**1.1 Chronic opioid therapy**

In this chapter we will refer to pain patients as those persons being treated with chronic opioid therapy for non-cancer-related pain. It is this patient population that has been associated with opiate abuse and diversion, and therefore monitoring these patients for drug use in a manner analogous to therapeutic drug monitoring is necessary. One of the most frequent complaints by patients seeing pain physicians is back pain, which is often associated with failed back surgery (Manchikanti et al., 2004; Michna et al., 2007). Currently opiate medications are one of the treatments of choice used by physicians to provide pain relief. These medications can induce euphoria as well as pain relief; because of this, opiates are frequently abused by this population, as well as the general population (National Survey on Drug Use and Health: Detailed Tables - Prevalence Estimates, Standard Errors, P Values, and Sample Sizes, 1995-2006; Webster & Dove, 2007). Additionally, these medications are associated with physical as well as psychological dependence and can pose addiction risks (Webster & Dove, 2007).

#### **1.2 Pain treatment**

One of the treatments of choice for chronic pain involves strong medications such as opioids, as well as additional or adjuvant medications (Chou et al., 2009; Trescot et al., 2006). Side effects of opioids include sedation, dizziness, nausea, vomiting, and constipation. Living day to day with any or all of these symptoms is challenging at the least and is compounded by the underlying pain these patients suffer from. Naturally, patients often

Diagnostic Accuracy and Interpretation

**2.2 Limitations of immunoassay** 

**2.1 Immunoassays** 

of Urine Drug Testing for Pain Patients: An Evidence-Based Approach 27

reasoning behind this focus is obvious; a positive result for a prohibited substance is a cause for a consequence such as job dismissal (Federal Register, 2004). Testing for these drugs usually follows scheduled guidelines established by the Substance Abuse and Mental Health Services Administration (SAMHSA) (Federal Register, 2004). Analytically, the testing involves qualitative immunoassay screening followed by confirmation by mass spectrometry. Testing for patients on chronic opioid therapy is a different paradigm as both positive and negative results are important. It also requires assays that are more sensitive

Immunoassays are tests that are based on the ability of an antibody to bind with a drug (Feldkamp, 2010). Antibodies are made in such a way that they bind with a specific drug, such as morphine. In one approach, manufacturers of point of care (POC) devices embed test strips with antibodies and install them in devices designed to interact with urine specimens (Amedica Drug Screen Test Cup). A urine specimen with the drug in it (in this example, morphine) will displace the drug-indicator molecule on the test strip causing the morphine drug indicator line to disappear or change color. These test strips are then visually inspected by the person administering the test. The absence or presence of a line or the change in color, such as on a home pregnancy test, indicates whether the result is positive or negative. The immunoassay antibody binding reaction can be measured in other, more sophisticated ways than using test strips, such as reference laboratory analytical instruments (Olympus Au640 Product Information; Siemens V-Twin Analyzer Product Information; Thermo Fisher Mgc-240 Analyzer Product Information). However, the fundamental property of immunoassays is

The qualitative immunoassay model of testing is only a partial UDT solution for the pain population (Gourlay et al., 2010; Hammett-Stabler & Webster, 2008; Nafziger & Bertino, 2009; Reisfield et al., 2007). There are a number of reasons for this. First, doctors treating patients for pain are concerned with negative as well as positive results. This is because a negative result can mean that a patient is not taking a prescribed medication. Second, workplace UDT assays do not fit the clinical medication regimen used in the treatment of pain patients and do not take into account the variable dosing often employed by pain patients as they try to balance their need for pain relief against the side effects of these medications (Gourlay & Heit, 2010a). In analytical terms this means that the cutoff for detection and quantitation (concentration of drug present) must be low enough to capture minimal use of the drug. Thirdly, the physicians need to have an exact indication of the medications the patients are taking. For example, a positive opiate test does not indicate whether the patient is on codeine, hydrocodone, morphine, or hydromorphone. That is, it measures the class not the particular drug. Each of these are specific medications the physician may choose to treat the patient with, so in order to establish compliance it is necessary to determine exactly which medication has been ingested and assure the patient is not taking additional opiates which could create an unsafe situation (Cone et al., 2008). Finally, if an immunoassay screening method is used, the antibody must detect all drugs of that particular class. Recent advances in designing opiate and benzodiazepine classes of drugs have resulted in agents which do not react well with the traditional antibodies. and

and can determine both the parent drug and one or more of its metabolites.

always the binding reaction of the antibody to the test drug (analyte).

attempt to minimize the side effects by taking less of the medication when side effects are particularly debilitating or unpleasant. "Chronic pain patients often adjust their dose of prescribed medication in response to changing levels of activity with no malicious or maladaptive intent. Although they may state that their pattern of use of medications is stable, this is often a statement made ''on average'' rather than a precise pattern of use. This is particularly evident with short-acting medications used in the treatment of breakthrough pain." (Gourlay & Heit, 2010b)

UDT is used to give confidence to both the physician and the patient that the patient is following the medication regimen and is therefore getting the most benefit from their treatment. In addition, the side effects of these medications often result in their misuse, underuse, and/or mixing of medications that are not prescribed (Manchikanti et al., 2004). This can also result in the social problems of abuse, misuse, or diversion of these medications. These factors require of pain physicians that they be particularly attentive to their prescribing practices. Adding to the complexity of managing pain patients is the fact that these medications are controlled substances and cannot be purchased over the counter, and so have high street value (Katz et al., 2003; National Prescription Drug Threat Assesment, 2009). This in turn requires of the physician that he or she determine whether patients under their care are compliant with their medication regime, binging on their medications, or diverting them for financial gain (Manchikanti et al., 2005, 2006a, 2006b).

#### **1.3 Complications of pain treatment**

Further compounding the situation, alcohol use is of major concern to the physician because alcohol-drug interactions can cause morbidity (Harmful Interactions: Mixing Alcohol with Medicines, 2007). Although physicians prohibit patient alcohol use during treatment with opiates or benzodiazepines, verbal contracts are commonly broken and therefore alcohol use must be monitored with (UDT) to manage the high risk of alcohol-drug reactions and mortality (Chou et al., 2009; Trescot et al., 2006). In addition, for reasons involving inadequate pain control, sleep deprivation, and psychological pathology, this patient population commonly takes other medications not prescribed by treating physicians as well as illicit drugs (Manchikanti et al., 2005, 2006a, 2006b). To respond to these potential problems, physicians traditionally relied upon behavioral assessment and pill counts to aid them in making treatment decisions. UDT has augmented these tools by providing physicians with objective, scientifically measurable outcomes to help them make decisions (Gourlay et al., 2010; Hammett-Stabler & Webster, 2008; Nafziger & Bertino, 2009; Reisfield et al., 2007). A detailed protocol of how to appropriately prescribe these controlled substances for this population is discussed in the book *Universal Precautions*, by Gourlay and Heit (Gourlay et al., 2005).
