Management of Drug-Drug Interactions: Considerations for Special Populations—Focus on Opioid Use in the Elderly and Long Term Care

Elderly patients requiring pain medication often have multiple pharmacologic and physiologic factors that can impact the choice of analgesic. This is also true for residents in long term care facilities. The choice of analgesic for these patients should balance the efficacy and safety issues for each analgesic.¹ If the pain is moderate to severe, an opioid is a viable option for these patients. One particular problem with prescribing opioids to the elderly and long term care residents is that opioid safety and efficacy have not been well studied in these populations. Studies of opioid therapy usually restrict study participants to adults with few medical conditions in order to limit confounding factors. However, many elderly and long term care residents have multiple medical conditions and compromised renal/hepatic function, and take multiple medications. As a result, it may be difficult to predict how these patients will respond to opioid treatment. Most guidelines and clinical studies focus on the central nervous system and gastrointestinal adverse effects of opioid treatment. In the elderly and long term care residents taking multiple medications, the potential for cytochrome P (CYP) 450 interactions should also be considered.^1-9

Risk Factors for Opioid Pharmacokinetic Drug-Drug Interactions in Specific Populations

The Elderly

On average, an elderly person takes 7 medications, and it is estimated that 46% of the elderly are at risk for at least 1 drug-drug interaction (DDI).¹⁰ Clinically significant DDIs may involve alterations in CYP450 metabolism.^11-13 Also, as people age, numerous physiological changes occur, which may also affect opioid pharmacokinetics and DDIs. For example, hepatic and renal functions decline as people age, and this can significantly impact opioid pharmacokinetics.^1,4,8,9 Pergolizzi (2008)⁴ noted that after the age of 50, there is a 1% decrease in the cardiac index each year, due to a variety of cardiovascular changes. Cardiovascular changes may impact renal and/or hepatic function and therefore pharmacokinetics.⁴ In patients with impaired renal function, the half-lives of many opioids and their active metabolites are increased and it is recommended that dosages be reduced accordingly. For example, oxycodone and its metabolites are excreted primarily via the kidney; plasma oxycodone concentrations are approximately 50% higher in patients with renal impairment (creatinine clearance <60 mL/min) than in subjects with normal renal function.¹⁴ In patients with impaired hepatic function, reduced hepatic mass and blood flow, plus reduced levels of CYP450 isoenzymes (which are required for the metabolism of many drugs), can alter concentrations of opioids in the circulation.

Some opioids are prodrugs, inactive (or significantly less active) drugs that require metabolism in the body to form an active metabolite.¹³ When the opioid pain medication is a prodrug, a decrease in levels of specific CYP450 isoenzymes may attenuate efficacy. For example, the CYP2D6 isoenzyme metabolizes the prodrugs hydrocodone, codeine, and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively). A patient’s reduced CYP2D6 activity may result in lower levels of the prodrug’s active metabolite and thus reduced efficacy.¹⁵

CYP450 metabolism plays a role in certain opioid DDIs. Many frequently used medications interact with the CYP450 system.^{2,11,12,16-18} Table 1^2,16-18 provides a list of common medications that can inhibit or induce CYP450 isoenzymes associated with metabolism of opioids. For example, a patient taking an opioid that requires metabolism by CYP2D6 (eg, codeine, hydrocodone, or tramadol) should not be prescribed a strong CYP2D6 inhibitor (eg, the antidepressants fluoxetine or paroxetine). Combining tramadol with fluoxetine can lead to both serotonin syndrome (a potentially lifethreatening elevation of serotonin levels) and loss of pain relief, because tramadol’s analgesic effect is primarily due to its active M1 metabolite.¹⁹

Some patients may be taking CYP450 inducers, such as rifampin and carbamazepine, which may increase the metabolism of some opioids and decrease analgesic effect. In this situation, an increase in the dose of the opioid may be necessary.²⁰

The changes in CYP450 isoenzymes may also impact the pharmacokinetics of other CYP450-dependent medications. As discussed in the other manuscripts in this supplement, polypharmacy for multiple medical conditions is common in the elderly.^8,9,21 The more medications the patient takes, the greater the risk of DDIs, including those involving opioids.^4,8,9,21

In addition to the hepatic and renal changes in the elderly, other physiological factors affect how the elderly respond to opioids and can increase susceptibility to DDIs. For example, opioids can lead to delirium, hallucinations, and cognitive problems, especially in patients with dementia or brain injury.⁹ Also, elderly patients with cardiovascular, cerebrovascular, or respiratory disease (and smokers) are more susceptible to respiratory depression, bradycardia, and hypotension.^4,9 Cancer, diabetes mellitus, and other illnesses can also impact opioid pharmacokinetics and efficacy/safety profile.⁹