**3. Drugs observed in pain patients**

Table 1 lists both licit and illicit drugs as well as alcohol and the frequency observed in the pain patient population tested by Millennium Laboratories. These observations are similar to those reported by Cone (Cone et al., 2008). The medications most commonly found in the urine of this population are clearly hydrocodone and oxycodone, followed by morphine and hydromorphone; codeine is not frequently prescribed for this population. Benzodiazepines are the next most prescribed group. Other opioid medications such as fentanyl, meperidine, tramadol, and propoxyphene are less frequently used**.** Use of the muscle relaxants carisoprodol is commonly seen. Marijuana is by far the most prevalent among the illicit drugs, followed by cocaine and methamphetamine. From the table it is clear that alcohol use is about 10% as measured by the presence of alcohol's metabolites ethyl glucuronide (EtG) and ethyl sulfate (EtS) (Crews et al., 2011a; Dahl et al., 2002; Helander & Beck, 2005; Helander et al., 1996; Schmitt et al., 1997; Stephanson et al., 2002; Wojcik & Hawthorne, 2007; Wurst et al., 2006; Wurst et al., 2004). These data show that in order to provide appropriate monitoring and decrease risk and mortality for this population, a broad test menu is needed. These same drugs are often abused and frequently found to be present though they had not been prescribed by the treating physician. Table 2 shows the frequency of these nonprescribed drugs in the pain patient population.

#### **3.1 Need for urine drug testing**

Many physicians prescribing opioids for non-cancer pain patients follow guidelines established by the American Pain Society (Chou et al., 2009). These guidelines specify the regular or periodic use of UDT as a component of treatment, including administering UDT upon assessing potential risk for substance abuse, misuse or addiction (Atluri & Sudarshan, 2003; Ives et al., 2006; Madras et al., 2009). Guidelines also suggest that doctors use UDT to monitor patient adherence to prescribed treatments and further state that periodic UDT is warranted because "the therapeutic benefits of these medications are not static and can be affected by changes in the underlying pain condition, coexisting disease, or in psychological or social circumstances" (Chou et al., 2009). In observation of these recommendations, many physicians use POC devices to obtain a real time, in-office assessment of patient compliance, illicit drug use and possible diversion (Manchikanti et al., 2006b, 2010).

#### **3.2 Point of care testing**

As mentioned previously, these POC devices are qualitative immunoassays that test for various drug classes as well as a few specific drugs. A typical POC device can measure 12 drugs or drug classes (Amedica Drug Screen Test Cup). The most commonly monitored agents are barbiturates, benzodiazepines, opiates, oxycodone, propoxyphene, methadone, tricyclic antidepressants and the illicit drugs methamphetamine, marijuana, cocaine, methylenedioxymethamphetamine (MDMA), and phencyclidine (PCP). The physicians use these screens to immediately detect adherence to regimen or non-adherence to the prescribed drug therapy. At that point they can elicit a more complete drug history, initiate a conversation assessing the need for additional medications not prescribed, or confront the

are used in much lower concentrations than the earlier-designed drugs (Fraser, 2001). This

Table 1 lists both licit and illicit drugs as well as alcohol and the frequency observed in the pain patient population tested by Millennium Laboratories. These observations are similar to those reported by Cone (Cone et al., 2008). The medications most commonly found in the urine of this population are clearly hydrocodone and oxycodone, followed by morphine and hydromorphone; codeine is not frequently prescribed for this population. Benzodiazepines are the next most prescribed group. Other opioid medications such as fentanyl, meperidine, tramadol, and propoxyphene are less frequently used**.** Use of the muscle relaxants carisoprodol is commonly seen. Marijuana is by far the most prevalent among the illicit drugs, followed by cocaine and methamphetamine. From the table it is clear that alcohol use is about 10% as measured by the presence of alcohol's metabolites ethyl glucuronide (EtG) and ethyl sulfate (EtS) (Crews et al., 2011a; Dahl et al., 2002; Helander & Beck, 2005; Helander et al., 1996; Schmitt et al., 1997; Stephanson et al., 2002; Wojcik & Hawthorne, 2007; Wurst et al., 2006; Wurst et al., 2004). These data show that in order to provide appropriate monitoring and decrease risk and mortality for this population, a broad test menu is needed. These same drugs are often abused and frequently found to be present though they had not been prescribed by the treating physician. Table 2 shows the frequency of these non-

Many physicians prescribing opioids for non-cancer pain patients follow guidelines established by the American Pain Society (Chou et al., 2009). These guidelines specify the regular or periodic use of UDT as a component of treatment, including administering UDT upon assessing potential risk for substance abuse, misuse or addiction (Atluri & Sudarshan, 2003; Ives et al., 2006; Madras et al., 2009). Guidelines also suggest that doctors use UDT to monitor patient adherence to prescribed treatments and further state that periodic UDT is warranted because "the therapeutic benefits of these medications are not static and can be affected by changes in the underlying pain condition, coexisting disease, or in psychological or social circumstances" (Chou et al., 2009). In observation of these recommendations, many physicians use POC devices to obtain a real time, in-office assessment of patient compliance,

As mentioned previously, these POC devices are qualitative immunoassays that test for various drug classes as well as a few specific drugs. A typical POC device can measure 12 drugs or drug classes (Amedica Drug Screen Test Cup). The most commonly monitored agents are barbiturates, benzodiazepines, opiates, oxycodone, propoxyphene, methadone, tricyclic antidepressants and the illicit drugs methamphetamine, marijuana, cocaine, methylenedioxymethamphetamine (MDMA), and phencyclidine (PCP). The physicians use these screens to immediately detect adherence to regimen or non-adherence to the prescribed drug therapy. At that point they can elicit a more complete drug history, initiate a conversation assessing the need for additional medications not prescribed, or confront the

illicit drug use and possible diversion (Manchikanti et al., 2006b, 2010).

complicates identification of these new agents by immunoassay.

**3. Drugs observed in pain patients** 

prescribed drugs in the pain patient population.

**3.1 Need for urine drug testing** 

**3.2 Point of care testing** 


Table 1. Drug and Metabolite Prevalence, Positivity, and Concentrations. N = 184,049 patient specimens. Test dates: 10/01/09–4/29/10.

Diagnostic Accuracy and Interpretation

of Urine Drug Testing for Pain Patients: An Evidence-Based Approach 31

Natural and Semi-Synthetic Opioids 13,241 25.75%

Total Creatinine Tests 69,888 Total RADAR C Positives 51,416

6-MAM (Heroin metabolite) 165

cTHC (Marijuana metabolite) 4,546

EDDP (Methadone metabolite) 1,381

Table 2. Incidence of Non-prescribed Use of Prescription Medications and Illicit Drugs.

Fentanyl 729 Meperidine 29 Methadone 271 Norfentanyl 204 Normeperidine 55 Norpropoxyphene 898 Propoxyphene 25 Tapentadol 17 Tramadol 770

*Natural and Semi-Synthetic Opioids 13,241*

Cocaine metabolite 1,710 Methamphetamine 320

**% POSITIVE 73.57%** *Benzodiazepine 14,559* 7-Amino-Clonazepam 3,864 Alpha-Hydroxyalprazolam 5,543

> Lorazepam 1,079 Nordiazepam 1,907 Oxazepam 1,803 Temazepam 363 *Illicit Drugs 6,769*

> > MDMA 17

Phencyclidine 11

Buprenorphine 809 Codeine 692 Hydrocodone 5,138 Hydromorphone 1,789 Morphine 1,317 Norbuprenorphine 73 Oxycodone 2,618 Oxymorphone 805 *Other 11,514* Carisoprodol 735 Ethyl Glucuronide 5,320 Ethyl Sulfate 4,820 Meprobamate 639 *Stimulants 954* Amphetamine 954 *Synthetic Opioids 4,379*

**DRUG CATEGORY OCCURRENCES % of TOTAL** Benzodiazepine 14,559 28.32% Illicit Drugs 6,769 13.17%

Other 11,514 22.39% Stimulants 954 1.86% Synthetic Opioids 4,379 8.52% **TOTALS 51,416 100.00%**


Table 1. (continued). Drug and Metabolite Prevalence, Positivity, and Concentrations. N = 184,049 patient specimens. Test dates: 10/01/09–4/29/10.

Norfentanyl 11,589 88.2% 626.8 236.6 8 - 47,354.9 8 Fentanyl 9,283 70.6% 109.4 36.1 2 - 33,050.7 2

Normeperidine 4,247 67.3% 1,456.3 339.5 50 - 276,993 50 Meperidine 2,522 40.0% 34,321.8 13,533.4 50.18 - 616,862 50

EDDP 12,109 97.5% 7,871.9 4,117.3 100.05 - 251,835 100 Methadone 11,792 95.0% 5,265.1 2,409.4 100.11 - 260,433 100

Hydrocodone 59,346 50.9% 2,564.4 859.9 50 - 477,876 50 Hydromorphone 51,205 43.9% 836.0 240.4 50 - 204,633 50 Oxymorphone 49,688 42.6% 5,760.2 1,298.6 50 - 1,512,220 50 Oxycodone 41,603 35.7% 11,207.3 2,124.5 50 - 5,947,380 50 Morphine 21,400 18.3% 29,611.8 9,600.3 50.06 - 1,995,940 50 Codeine 3,686 3.2% 4,752.0 828.4 50.01 - 233,036 50 6-Acetylmorphine 465 0.4% 1,108.8 275.7 10.01 - 24,069.1 10

Phencyclidine 23 100.0% 539.4 87.5 10.89 - 3,718.53 10

Norpropoxyphene 6,395 100.0% 5,524.3 2,026.9 100 - 167,037 100 Propoxyphene 2,780 43.5% 1,919.5 583.6 100 - 178,006 100

Tapentadol 277 100.0% 11,557.1 6,870.3 52.05 - 492,895 50

Tramadol 6,521 100.0% 19,288.0 8,191.4 100 - 601,928 100

Table 1. (continued). Drug and Metabolite Prevalence, Positivity, and Concentrations. N =

*Fentanyl* 13,141 *14.1%*

*Meperidine* 6,310 *7.3%*

*Methadone* 12,415 *11.0%*

*Opiates* 116,683 *64.6%*

**Total Specimens Tested 93,526**

**Drug Class**

**Total Specimens Tested 86,344**

**Total Specimens Tested 113,073**

**Total Specimens Tested 180,487**

**Total Specimens Tested 104,137**

**Total Specimens Tested 133,992**

**Total Specimens Tested 66,797**

**Total Specimens Tested 54,111**

*Phencyclidine* 23 *0.02%*

*Propoxyphene* 6,397 *4.8%*

*Tapentadol* 277 *0.4%*

*Tramadol* 6,521 *12.1%*

184,049 patient specimens. Test dates: 10/01/09–4/29/10.

**N % Mean Median Range Cutoff Positive Positive (ng/mL) (ng/mL) (ng/mL) (ng/mL)**


Table 2. Incidence of Non-prescribed Use of Prescription Medications and Illicit Drugs.

Diagnostic Accuracy and Interpretation

BZO Benzodiaze-

TCA

pines

Tricyclic Antidepressants

results should be confirmed by mass spectrometry.

give a positive at higher concentrations.

Vick's Inhaler contains l-methamphetamine.

**3.3 Determining appropriate UDT cutoffs** 

pain patient population (Pesce et al., 2011).

of Urine Drug Testing for Pain Patients: An Evidence-Based Approach 33

Oxazepam, nordiazepam, temazepam, alprazolam and other benzodiazepines to

MTD Methadone Methadone Verapamil, quetiapine

Amitriptyline, nortriptyline, imipramine, desipramine, doxepin and other tricyclics to

1 While most immunoassays are highly selective for their target compounds, cross reactive compounds and adulterants, particularly when present at high concentrations may result in a false positive. Additional cross reactants have been reported and cross reactivity may vary between immunoassay manufacturers and lot to lot. The manufacturers of point of care test devices recommend that positive

2 OPI300 is an assay to detect codeine, morphine, hydrocodone and hydromorphone. Oxycodone may

3 OXY is an assay to detect Oxycodone. Other opiates, esp. codeine, morphine, hydrocodone and

4 Adderall contains amphetamine. Benzphetamine (Didrex) is metabolized to d-amphetamine and dmethamphetamine. Selegiline (Eldepryl) is metabolized to l-amphetamine and l-methamphetamine.

Sensitivity of detection currently used in many immunoassays may not be appropriate for the pain patient. This is because manufacturers set cutoffs for assays to identify overdose in emergency unit settings (Fraser & Zamecnik, 2003; Fraser, 2001; Hattab et al., 2000; Wingert, 1997). There is a need to establish appropriate cutoffs for patients on clinical doses of their medications rather than the high concentrations encountered in overdose situations. Specifically, studies have been conducted that better identify the appropriate cutoff for the

One definition of appropriate cutoff levels is one that captures 97.5% or more of the population on a specific drug (Pesce et al., 2011). An example of the importance of setting appropriate cutoffs is for the drug clonazepam (West et al., 2010b). When measured by immunoassay using a nominal cutoff of 200 ng/mL, only 28% of the patients on the drug were determined to be compliant. When the same samples were measured by LC-MS/MS technique using a cutoff of 200 ng/mL, the group was found to be 70% compliant. Finally, when the LC-MS/MS cutoff was lowered to 40 ng/mL the group was 87% compliant. This study showed that first the immunoassay was insensitive in that the nominal 200 ng/mL cutoff did not apply to clonazepam, and second, a lower cutoff was needed to appropriately categorize compliance. Other studies have shown the need for lower cutoffs for pain medications (Mikel et al., 2009; Pesce et al., 2010a). As the consequences to the patient of dismissal from a practice can be very large and even life-changing (e.g., loss of insurance, loss of job or income), it is essential that physicians do not unjustifiably dismiss even a

Oxaprozin, sertaline

Cyclobenzaprine, carbamazepine, diphenhydramine

Codeine, morphine, hydrocodone and hydromorphone

varying degrees

varying degrees.

OXY3 Oxycodone Oxycodone and oxymorphone

Table 3. False Positive Results: Immunoassay Cross Reactants.

hydromorphone may give a positive result at higher concentrations.

patient about illicit drug use. Point of care devices are extremely useful because they provide physicians with immediate information, particularly on initial patient intake. Of course, like many CLIA-waived (or simple) test devices, they do have limitations, inasmuch as they require that a person visually inspect them in order to interpret the results. For this reason as well as the fact that these units are not 100% accurate, manufacturers of POC devices recommend that doctors not confront patients without first confirming the POC results (Table 3) (Amedica Drug Screen Test Cup). Table 3 lists a number of known drugs or agents that cause false positive results in POC immunoassays. In contrast with POC immunoassay tests, which only show a positive or negative result, laboratory-based immunoassays are often semi-quantitative (Feldkamp, 2010). This means that a positive result for morphine will also indicate approximately how much morphine is in the specimen. These immunoassays have quality control and proficiency testing surveys that make the results more objective and reliable than those obtained using POC devices (American Proficiency Institute 2011 Catalog of Programs, 2011; College of American Pathologists 2011 Surveys and Anatomic Pathology Education Programs, 2011).


patient about illicit drug use. Point of care devices are extremely useful because they provide physicians with immediate information, particularly on initial patient intake. Of course, like many CLIA-waived (or simple) test devices, they do have limitations, inasmuch as they require that a person visually inspect them in order to interpret the results. For this reason as well as the fact that these units are not 100% accurate, manufacturers of POC devices recommend that doctors not confront patients without first confirming the POC results (Table 3) (Amedica Drug Screen Test Cup). Table 3 lists a number of known drugs or agents that cause false positive results in POC immunoassays. In contrast with POC immunoassay tests, which only show a positive or negative result, laboratory-based immunoassays are often semi-quantitative (Feldkamp, 2010). This means that a positive result for morphine will also indicate approximately how much morphine is in the specimen. These immunoassays have quality control and proficiency testing surveys that make the results more objective and reliable than those obtained using POC devices (American Proficiency Institute 2011 Catalog of Programs, 2011; College of American

Pathologists 2011 Surveys and Anatomic Pathology Education Programs, 2011).

(contains THC),

Codeine, morphine, hydrocodone,

COC Cocaine Cocaine Unknown/Infrequent

hydromorphone. Also, poppy seeds that contain morphine.

Occasionally: benzphetamine, selegilene, Vicks Nasal

Amphetamine, Adderall. Occasionally: benzphetamine, selegiline, Vicks Nasal Inhaler4

Methamphetamine.

Methylenedioxymethamphetamine

other barbiturates

Butalbital, phenobarbital, secobarbital, amobarbital and

Inhaler4

**Class Target Drugs1 Compounds That May** 

**Cause A False Positive1**

Phenylpropanolamine,

phenylpropanolamine,

Phenylpropanolamine,

Unknown/Infrequent

Prilosec, Protonix , efavirenz, NSAIDs

Oxycodone

ephedrine, pseudoephedrine,

ranitidine, phentermine

Adderal,

ephedrine, pseudoephedrine, ranitidine, phentermine

Venlafaxine, dextromethorphan, diphenhydramine

ephedrine, pseudoephedrine, ranitidine, phentermine

**POCT Kit Abbreviation** 

MDMA

OPI3002 Opiates

AMP Ampheta-

MET Methampheta-

BAR Barbiturates

**Drug or Drug** 

mines

mine

Methylenedioxymetham phetamine

PCP Phencyclidine Phencyclidine

THC Marijuana Marijuana and Marinol


Table 3. False Positive Results: Immunoassay Cross Reactants.

1 While most immunoassays are highly selective for their target compounds, cross reactive compounds and adulterants, particularly when present at high concentrations may result in a false positive. Additional cross reactants have been reported and cross reactivity may vary between immunoassay manufacturers and lot to lot. The manufacturers of point of care test devices recommend that positive results should be confirmed by mass spectrometry.

2 OPI300 is an assay to detect codeine, morphine, hydrocodone and hydromorphone. Oxycodone may give a positive at higher concentrations.

3 OXY is an assay to detect Oxycodone. Other opiates, esp. codeine, morphine, hydrocodone and hydromorphone may give a positive result at higher concentrations.

4 Adderall contains amphetamine. Benzphetamine (Didrex) is metabolized to d-amphetamine and dmethamphetamine. Selegiline (Eldepryl) is metabolized to l-amphetamine and l-methamphetamine. Vick's Inhaler contains l-methamphetamine.
