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By Linda J. Tristani, B.S., Pharm.D., and Jeffrey Fudin, B.S., Pharm.D., DAAPM
 Introduction
Use of multiple medications may afford the patient a more favorable side effect profile while improving efficacy over single agent analgesics. As the patient ages however, we are faced with a higher potential for multiple drug-drug and drug-disease interactions. When treating pain in this population, the benefits and risks of rational polypharmacy may be more complex compared to the population at large.
How Age Changes Us
As humans age, certain physiological changes are inevitable: the amount of stomach acid produced is decreased, motility slows, kidney function declines, and gait and balance changes occur over time. Likewise, elderly persons are more likely to have concomitant disease states requiring a multitude of medications. These physiological changes coupled with a complex medication profile will likely factor into the success or failure of chronic pain treatment while carefully selecting and titrating the most rational medication(s) for each patient. As the population continues to age, common co-morbid medical issues we may need to consider include hypertension, diabetes, hypercholesterolemia, obesity, syncope, achlorhydria, reduced kidney function, heart disease, and more.
Pain Medicine for the Elderly
Pain, both acute and chronic, is a common complaint from the geriatric population. Acetaminophen (APAP) is a very effective drug for occasional minor pain or fever, but chronic use may be associated with the increased risk for adverse events including interstitial nephritis2. APAP may also affect the International Normalized ratio (INR) in patients requiring warfarin3 for a number of problems, such as for prophylaxis following a myocardial infarction, history of atrial fibrillation, post-surgical knee replacement, and deep vein thrombosis. APAP has the potential to augment the effects of warfarin increasing the risk for bleeding. However, the risk of iatrogenic bleeding is far greater when combining non-steroidal anti-inflammatory (NSAIDs) and warfarin. NSAIDs are indicated for minor-to-moderate pain, fever, and/or inflammation. NSAIDs, such as ibuprofen or diclofenac, are often used for moderate pain, but these also have potential risks associated with chronic use. Some examples of these risks include:
• An increased risk of gastrointestinal (GI) bleed.
• A 10.5 fold increased risk of congestive heart failure (CHF) after a first event.
• Adverse effects on kidney function.
• Drug-drug interactions 4,5.
Therefore, patients with a history of CHF or renal insufficiency should avoid use of chronic NSAIDs. Likewise, diabetes and hypertension, which are prevalent in the elderly, are commonly treated with angiotensin converting enzyme inhibitors (ACEIs), which otherwise provide kidney protection; NSAIDs antagonize the effects of ACEIs and chronic use of NSAIDs should be avoided in this patient population as well. Cyclo-oxygenase-2 specific drugs (COX-2) such as celecoxib are also indicated for moderate pain and have a decreased risk for GI bleed compared to traditional non-selective NSAIDs. But, while COX-2 specific inhibitors may have a reduced risk for GI bleed, they have a higher propensity for thrombo-embolic risk because they skew the prostaglandin cascade by increasing prostacyclin. Therefore, these are associated with a greater risk for clotting, and it may not be appropriate in an elderly person with a history of deep vein thrombosis, stroke, or other coagulation anomalies.
Alternative therapies to APAP, COX-2 inhibitors, and NSAIDs for chronic pain are tramadol and opioids. Tramadol is an analgesic that has actions at the mu-opioid receptor, as well as the noradrenergic and serotonergic systems. It is a synthetic agent whose chemical structure is different from typical opioids, and its efficacy has been established for numerous forms of chronic pain including cancer pain, lower back pain, and neuropathic pain6. Although drowsiness and respiratory depression are less pronounced with tramadol compared to other opioids, other side effects may limit its use in the elderly population. Tramadol has the potential to lower the seizure threshold when combining tramadol with an antidepressant or other medications that lower the seizure threshold. As a single agent at FDA-approved doses, the propensity for tramadol to increase seizure risk is low7. Healthcare providers must consider, however, that reduced kidney function in the elderly may elevate serum levels above that which we would expect in a young healthy adult. Also, there will be a higher likelihood of drug-drug interactions that could potentially elevate serum levels if the patient were receiving an inhibitor of cytochrome P450 enzymes 3A4 or 2D6. Constipation is a common side effect of tramadol and can be severe, especially in the elderly. Notably, doses of tramadol may need to be adjusted when combined with warfarin therapy as this combination can potentiate the effects of warfarin leading to an increased risk for bleed.
Initiating opioids such as morphine and oxycodone may be a safe alternative for the management of chronic pain in the elderly; however, care should be taken to start opioid naïve patients at low doses to assess tolerability8. These agents do not exacerbate hypertension, pose no increased risk for bleeds when combined with warfarin therapy, and do not increase the risk for thromboembolism. However, opioids still come with a variety of side effects that are concerning for the elderly population. Of important note for example, morphine has 3-glucuronide and 6-glucuronide metabolites, the latter of which is neurotoxic. Accumulation of the 6-glucaronide metabolite can occur with reduced renal function exposing the patient to neurotoxicity. Another side effect common to all opioids is constipation, which can be severe. Most patients receiving long-term opioid therapy may also require concomitant laxative therapy9. Urinary retention is another concern and may need to be considered, especially for patients with benign prostatic hyperplasia and existing comorbidities that include urinary retention. Like tramadol, opioids also have the potential to lower the seizure threshold, although the risk is lower. Despite these adverse effects, opioids may be the best option in some patients for addressing mild-to-severe pain for patients who do not achieve adequate pain relief with APAP or NSAIDs. If opioid use is inevitable for an elderly patient, use of an extended release product should be considered to avoid peaks in serum concentration and to provide sustained analgesia10.
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