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9 Articles in Volume 17, Issue #3
Anxiety and Pain
Central Pain in Rheumatoid Arthritis
Imagine Dragons’ Dan Reynolds Educates People About Ankylosing Spondylitis
Letters to the Editor: Ehlers-Danlos Syndrome, Arachnoiditis
Managing Cancer-Related Pain: A Look at Alternative Approaches
Pain Management in the Elderly: Focus on Safe Prescribing
Painful Genetic Diseases
Responding to Women's Pain Early and Effectively
The 5 Most Misunderstood Terms in Pain Medicine

Pain Management in the Elderly: Focus on Safe Prescribing

Choosing pain medications for elderly patients requires a broad knowledge of polypharmacy, drug-drug interactions, and pharmacokinetics.

In 2015, the number of people in the United States age 65 or older reached 47.8 million.1 As we have been reporting in Practical Pain Management, the prevalence of chronic pain among the elderly is a growing concern.2,3 A recent study found that 52.3% of patients age 65 and older reported having bothersome pain in the last month; three-quarters of them reported having pain in more than 1 location.4

Safe pain management in the elderly requires  care of drug-drug interactions.

Due to the greater presence of multiple comorbidities in the elderly, which often necessitates polypharmacy, there is an increased risk of adverse events (AEs) when these patients take analgesic medications. This article will examine the most commonly used pain management therapies, outlining their pharmacokinetic and safety profiles in the elderly population.

Problems Associated With Medical Pain Management in the Elderly

Aging is the physiologic process of degeneration, resulting in the deterioration of cellular structure and organ system failure.5 Select organ systems that are particularly important when initiating and dosing analgesics include the gastrointestinal (GI), hepatic, renal, cardiovascular, and respiratory systems. The physiologic changes that occur with aging have important pharmacokinetic implications, which may translate into increased risks for AEs and drug-drug interactions and present significant challenges to clinicians trying to provide appropriate pharmacotherapeutic regimens.

There are a multitude of age-related pharmacokinetic changes clinicians should consider before selecting therapies. Decreases in gastric secretion and intestinal motility lead to decreased absorption of specific nutrients and altered absorption of certain drugs.6,7 The aging adult may have increases in body fat and decreases in lean body mass, total body water, and serum albumin that may impact the distribution of medications.8 Circulating albumin and other proteins, such as alpha-glycoprotein, bind many different analgesic drugs, the most common examples being nonsteroidal anti-inflammatory drugs (NSAIDs) and tricyclic antidepressants (TCAs). This becomes an important issue if more unbound drug becomes available for activity, toxicity, and drug-drug interactions in older patients compared with younger patients with adequate circulating proteins. Various changes can increase the volume of distribution and half-life of lipophilic drugs, while increasing plasma concentrations of hydrophilic and highly protein-bound acidic drugs.8

Changes in hepatic and renal function that occur in the elderly population can affect drug metabolism and elimination. Hepatic volume and hepatic blood flow both decline with age.6,8,9 Although the clinical impact that normal aging has on overall drug metabolism remains controversial, it is generally accepted that there are slight reductions in phase I metabolism and little to no reductions in phase II metabolism.6,8,9 However, concurrent cirrhosis, chronic liver disease, or chronic kidney disease all have been shown to impact drug metabolism to a greater extent.6-9 Similarly, aging is associated with progressive nephrosclerosis and decreased renal blood flow, resulting in an overall decreased glomerular filtration rate that may subsequently cause increased serum concentrations of renally cleared drugs and their metabolites.8,10 The decline in both hepatic and renal function may lead to an increased propensity toward AEs and drug-drug interactions due to elevated parent drug/metabolite concentrations.

Although all the above characteristics can lead to unintended accumulation of parent drugs and their metabolites, other processes of aging also may increase risk due to their interactions with the mechanisms of the therapies themselves. One example is changes in cardiovascular health, such as hardening of elastic arteries, enhanced pulse wave velocity, and prolonged ejection fraction, all of which increase blood pressure, left ventricular hypertrophy, and cardiac risk.5,11 The GI changes cited above also may increase the prevalence of constipation in this population.6,7 Decreases in the elasticity of the lung and increased chest wall rigidity inevitably lead to reductions in respiratory ability, which increases the risk of respiratory depression.5 Finally, this population is at increased risk of falls and is much more susceptible to the cognitive and sedative effects elicited by many pain management medications.

Although there are well-founded guidelines and several published review articles to assist with treatment selection, physicians still have reservations when managing pain in this population. Therefore, clinicians must take a patient-centered approach to pain management. They should view each elderly patient as an individual, accounting for comorbid disease states and pharmacokinetic and safety profiles to promote selection of the safest and most efficacious pain management therapy.  

Current Geriatric Pain Management Recommendations

In 2009, the American Geriatric Society (AGS) published evidence-based guidelines for treating pain in the elderly.12 The AGS guidelines recommend acetaminophen as the initial (first-step) and ongoing pharmacotherapy for pain management; opioids are recommended for the treatment of moderate-to-severe pain, and adjunctive analgesics are to be used for patients with specific pain types, such as neuropathic pain. The guidelines recommend that analgesics such as NSAIDs, corticosteroids, and TCAs be avoided due to their potential to cause AEs and worsen certain disease states.

In general, clinicians accept that mild pain can be managed by non-pharmacologic therapy such as heat or ice, massage, and other non-medication modalities; moderate pain can be treated with all of these modalities plus over-the-counter (OTC) medications and/or nonopioids; and that severe pain may require intermittent or regular use of opioids. Consistent with AGS guidelines, pharmacological management of persistent pain is warranted in this population if pain “affects physical function or quality of life.”12

Since the publication of the AGS guidelines, awareness of an “opioid epidemic” related to both prescription and illicit drugs has become a public health concern. However, the AGS has not updated its guidelines. Therefore, clinicians must base their recommendations on several reviews outlining the evidence, or lack thereof, about safe and effective pain management in the elderly.6,13-18 This review discusses the pharmacokinetic and safety profiles of the most commonly used pain management therapies.

Acetaminophen

Acetaminophen generally is thought to be a relatively safe agent for elderly patients when it is used at therapeutic doses.19 Notwithstanding, just last month a new study highlighted the fact that acetaminophen has no advantages for the management of osteoarthritis, a common condition among the elderly, compared to placebo.20 The safety profile of acetaminophen (common AEs typically are mild and include nausea, vomiting, pyrexia, headache, and insomnia) also makes it a reasonable choice for elderly patients. In addition, acetaminophen avoids some of the more severe cardiovascular, respiratory, and cognitive AEs common with many other analgesics.21

However, it is important to consider risk factors that are associated with acetaminophen-induced hepatotoxicity, including liver disease, use of multiple acetaminophen-containing products (increasing the dose of acetaminophen), and simultaneous use/abuse of alcohol and opioids.19,21

Acetaminophen primarily is metabolized by the liver: 50% to 70% of the drug is eliminated through glucuronidation via different UDP-glucuronosyl transferases, 25% to 35% through sulfation via sulfotransferases, and about 5% to 15% through phase I metabolism via cytochrome (CYP) P450 2E1.22 It is this last phase, oxidation through CYP2E1, that generates the reactive metabolite of N-acetyl-p-benzoquinone imine (NAPQI) that is responsible for hepatotoxicity.

It also is important to consider acetaminophen’s ability to interact with warfarin, an anticoagulant that is commonly used in the elderly.23 It has been shown that acetaminophen, at therapeutic doses, can potentiate warfarin’s anticoagulant effect and prolong a patient’s international normalized ratio. The mechanism of this interaction has been postulated to be:

  • Interaction at the level of CYP2C9 that reduces the metabolism of warfarin
  • Inhibition of  vitamin K-dependent enzymes by the NAPQI metabolite of acetaminophen
  • Acetaminophen hepatotoxicity23

NSAIDs

NSAIDs are a commonly used and prescribed class of medication for pain management, with many different products and formulations available. Although the AGS recommends against NSAID use, with certain exceptions, the use of OTC NSAIDs still is alarmingly frequent in high-risk populations, including the elderly.12,24 The prevalence of non-adherence to OTC NSAIDs in the general population is equally alarming. A survey conducted by Wilcox et al found that only 30% of those taking OTC NSAIDs read the dosage guide, 12% did not read anything on the label, and 44% were consuming more than the recommended dosage.25 This can be particularly dangerous in the elderly, due to the many risks associated with NSAID therapy that mainly arise from its pharmacologic mechanism of inhibiting cyclooxygenase (COX) enzymes.

Because of concerns about opioids, many clinicians are shying away from their use in favor of alternatives such as NSAIDs. However, NSAIDs can prove far more dangerous than opioids or other alternative agents, and clinicians should evaluate every patient for individual NSAID risks before they initiate these agents. Several studies have been published highlighting the overall impact NSAID use can have on mortality, and Table 1 summarizes these studies.26-28

The incidence of peptic ulcer disease and GI bleeding with NSAID use increases with age,29-33 and although this risk may be diminished with use of selective COX-2 inhibitors (Celebrex),34-38 there still is a general increase in risk.32 Simultaneous use of gastroprotective drugs, such as proton pump inhibitors (taken 30 minutes before meals), may reduce this GI risk.33,39 It is important to note that there have been theorized consequences from long-term use of proton pump inhibitors, particularly increased risk of osteoporosis/osteopenia; however, there is currently insufficient data to support this hypothesis.40 Proton pump inhibitors may increase the risk of infections and alter calcium and magnesium absorption. However, an assessment should be made of the impact that these risks might have compared to their beneficial gastroprotective effects before initiating PPIs in the elderly population.40,41

NSAIDs also are well known for their inhibition of prostaglandin synthesis within the vasculature, which results in vasoconstriction that elevates blood pressure and increases overall peripheral resistance.42 Prostaglandin inhibition within the macula densa, ascending loop of Henle, glomerulus, and afferent and efferent arterioles of the kidneys leads to fluid and electrolyte disturbances, such as sodium, water, and potassium retention, and increases the risk of congestive heart failure, acute renal failure, nephrotic syndrome, and renal papillary necrosis.42,43 As noted, the elderly already are more susceptible to these cardiovascular and renal toxicities due to aging, and the above actions only add to this. Additionally, NSAIDs pharmacodynamically interact with multiple classes of blood pressure medications—including diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and beta-blockers—decreasing their efficacy and increasing toxicity.42.43

Finally, there are hematologic effects associated with NSAID use: inhibition of COX-1–mediated production of thromboxane A2 increases the risk of bleeding, and inhibition of COX-2–mediated production of prostaglandin E2 can increase the risk of thrombotic events.44 Specifically, NSAIDs reversibly bind to the Ser529 site of COX-1 on platelets, which is the same site aspirin irreversibly binds to provide long-term platelet inhibition and elicit its cardioprotective effect.45 If, for example, aspirin is not administered prior to NSAIDs, the NSAID can block the cardiovascular benefit of aspirin therapy.45 Notably, naproxen (Aleve) has been shown to have some cardioprotective effects compared to other NSAIDs. Conaghan et al found that naproxen may decrease the risk of vascular events compared to ibuprofen, diclofenac, and other non-naproxen NSAIDs.46

Although the above-mentioned AEs are related to all types of NSAIDs, it is extremely important to recognize that systemic exposure to topical diclofenac sodium gel (Voltaren) 1% is vastly reduced compared with oral diclofenac.47 In fact, the average peak plasma concentration of topical diclofenac was found to be 158 times lower than that of oral diclofenac.48 This, theoretically, decreases the GI, cardiovascular, renal, and hematologic risk of the topical formulation.47 Thus, topical diclofenac could have a specific niche for use in elderly patients.

Antidepressants

Antidepressants, TCAs, and selective serotonin-norepinephrine reuptake inhibitors (SNRIs) commonly are used as adjunctive therapy for the management of neuropathic pain. Both classes of medications relieve neuropathic pain through the inhibition of serotonin and norepinephrine reuptake transporters, with the primary mediator being norepinephrine.49-51

Although TCAs have a wealth of efficacy data supporting their use in neuropathic pain, mechanistically they are relatively “sloppy” drugs.52 For instance, TCAs non-selectively bind to postsynaptic alpha-adrenergic, histaminergic, and muscarinic receptors, causing a profusion of AEs such as sedation, confusion, constipation, and cardiac conduction abnormalities.49,50 These are all problems that can be extremely detrimental in the elderly, which is why the AGS recommends that TCAs be avoided in this patient population.12

SNRIs bind much more selectively to serotonin and norepinephrine reuptake transporters, resulting in a more favorable AE profile.49-51 There are 5 SNRIs available on the market: desvenlafaxine (Pristiq, Khedezia, others), duloxetine (Cymbalta, others), levomilnacipran (Fetzima), milnacipran (Savella), and venlafaxine (Effexor).

Although duloxetine and milnacipran are the 2 SNRIs that are FDA-approved for the management of neuropathic pain,53,54 duloxetine and venlafaxine are the 2 most commonly used SNRIs for this indication in the general population. More than 70% of duloxetine is excreted by the kidneys and about 30% is metabolized via CYP1A2 and CYP2D6 to inactive metabolites.53 It is recommended that duloxetine be avoided in patients with creatinine clearance (CrCl) <30 mL/min because it has been associated with an approximately 2-fold higher area under the curve in patients with end-stage renal disease.55-57 Venlafaxine primarily is metabolized via CYP2D6 into its active metabolite O-desmethylvenlafaxine, making it much more susceptible to drug-drug interactions and pharmacogenomic variability.51

Although the 3 other SNRIs are rarely used, they are viable options in the elderly population who are not candidates for venlafaxine or duloxetine due to their pharmacokinetic profiles. Milnacipran, approved for the management of fibromyalgia, has shown a prolonged half-life in patients with diminished renal function; about 55% of the agent is excreted by the kidneys and 45% is metabolized via phase II enzymes.54,55 Levomilnacipran, the active enantiomer of milnacipran, has a much higher potency toward norepinephrine reuptake transporters compared to serotonin reuptake transporters.58 Pharmacokinetically, it is about 58% renally cleared and about 42% metabolized into inactive metabolites via phase II enzymes.57,58 The active metabolite of venlafaxine, O-desmethylvenlafaxine, is commercially available as desvenlafaxine. This medication is about 55% metabolized via phase II enzymes into inactive metabolites and about 45% renally cleared as unchanged drug.59

While these 3 SNRIs do undergo a substantial amount of renal elimination that requires dosage adjustments in those with renal dysfunction, the fact that they undergo phase II metabolism greatly reduces the risk of drug-drug interactions and/or pharmacogenomic variability. Additionally, unlike duloxetine, they may all be used in patients with CrCl <30 mL/min, and only milnacipran and levomilnacipran are recommended for avoidance in patients with end-stage renal disease.54,58

Although SNRIs generally have a more tolerable safety profile compared to their TCA counterparts, they are still prone to their own degree of AEs, including the risk of serotonin syndrome. In 2006, the FDA issued an alert regarding this risk with concomitant use of selective serotonin reuptake inhibitors (SSRIs), SNRIs, and 5-hydroxytryptamine receptor agonists (triptans).60 Additionally, inhibition of serotonin reuptake in platelets may lead to a reduction in serotonin-induced platelet aggregation and vasoconstriction, making patients—especially those who are taking anticoagulants, antiplatelets, and/or NSAIDs—more susceptible to prolonged bleeding.61-63 Finally, SNRIs can increase blood pressure and heart rate through their noradrenergic profile, which may also be dangerous in elderly patients, who are at higher cardiac risk.64,65

Researchers and authors of articles on pain management often struggle with where to include tramadol (Ultram, ConZip, others), as it has weak opioid activity combined with its reuptake blockade of both serotonin and norepinephrine, the latter of which likely provides the bulk of analgesia when combined with tramadol’s first metabolite, O-desmethyl tramadol. In the elderly, tramadol is extremely constipating. In terms of daily morphine equivalents, tramadol dosing should be considered the same as for an opioid-naïve patient because the binding affinity of tramadol is so low.66 Another risk that is sometimes overlooked is that abrupt tramadol cessation has a high likelihood of causing serotonin withdrawal, which could otherwise be blunted or absent if the patient is concurrently receiving an SSRI or SNRI.

Anticonvulsants

Anticonvulsants also are commonly used as adjunctive treatment for neuropathic pain. Although several different types of anticonvulsants have been shown to modulate neuropathic pain activity, the 2 most commonly used are gabapentin (Neurontin, others) and pregabalin (Lyrica). Both gabapentin and pregabalin pre-synaptically bind to the a2d-subunit on voltage-dependent calcium channels, modulating calcium influx and reducing overall excitatory neurotransmitter release.67 The difference between the agents is that pregabalin has increased binding affinity to the subunit and has predictable linear absorption compared to gabapentin.68

Both drugs are eliminated almost entirely by the kidneys, and both require dose reductions in patients with renal insufficiency.67 This characteristic allows them to avoid many pharmacokinetic interactions, but commonly reported AEs include somnolence and dizziness.69,70 In fact, anticonvulsants, including gabapentin and pregabalin, have been associated with increased rates of falls in several studies of elderly patients in the community and in nursing homes.71-73 Despite this, the most recent AGS Beers Criteria recommends to reduce the dose or avoid gabapentin and pregabalin if there is comorbid renal insufficiency present.74 Regardless of Beers Criteria’s recommendation, it is important to screen all elderly patients for fall risk before prescribing any medications, including all anticonvulsants.

Skeletal Muscle Relaxants

For pain associated with muscle spasticity and spasm, skeletal muscle relaxants can be particularly beneficial. However, each of these agents has a unique AE profile that may cause significant problems in elderly patients. Long-term cyclobenzaprine use can be particularly dangerous in this population due to the structural similarity to the TCA amitriptyline.75 This results in an AE profile that is similar to that of the TCAs outlined above, including significant cardiac risks.

Benzodiazepines, which have muscle relaxant effects, are associated with sedation and increased risk of falls.74 Further, when a benzodiazepine is combined with an opioid, the risk for potentially fatal opioid-induced respiratory depression increases. In August 2016, the FDA added a new black box warning for all opioid and benzodiazepine products that discusses “serious risks associated with using these medications at the same time, including the risk of extreme sleepiness, respiratory depression, coma, and death.”76

Tizanidine, an a2 agonist, can cause orthostatic hypotension and also can increase the risk of falls in a frail population.77

A comprehensive review is outside of the scope of this article; however, a complete comparison of all skeletal muscle therapies can be found in A Review of Skeletal Muscle Relaxants for Pain Management.78

Opioids

Approximately 39% of nursing home residents are on an opioid-based pain management plan.6 Choosing the safest medication requires a thorough analysis of the risk and benefits. There are a plethora of options within the opioid class that vary greatly in potency toward the m-opioid receptor, mechanisms of action, and pharmacokinetics. Because of the inherent life-threatening dangers associated with opioid drug interactions, we include Table 2 to highlight some important differences among opioid medications.

Due to the prevalence of polypharmacy in the elderly, opioids metabolized via phase II enzymes, such as hydromorphone (Dilaudid, Exalgo, others), oxymorphone (Opana, others), levorphanol, tapentadol (Nucynta, Nucynta ER), and morphine, which are less prone to drug-drug interactions, may be safer in some instances than those metabolized by phase I enzymes. Notably, morphine is metabolized into 2 major metabolites, morphine-6-glucuronide (M6G), which is an m-opioid agonist, and morphine-3-glucuronide (M3G), which lacks analgesic activity but yields neuroexcitatory effects that induce allodynia, myoclonus, and seizures.79 The M6G metabolite has opioid agonist activity and a very long half-life, which could lead to accumulation in patients with reduced renal function.79

Perhaps more important than pharmacokinetic considerations are the toxic effects all opioids elicit due to m-opioid receptor agonist activity that may be potentiated in the elderly patient. This pharmacologic mechanism slows gastric motility, decreases fluid reabsorption, and causes diminished tone to the anal sphincter, all of which contribute to constipation. Opioid agonist activity also diminishes chemoreceptor response to carbon dioxide, leading to carbon dioxide accumulation and, consequently, respiratory depression, cognitive impairment, dizziness, and somnolence.80

Two of the safer opioid options are buprenorphine (Butrans, Belbuca, others) and tapentadol. Buprenorphine, a partial agonist at the m-opioid receptor and potent antagonist at the k-receptor, has lower intrinsic activity at the m-opioid receptor that improves its safety profile compared to other opioids.81 Specifically, respiratory depression risk decreases at higher doses and transdermal delivery avoids m-opioid receptors along the GI tract, minimizing constipation; in addition, it is thought that buprenorphine’s k antagonist activity diminishes the likelihood of sedation and cognitive impairment.6,82-84 Tapentadol is another m-opioid receptor agonist with a seemingly more tolerable GI toxicity profile, showing lower rates of nausea, vomiting, and constipation compared to oxycodone (Oxycontin, Roxicodone, others).85-89

Regardless of the opioid chosen for any geriatric patient, there are general principles of opioid therapy that need to be given greater attention when opioids are used in the elderly population. These include starting at lower doses than one would use in a younger patient, titrating extremely slowly, monitoring frequently, and using extended-release (ER) preparations when possible. Longer-acting preparations are particularly advantageous in the elderly because, generally, those formulations result in lower maximum plasma concentrations, reduced fluctuations in peak/trough concentrations, prolonged duration within the therapeutic window, and more consistent serum drug levels. Due to these benefits, when taken as prescribed, ER formulations can reduce the risk for respiratory depression and other toxicities compared to immediate-release formulations.90,91

Care must be used when converting between any opioid medications, but particularly from fentanyl transdermal patches to another opioid because, in the authors’ experience, measurable serum fentanyl levels in the elderly patient may be drastically reduced. Consider that if only 10% of a 100 mcg/hour fentanyl patch is absorbed and it is replaced with oxycodone, even at a 50% dose reduction, this could cause death.  Therefore, this transition must be made with extreme caution.

Conclusion

Geriatric patients often are complicated cases with multiple comorbid disease states that require multiple medications. It is imperative that the risks of any therapeutic option are assessed completely before initiation of a new drug treatment and during the titration process. This can cause providers to be hesitant when faced with selecting an appropriate therapy for pain management. Clinicians must consider the many drug-drug interactions and drug-disease interactions, and have a healthy respect for the variable pharmacokinetic impact of aging on prescribed medications from all classes, including those outside of analgesic therapy.

Last updated on: May 15, 2017
Continue Reading:
The 5 Most Misunderstood Terms in Pain Medicine

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