Potential Issues Associated with Polypharmacy

Phoenix—For decades, clinicians prescribed an opioid or nonsteroidal anti-inflammatory drug (NSAID) to treat patients with chronic pain. Currently, they are much more likely to utilize a polypharmacy approach, using multiple drugs to achieve pain relief with minimal toxicity.

However, polypharmacy comes with potential problems such as drug/drug and drug/disease interactions that can complicate matters.

“We have significant issues [with polypharmacy],” said Kathryn L. Hahn, PharmD, pharmacy manager at Bi-Mart Corporation in Springfield, Oregon, who spoke during a session at the AAPM meeting. “Things are happening that we do not even know about.”

Dr. Hahn, an affiliate faculty member at Oregon State University’s College of Pharmacy, said clinicians, in the past, have used the same approach to treat any type of pain. Recently, though, industry professionals are recommending utilizing specific therapies for different pain mechanisms.

The most common suggestion is implementing multimodal therapies or combination pharmacotherapies to increase effectiveness and minimize risk. Dr. Hahn said polypharmacy refers to using multiple medications to treat the same condition, using multiple drugs from the same class, or using multiple drugs with the same or similar mechanisms of action to treat different conditions.

Polypharmacy has numerous goals, including using lower drug doses to minimize adverse effects and increase adherence, maintaining analgesic efficacy by combining short-acting and long-acting agents to prevent breakthrough pain, and targeting different but associated symptoms or different locations of the disease process. Dr. Hahn added that polypharmacy sometimes has advantages over monotherapies. Yet, treating pain has become “much more complicated,” according to Dr. Hahn.

Therapeutic options for pain include opioid analgesics, simple analgesics such as acetaminophen, salicylates, and NSAIDs, and adjuvant analgesics such as antidepressants, anticonvulsants, muscle relaxants, sleeping agents, steroids, cannabinoids, antihistamines, antipsychotics, and anxiolytics.

With all of those choices, Dr. Hahn said drug/drug interactions are becoming more prevalent. Most of the research involves prescription opioid abuse, misuse, and addiction, but Dr. Hahn said other safety concerns related to prescribing might be overlooked.

She said there are potential harmful interactions between opioids and other medications. For instance, research has shown a majority of patients taking opioids also take adjunctive medications, while 78% of patients with pain take over-the-counter drugs. In addition, patients often use multiple prescribers who may be unaware of what drugs patients are taking.

Dr. Hahn defined drug/drug interactions as ≥2 drugs that affect each other by changing metabolism (by induction or inhibition), elimination (clearance), effectiveness, or toxicity. She said a major concern involves drugs metabolized and cleared via the cytochrome P450 (CYP450) enzyme system in the liver and gastrointestinal tract. Patients who receive multiple CYP450 metabolized drugs can increase or decrease the actions of enzymes to alter metabolism, leading to higher or lower than expected drug levels.

A retrospective analysis of a commercial and a Medicare database found that 27% of 100,159 patients with chronic low back pain took ≥2 CYP450 medications, with women and younger people (those between 35 and 54 years of age) more likely to be on multiple CYP450 therapeutics.

There are numerous ways to mitigate the risk of drug/drug interactions, according to Dr. Hahn. She said patients should know the medications that are metabolized via the CYP450 enzyme system that may interact with opioid analgesics. In addition, clinicians should review what medications patients are taking, including over-the-counter drugs, supplements, herbal remedies, alcohol, and other legal or illegal substances, and if the patients made any changes to their regimen. Providers should also tell patients of any adverse or lethal effects associated with medications and warn them that alcohol and drugs such as cannabinoids and cocaine can exacerbate opioid/drug interactions.

Further, clinicians should initiate CYP450-affected opioid analgesics and coprescribed CYP450 inhibitors at low doses and then increase the doses gradually. If possible, they should prescribe drugs that are metabolized via other pathways or by multiple CYP450 enzymes rather than a single enzyme. Although monitoring the type and amount of opioid is important, a small supply of a short-acting opioid or an ongoing prescription for a long-acting opioid could be problematic if there is a significant opioid/drug interaction.

Dr. Hahn also suggested that clinicians should use caution when switching or rotating opioids such as a non-CYP metabolized opioid (morphine) to a drug affected by CYP metabolism (methadone) or from a CYP-metabolized adjuvant (carbamazepine) to a non-CYP metabolized adjuvant (gabapentin).

Clinicians should take interactions between methadone and other drugs into special consideration, according to Dr. Hahn. Drugs such as amiodarone, cimetidine, ciprofloxacin, diazepam, and fluconazole can raise methadone levels, while antiretrovirals, barbiturates, carbamazepine, and rifampin can decrease methadone levels. Other substances can affect methadone levels, too, with grapefruit juice raising the levels and tobacco decreasing the levels.

To minimize methadone/drug interactions, Dr. Hahn suggested using alternative, noninteracting drugs when possible, maintaining an accurate profile of the prescriptions and over-the-counter drugs patients are taking, monitoring signs and symptoms of opioid withdrawal or overmedication, and avoiding concurrent administration of drugs with overlapping adverse effect profiles. Other tips include considering pre-existing disease states and being aware that patients may not adhere to complex therapeutic regimens.

Drug/disease state interactions are a potential problem, too, according to Dr. Hahn. She defined the interactions as the positive or negative impact of ≥1 drugs on a pre-existing condition, disease state, or pathological process.

For instance, she cited patients with reduced renal function who took meperidine, which led to normeperidine accumulation, causing excessive central nervous system stimulation and a lowered seizure threshold. Another example is when a patient’s QT interval is prolonged when taking methadone, he or she may be at an increased risk for an arrhythmia, which can lead to syncope, ventricular fibrillation, or death. Dr. Hahn said if the QT interval is prolonged by ≥500 ms, patients should discontinue taking methadone, change their dose, or switch drugs.

Despite these issues, Dr. Hahn said that when used rationally and appropriately, polypharmacy can be effective, particularly for chronic pain. For instance, clinicians could introduce a second drug to a patient’s regimen to lower the dose of the first drug, which may reduce his or her intolerance to the initial drug. Other potentially positive aspects of polypharmacy include using ≥2 drugs with different mechanism of actions or ≥2 drugs with synergistic interaction, combining immediate release and long-acting analgesics, and adding a nonopioid medication to an ongoing opioid treatment regimen.

When polypharmacy is utilized correctly, Dr. Hahn said, clinicians can make the treatment of a comorbid disease more effective by aggressively treating the primary disease, addressing different locations of the disease process, and targeting different symptom clusters that are products of the disease or the comorbid disease.

Common reasons for failure in polypharmacy concerns clinicians who are inattentive to, or do not adequately understand, pharmacology, according to Dr. Hahn.