive UDT, 134 subjects (134/358: 37.4%) showed a positive UDT but due to a prescribed drug such as opioid or benzodiazepine (Figure 2). The remaining 148 subjects (148/358: 41.3%) showed PUD. Compared with the data from the Research Group, the results showed that subjects in the Clinical Group were more likely to show PUD (41.3%) than those in the Research Group (14.8%; P>0.01) .

Figure 2
A flowchart illustrates the results of urine drug test (UDT) in clinical pain patients (Clinical Group). DOA: drugs of abuse. PUD: positive UDT due to non-prescribed controlled or illicit drugs.

Clinical factors associated with positive UDT

Age

Age did not seem to be a significant factor in the outcome of UDT in either the Clinical Group or the Research Group as illustrated in Table 2.

Gender

In the Research Group, 51 pain subjects with PUD were equally divided between males and females (Table 2). In the Clinical Group, male subjects were more likely to be prescribed opioid therapy than non-opioid therapy (55.6% vs. 41.5%), while female subjects were more likely to be prescribed non-opioid therapy than opioid therapy (44.4% vs. 58.5%). This gender difference was statistically significant (p = 0.0164). Although male subjects in the Clinical Group were more likely to be prescribed opioid therapy, the rate of PUD was not statistically different between male (54.1%) and female (46.0%) subjects in this group (p = 0.4524).

Opioid therapy

Overall, more subjects with PUD in both Clinical Group and Research Group were prescribed opioid therapy than non-opioid therapy (Figure 3). In the Research Group, 73% (37/51) pain subjects with PUD were prescribed opioid therapy as compared to 27% (14/51) pain subjects with PUD who were not prescribed opioid therapy. In the Clinical Group, pain subjects who were prescribed opioid therapy had a significantly higher PUD rate (138/148: 93.3%) than pain subjects who were not prescribed opioid therapy (10/148: 6.7%; p < 0.0001). The data from both groups indicates that subjects on opioid therapy were more likely to show PUD.

Figure 3
Percent of subjects on opioid therapy versus no-opioid therapy showing PUD (positive UDT with non-prescribed controlled or illicit drugs).

Type of DOA detected in positive UDT

Research Group

Of 51 pain subjects with PUD in this group, cocaine (51.0%), benzodiazepine (33.3%), and cannabinoids (27.5%) were the top three DOAs (Table 3).

Table 3
Drugs of Abuse

Clinical Group

In this group, cannabinoids (66.2%) was the most commonly detected drug followed by benzodiazepine (35.8%), and cocaine (29.7%), as detailed in Table 3. These results indicate detection of a different set of DOA in the Clinical Group as compared to that in the Research Group.

Discussion

In this study, we analyzed 1,874 UDT results from 1) clinical pain patients under treatment at the MGH Center for Pain Medicine (Clinical Group) and 2) subjects who voluntarily participated in pain research studies at the MGH Center for Translational Pain Research (Research Group). Our results showed that 1) there was a higher rate of PUD in clinical pain patients (41.3%) than pain subjects participating in research studies (14.8%); 2) although subjects in the Research Group were informed ahead of time that UDT will be conducted as a screening test, many study subjects still showed PUD; 3) there were different types of DOA between clinical pain patients (top DOA: cannabinoids) and study subjects (top DAO: cocaine); and 4) a common factor associated with DOA in a positive UDT was prescription opioid therapy in both Clinical Group and Research Group.

There are several important limitations of this study. First, since our results were obtained from a single academic hospital located in a northeastern region of the United States, the data may not be representative of the general population and may have a regional bias. Second, psychological comorbidities may be different between subjects in the Clinical Group versus Research Group because subjects with psychological comorbidities are often excluded from participating in pain research studies. Since the data on psychological comorbidities was often incomplete in clinical pain patients (Clinical Group), we were unable to determine whether psychological comorbidities would have contributed to the difference in the rate of PUD between these two groups. Third, there may have been a significant change in the type of DOA over the past several years due to new marijuana laws in several states. Our data were collected from 2003 to 2011 and may not have reflected this change. Fourth, UDT conducted in the Clinical Group versus Research Group was different. The former was random and the latter was mandatory (pre-scheduled), which could either under-represent (false negative) or over-represent (false positive) the rate of positive versus negative PUD rate in these groups. Therefore, the difference in the rate of positive PUD between these two groups may not reflect a true difference but a procedural artifact. Indeed, there is a dearth of published information that truly evaluates the impact of scheduled versus random testing on the rates of positivity UDT. These issues may be addressed in future studies by including multiple centers and a larger sample size.

UDT can be complicated by false-positive or false-negative results and is subject to erroneous interpretations [13, 14]. For example, false-positive cocaine findings were determined by more sensitive chromatography-mass spectrometry (GC-MS) testing in surgical patients [15], although it is noted that false positive cocaine findings are rather rare as compared to false positive amphetamine findings. In a retrospective chart review study, there was a high rate of false-negative findings on methadone, heroin, and benzodiazepines [8]. Some studies have suggested using modified UDT techniques such as directed mass spectrometry testing to improve the accuracy [16], whereas another study evaluating office-based UDT with immunoassay and liquid chromatography tandem mass spectrometry (LC/MS/MS) appears to suggest that UTD with immunoassay in the office setting might be appropriate [13]. It should be noted that using immunoassay as the only method of UDT in an office setting remains controversial with regard to the accuracy and cost-effectiveness [8, 13]. Nonetheless, additional studies are needed to reach some consensus on this topic. In our study, samples from both Clinical Group and Research Group were analyzed by a standardized central toxicology lab at MGH using immunoassay, which is also routinely used in our clinical practice. Although possible false positive or false negative results could not be ruled out in this study because no follow-up plasma samples were obtained from these subjects, the degree of uncertainty regarding false UDT results would be similar in both groups since the same method of UDT was used for both groups. In addition, we excluded those subjects who had a positive UDT with a prescribed drug from the PUD category. As such, only those subjects with a positive UDT with non-prescribed DOA were included in the PUD category. However, it is important to point out that accuracy of the reported positive UDT rates in this study would be influenced by the presence of false positives and false negatives findings of immunoassays used in both groups.

This study was not meant to examine the issue of treatment compliance in pain patients prescribed opioid therapy. Instead, we focused on whether subjects in the Research Group, when compared to those in the Clinical Group, would 1) have a lower rate of PUD because study subjects were pre-scheduled as compared to random UDT in clinical patients and 2) show different types of illicit drugs. Indeed, our data showed a high rate of PUD in pain patients in the Clinical Group. Surprisingly, a substantial number of study subjects (14.8%) still showed PUD. Unlike subjects in the Clinical Group who had random UDT, subjects in the Research Group were informed of a mandatory UDT at their first visit in order to be enrolled into a research study. A possible explanation for this situation is that study subjects were either unaware of the sensitivity of UDT or knowingly ignored UDT hoping that none would be detected. Nevertheless, our finding strongly argues for conducting a routine UDT in pain research studies in order to improve the overall data interpretation, and such tests may better be conducted randomly instead of prescheduled.

The literature remains unequivocal with regard to the rate of PUD in chronic pain management, but a range of 10.8–34% positive UDT has been reported [14, 17]. In one study, 12.6% positive UDT for illicit drugs was reported and marijuana was the top substance detected [11]. In another study, 16% of chronic pain patients, with or without being prescribed opioid therapy, were found to be positive for illicit drugs and again marijuana was on top of the list [18]. In a large sample of 20,089 UDT of chronic pain patients, nearly 35% of these samples tested positive for opioids. Unfortunately, this study did not clarify whether a portion of these positive findings were from patients prescribed with opioid therapy [19]. Of significance to note is that propoxyphene continues to be detected in UDT even after its withdrawal from the US market [20].

While age and gender did not appear to be a significant factor in the outcome of UDT in this study, being prescribed opioid therapy is likely to be closely linked to PUD. Combining subjects from both Research Group and Clinical Group, we find that those subjects prescribed opioid therapy had a significantly higher rate of PUD than those who were not prescribed opioid therapy. With regard to the type of DOA, the top three DOA were different between the Research Group and Clinical Group. The Research Group showed a significantly higher positive rate for cocaine than the Clinical Group, whereas the Clinical Group had a significantly higher positive rate for cannabinoids. Interestingly, both groups had a similar rate for benzodiazepines, which was the second top drug on the list of DOA in both groups. Moreover, subjects in the Clinical Group who were not prescribed opioid therapy showed a high rate of PUD for non-prescribed opioids in their urine samples (data not shown), suggesting that a significant portion of chronic pain patients who were not prescribed opioid therapy were nevertheless actively using un-prescribed opioid drugs. Other factors that could be linked to PUD may include a history of substance or alcohol abuse, depression, and anxiety. Unfortunately, we were unable to make such an analysis because of the incomplete information from pain patients in the Clinical Group.

Some investigators have suggested that UDT should be routinely performed to create a better practice program for opioid therapy [21], although the validity of UDT as a useful monitoring method for treatment compliance remains uncertain [22]. Some studies suggest that repeated UDT may serve to deter illicit drug use in pain patients treated with opioid therapy. For example, a retrospective study found that the rate of positive UDT was decreased from the initial 23% to 9% after 14 clinical visits when UDT was performed in-between these visits [23]. In one study conducted in a primary care setting, the number of UDT conducted was increased after implementation of an opioid risk reduction initiative [11]. Specifically, the number of ordered urine drug tests was increased almost 16 times after the initiative. However, the rate of illicit drug detection in UDT did not significantly differ before and after the initiative. In another study, a correlation was found between positive UDT for illicit drugs and negative UDT for a prescribed opioid [14, 17]. These are all important issues to be examined in future studies.

In summary, our results indicate that PUD is a common finding in both clinical pain patients and subjects voluntarily participating in pain research studies, particularly in those pain subjects prescribed opioid therapy, although the actual rate of positive UDT in these groups may not be known due to the possibility of false positive and false negative findings. It should also be noted that the results of this study were obtained from a tertiary care center in an academic hospital and may not be applicable to pain centers and clinics in different settings. However, since many subjects participating in pain research studies showed PUD despite being informed of UDT ahead of time, the data suggests that UDT should be used as a routine screening test in pain-related research studies and may be performed as a random instead of a pre-scheduled test.

Footnotes

Conflict of Interest:

The authors claim no conflict of interest.

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