Economic Implications of Potential Drug–Drug Interactions in Chronic Pain Patients

Robert Taylor Jr; Joseph V Pergolizzi Jr; R Amy Puenpatom; Kent H Summers


Expert Rev Pharmacoeconomics Outcomes Res. 2013;13(6):725-734. 

In This Article

Abstract and Introduction


Chronic pain patients may be subject to polypharmacy because of long-term pharmacological pain treatment and additional comorbidities. Many chronic pain patients expose themselves to potential drug–drug interactions (DDIs) and these interactions can have unintended and severe consequences. Prevalence and costs associated with DDIs are inconsistent and has led to an inadequate level of awareness among the medical community; therefore, it has become necessary to re-evaluate the rates of DDIs in chronic pain patients. Utilizing medical and prescription claims databases, five studies were conducted to assess the health care utilization of and associated financial payments for patients >18 years with chronic noncancer pain. The studies evaluated drug–drug exposures with the potential to cause DDIs specifically occurring through the CYP450 enzyme system. The studies reported that drug–drug exposures are prevalent, costly and can occur in any age group and that physicians should consider ways to limit their patients' exposure to potential DDIs.


Opioid analgesics may be appropriately prescribed for certain chronic pain patients.[1–4] Several well-known opioid analgesics are metabolized via the cytochrome P450 (CYP450) enzyme system, namely codeine, fentanyl, hydrocodone, methadone, oxycodone and tramadol.[5] These are by no means the only agents metabolized via CYP450. When more than one active agent is metabolized simultaneously by way of the CYP450 system, the patient is exposed to a potential pharmacokinetic drug–drug interaction (DDI). A pharmacokinetic DDI has been defined as two or more drugs interacting in such a way that the effectiveness and/or toxicity of one or more of those agents are affected.[6] Patients who take two or more CYP450-metabolized agents concurrently are exposed to a potential DDI. Thus, the likelihood of having drug–drug exposures (DDEs), which is exposure to the risk of a DDI, could be prevalent, yet the general public, health care community and government may not recognize their importance.

Chronic pain associated with osteoarthritis (OA) and chronic lower back pain (cLBP) already represents an enormous financial burden to the health care system, society and patients;[7–10] partially driven by increased costs due to DDIs. For example, the literature has associated DDIs with increased hospitalization rates, extended hospital stays and morbidity.[11–14] In addition, literature also supports that drug-related adverse effects can increase costs significantly.[15–17] However, the economic implications of DDEs and DDIs are complex and not well documented. Since there is no adequate estimation of the prevalence rates of DDIs in the chronic pain patient, current valuations are most likely to be inaccurate and low. Since DDIs can potentially cause adverse effects, it is fair to expect that they would also increase costs for inpatient and ambulatory patient care. Therefore, it seems appropriate to study pharmacokinetic DDIs and how the costs of these DDIs further contribute to the overall cost of the health care system.

The reported prevalence of DDIs has been inconsistent throughout the literature. Reasons may include the types of patient populations analyzed, the types of drugs analyzed and the way the DDIs were identified (physician self-report versus electronic medical system). Studies estimating the prevalence of DDIs have presented wide ranges, 2–30% for hospitalized patients and 9–70% for ambulatory patients.[18–20] A major limitation in many studies can be the method of detection, especially if identification relies solely on the physician. Physicians' and pharmacists' track record of identifying DDIs have been shown to be poor, and many prevalence studies are most likely underestimated.[21] For example, one study documented a 53% success rate of identifying moderate to severe DDIs,[22] whereas another study showed that physicians missed 21% of the DDIs that necessitated a change in clinical management.[23] Identification of such interactions is not always transparent. DDIs present themselves as an alteration in patient physiology and thus can mimic almost any clinical presentation. Symptoms of pharmacokinetic DDIs may manifest as expected side effects (e.g., agitation, somnolence, gastrointestinal tract symptoms) and appear to reflect typical heterogeneity of patients' responses. In addition, they may be confused or associated with the symptoms of the disease being treated or even be confused with the physiological changes of aging, especially in geriatric patients.[24] More recently, physicians and pharmacists may be placing more reliance on electronic record keeping to identify and alert themselves of medication errors.[25,26] However, effectiveness in preventing DDEs by physicians or pharmacists is limited by clinical awareness of the seriousness and scope of DDEs. Furthermore, such electronic systems may not link with other physician systems, thus the patient data from multiple prescribers would not be captured. All of these situations can make the detection of DDIs difficult, which in turn leads to an underestimation of their apparent clinical relevance.

To shed light on the DDI issue, we reviewed five retrospective database studies in order to gain a better understanding of the prevalence of DDEs in the chronic noncancer pain patient and to determine if this prevalence rate would have any significant economic impacts.[27–31] These broad, large-scale, foundational studies sought to quantify the economic implications of DDEs in chronic pain patients who were taking opioid analgesics metabolized through the CYP450 enzyme pathway. DDIs are more difficult to identify and thus focus was on DDEs, which increase the potential risk for DDIs.