UDM Solutions

Discovering the Invisible Patient with Pharmacogenetic Testing

We are discovering more and more the important role genes play in how our bodies process drugs. Pharmacogenetic testing provides a way to look at a patients’ genes that play a role in drug metabolizing. Identifying unique characteristics of these genes can assist in individualizing pharmacotherapy for chronic pain treatment.¹

Clinicians understand that visible differences between patients, such as age and weight, can affect how that patient will respond to pain treatment. What is currently less understood are the important invisible differences that also affect therapy. A primary cause of variation in drug response is interindividual variations in the genes that encode for the “proteins and enzymes involved in the transport and metabolism of drugs”.² As Meijerman explains, “interindividual differences in the pharmacokinetics (PK) of drugs represent a major clinical problem. Because of these differences, plasma levels of drugs are poorly predictable, which might lead to unexpected toxicities or undertreatment of patients”.² By identifying these genetic variations through a one-time genetic test, we can better prescribe a pharmacotherapy regimen that is optimal for each individual patient.

Specifically, “it is the role of the highly polymorphic CYP2D6 gene that is of the greatest clinical interest with respect to the observed interindividual variability in the opioid response”.¹ The CYP2D6 gene metabolizes many drug classes, including the opioids. Variation in the DNA encoding for these enzymes can cause them to metabolize faster or slower.¹ As also illustrated in the UDM handbook:

DNA sequence variations are associated with:

• Lack of enzymatic activity (poor metabolizer)
• Reduced enzymatic activity (intermediate metabolizer)
• Enhanced enzymatic activity (ultra-rapid metabolizer)

“The use of CYP2D6 genotyping to make therapeutic recommendations to improve therapeutic efficacy and to prevent toxicity in patients is promising and clinically relevant”.² Pharmacogenetic testing can provide us with “invisible” genetic information on a patient’s propensity for a drug reaction that allows us to further objectify each individual’s pain regimen, and thus minimize the practice of trial-and-error prescribing.¹

1. Urine Drug Monitoring: Opioids Handbook
2. Meijerman Irma, Sanderson Linda M., Smits Paul, Beijnen Jos H., Jan H.M. Schellens. “Pharmacogenetic Screening of the Gene deletion and Duplication of CYP2D6.” Drug Metabolism Reviews, 39: 45–60, 2007.

4 No-Cost Ways to Break Down the Patient-Clinician Communication Time Barrier

Open and thorough patient-clinician communication is important both for efficacy of treatment and efficiency of office visits. Certain barriers can impede this. For patients, these barriers may be psychosocial factors such as personality, beliefs, socio-economic status and/or conceptions about their treatment. Additionally, patients can underestimate their own importance in the outcome of their pharmacotherapy. While certain psychosocial dynamics can also be a factor for clinicians, a commonly cited communication barrier is a lack of time. Studies and research have sought to address these issues in communication by developing methods to improve the clinician-patient relationship. By incorporating these methods with the use of laboratory diagnostics, medical history and pharmacogenetic data, clinicians are able to enhance the quality and efficiency of health care through more accurate diagnostics, improved patient adherence, increased patient satisfaction and decreased malpractice litigations.

Some patients may refrain from openly communicating with their clinicians out of fear that they will be perceived negatively. As demonstrated my blog entitled “Real-Life Opportunities to Improve Pharmacotherapy,” patients may endure needless pain because they do not want to “upset” anyone or be viewed as “a difficult patient.” Patients should understand that by telling us how they are responding to treatment they are contributing in a proactive manner that is important to individualize and improve their pharmacotherapy. The following ideas may help us to portray this to patients:

1. Build Trust and Encourage Open Communication: According to a comprehensive review of studies on patient-clinician communication and relationships, “A warm greeting, eye contact, a brief non-medical interaction, or checking on an important life event can build rapport in less than 1 minute.”¹ These gestures improve the course of treatment for both clinician and patient by developing a mutually beneficial relationship; and, they require virtually no additional time the office visit.
2. Understand Patients as Individuals: Empathizing with our patients’ concerns about their treatments and understanding them as individuals allows us to take into account what psychosocial factors may be affecting their pharmacotherapy. This in turn improves our ability to create a pharmacotherapy that is specific to them, enhancing its efficacy and reducing the need for future adjustments.
3. Ensure that Patients Understand Their Treatment: Clinicians can take a preventative approach to improving adherence by eliminating confusion (e.g., complex regimens) and helping patients understand all aspects of their treatment. Opening up this dialogue also aides in creating an environment where patients can candidly discuss any other factors affecting adherence.
4. Offer Suggestions to Improve Communication: As clinicians, we can also offer patients suggestions to improve communication, such as writing down their questions before they come to their office visit. This helps assure that all of their concerns are addressed, reiterates the importance of their active role in their treatment, and ensures that the office visit is utilized most effectively.

Better communication leads to better treatment, and neither requires any extra time. In effect, establishing an open and communicative patient-clinician relationship can save future time spent adjusting and making changes from miscommunication or factors affecting adherence that could have been addressed if communicated initially. Psychosocial factors or concerns about how their clinician perceives them may inhibit some patients from openly communicating with their clinician. Alleviating these concerns can help to create an environment where patients feel comfortable disclosing all information pertinent to their pharmacotherapy and can help patients to understand the importance of doing so. Employing empathy and education strengthens the patient-clinician relationship and results in better treatment and more satisfied patients. Patient satisfaction has been shown to decrease malpractice litigations. Information provided by patients regarding the effects of their treatment can be used with laboratory diagnostics, medical history and pharmacogenetic data to further individualize pharmacotherapy and improve the quality of health care.

1. Roxanne Nelson and Charles Vega MD, Improving Communication Skills Enhances Efficiency and Patient-Clinician Relationship. Medscape Medical News 2008.

Real-Life Opportunities to Improve Pharmacotherapy

My friend, who is in her eighties, was recently hospitalized for back surgery and then stayed at a nursing home/rehabilitation center after her hospital discharge. Both in the hospital and in the nursing/rehabilitation facility, she was under-treated for her pain. In the hospital, she was prescribed hydrocodone as needed (PRN) and morphine around the clock (ATC). She was not being administered her morphine ATC and was mostly being administered hydrocodone which did not alleviate her pain. Only after I spoke with her clinicians did she receive her morphine as ordered. Even then, her morphine dose would be administered late, leaving her in pain during the intermediate time interval.

When I visited her at the nursing home, a mutual friend informed me that although she was in extreme pain, she did not want to "upset" anybody and was reluctant to inform her physician of her pain. Her prescription regimen was for oxycodone every eight hours PRN, and she would have to ask her nurse for the pain medication every time. With this regimen, she experienced pain during the entire 3-4 hours prior to her next dose. I told her that I would speak to her physician to review her pain medication. At first, she was extremely anxious because she feared she would be perceived as a difficult patient. Later, however, she thanked me. After communicating with her clinicians, she was ordered a slightly lower dose of oxycodone every four hours ATC. This helped better control her pain and contribute to a better quality of life during the post surgical period.

In both my personal and professional experience, it is extremely common that patients are prescribed generic medication regimens that are not individualized for their specific needs compounded by an ineffective follow-through by practitioners for optimizing patient pharmacotherapy. My personal friends and family have been affected by this type of healthcare standard that currently exists. As clinicians, we need to transform the subjective and generic dynamic in which we select, prescribe and monitor medication regimens, especially for our elderly patients, and create a scientific standard founded on objectifying their pharmacotherapy.

If my friend had undergone clinically relevant genetic testing, especially cytochrome P450 (CYP450) 2D6 testing, her team could have obtained objective data to assist in optimizing her pain medication regimen at the initiation of treatment. As a clinician, I wanted to know her CYP2D6 metabolism prior to making my recommendations to her team. In addition, we need to create the environment, communication tools and time needed to help enhance communication with our patients. We need to take into account the various psycho-social and biological factors that can impede our ability to individualize treatment. My friend could have been assigned a regimen that was individualized for her. Instead, she endured weeks of pain until her final regimen adjustment. This situation was worsened by a breakdown in communication and follow through between my friend and those responsible for her care. We need to improve our patients' pharmacotherapy and safety by implementing these tools as the standard of care, especially in our elderly population.

Fortunately, my friend has since recovered from her post surgical pain and is doing well.

Why Determining Drug Dose in Urine is a Myth

I have had several conversations where I have been asked if urine levels depict the dose and frequency of drugs detected in the urine. There is concern for both prescription medications (prescribed by that clinician or prescribed by other clinicians) and non-prescribed drugs. Clinicians need and want to determine a patient's adherence and extent of patient adherence. We also want to know if the medication, dose, and frequency prescribed is the best combination for our patient. We need to know how the patient is taking their medication so we can prescribe or adjust their medication accordingly. If a person takes too much or is not taking their medication, they can become ill either because of the medication or because the condition is not being treated appropriately. For these reasons and many more, it is understandable that clinicians are looking for a measurement that tells them specifically the drug dose and frequency that a patient is taking. Unfortunately, drug dose cannot be determined in a urine specimen. The only way you can know exact oral dosage and frequency is if you administer each dose to that patient.

Anne Nafziger, MD, MHS, PhD and Joe Bertino, Jr., PharmD, FCP, two clinicians who both have over 20 years of experience in drug development, clinical pharmacology, and clinical research and are also authors of the UDM: Opioids handbook, have published an exceptional article titled "Utility and Application of Urine Drug Testing in Chronic Pain Management With Opioids" in the January 2009 issue of the Clinical Journal of Pain. The article specifically describes the inability to determine oral drug dose in urine. One primary reason is genetic variations among people. A patient's genetic profile contributes to the rate and extent of ADME (absorption, distribution, metabolism, excretion). The genetic makeup of individuals is unique and therefore drug ADME is unique to that person. The article also states that in addition to differences between individuals, ADME may vary within a single person on a day to day basis. Due to these facts among others covered in the article, the authors state "...without blood concentration data, evaluating quantity of excreted parent drug in urine will not provide unequivocal evidence of patient ...(adherence) with recommended dosing."

So where do we go from here? Ultimately the goal is give our patients optimal pharmacotherapy. Currently, in the clinician-patient relationship, there is information we may collect and analyze to assist in assessing patient adherence. To move even closer to our goal, we need to utilize new tools and state-of-the-art technology. The motivation to write the UDM:Opioids handbook stemmed from the need for clinicians to obtain this information. Because UDM is a comprehensive monitoring strategy, it can provide more clinically relevant information than strictly knowing if the patient is taking the exact dose prescribed at the exact frequency prescribed. This will help shift the focus from drug dose to drug efficacy, and that is what will truly enhance our patients' treatment outcomes.