Pharmacologic Management of Persistent Pain in Older Persons
Despite a high incidence of pain in older persons,1 it has been demonstrated that this population is less likely to be adequately treated for pain, as compared with younger individuals.2 Challenges to delivery of effective pain relief to older persons include an increased potential for drug-drug/drug-disease interactions due to multiple comorbidities and concurrent medications, pharmacokinetic and pharmacodynamic differences in older persons that can contribute to altered drug sensitivity and increased adverse drug reactions (ADRs), and noncompliance due to misinformation about ADRs and fears of addiction or dependence. In addition, because of growing concerns about the cardiovascular (CV) safety of nonselective and cyclo-oxygenase (COX) -2 selective nonsteroidal anti-inflammatory drugs (NSAIDs), in addition to risks of gastrointestinal (GI) bleeding, clinicians are faced with the challenge of selecting other safe and effective medications for pain management. Clinicians should consider low-toxicity pharmacologic approaches, such as topical therapies with demonstrated efficacy and rational polypharmacy using lower doses of mechanistically different agents for synergistic or additive therapeutic effects to complement nonpharmacologic treatments. This article provides an update of the efficacy, tolerability, and safety of pharmacologic agents commonly used for management of pain in older adults. For dosing recommendations of the drugs discussed in this review, please refer to the most recent edition of Geriatrics At Your Fingertips.3
Topical Analgesics and Other Peripherally Acting Treatments
Topical agents penetrate the skin and act on peripheral nerves and soft tissue directly underlying the application site.4 Because they lack significant systemic absorption, they have limited potential for clinically significant systemic effects or drug-drug or drug-disease interactions.5
Lidocaine Patch 5%
The lidocaine patch 5% is designed to be applied directly over a painful area. Believed to act by decreasing ectopic discharges within superficial sensory afferents via blockage of voltage-gated sodium channels, lidocaine diffuses through the skin after topical application to act locally without achieving clinically significant serum drug levels.4 Because systemic absorption of lidocaine via this delivery system has been shown to be minimal (approximately 10% of levels used to treat cardiac arrhythmias), it has a low potential for adverse effects. In addition, the patch provides a physical barrier against skin rubbing that provokes pain in patients with allodynia.6 Currently approved by the Food and Drug Administration (FDA) for treatment of pain associated with postherpetic neuralgia (PHN),7 clinical trials have also shown it to be effective and well tolerated for management of other neuropathic pain syndromes, including diabetic neuropathy8 and refractory neuropathic pain of various origins.9 It has been reported to be effective as add-on therapy for low back pain10 and osteoarthritis.11
The lidocaine patch 5% has been well tolerated in clinical trials. The most common ADRs are localized skin reactions (ie, erythema, edema) that are generally mild and transient, and resolve spontaneously within minutes to hours (Table).5 Clinically significant drug interactions, systemic ADRs,6 and sensory loss (ie, local anesthesia)12 have not been reported with the lidocaine patch 5%. Some patients have reported recurrence of pain during the off-patch intervals with the FDA-approved dose (ie, up to 3 patches for 12 hr on/12 hr off),6 and published pilot studies have demonstrated a similar safety profile with applications up to 18 to 24 hours.6,8
Topically applied, the active component of hot chili peppers, capsaicin, displays analgesic properties.13 Research suggests that its analgesic activity is related to its effect on C-nociceptive fibers14 and its binding to a specific vanilloid receptor (VR-1),15 which causes both depletion of substance P in innervated tissues and afferent termination zones in the central nervous system (CNS), and reduction of inflammatory nociceptive signaling in the periphery.14 When administered with stable doses of oral analgesic medications in double-blind controlled trials, capsaicin has been effective for the treatment of diabetic neuropathy,16 PHN,17 and osteoarthritis and rheumatoid arthritis.18 It is reported to also provide pain relief for other neuropathic pain syndromes, including trigeminal neuralgia,19 cluster headaches,20 and complex regional pain syndrome.21
The most common ADR is burning pain at the application site (Table).16 While this effect can be decreased with use of a topical anesthetic spray13 and routine hand washing after contact, capsaicin has also been shown to induce epidermal nerve fiber degeneration occurring as early as 3 days after beginning therapy.22 The long-term consequences of this are not known. Dosed on a regular schedule—every 6 hours—it generally takes 2-4 weeks to achieve a clinical effect.13 The usefulness of capsaicin is limited by the necessity for repeat applications, its delayed therapeutic effect, and application site pain, and it should be reserved as a second-line or adjuvant agent.
Diclofenac epolamine 1.3% patch has recently been made commercially available as a prescription topical NSAID treatment indicated for acute pain due to minor sprains, strains, and contusions, but it is often used for localized joint pain. Blood levels of diclofenac from this formulation are appreciably lower than equivalent doses taken orally, with the consideration that short- or long-term use may be better tolerated. There were not enough older patients in clinical trials to draw specific conclusions about risks in the geriatric population. Nevertheless, the usual cautions with regard to NSAID risks in this population, including drug-drug interactions, especially with commonly used agents such as cardioprotective aspirin, and decreased metabolic clearance due to age-related reductions in renal function, should be kept in mind.23
Diclofenac sodium 1% gel is a topical formulation approved for the treatment of osteoarthritis pain. This formulation also has greatly reduced systemic levels, as compared with oral equivalent doses. Comparative studies of this formulation versus oral diclofenac have shown significantly greater GI safety, but, in the absence of long-term CV studies, an ongoing benefit-to-risk evaluation should accompany chronic use.24
Corticosteroids, useful alternatives to NSAIDs in some clinical situations, can be administered via intra-articular, topical, oral, rectal, or parenteral routes.25 Indicated for various inflammatory disorders,26 they have also been shown to provide analgesia in arthritis and relief from compressive symptoms caused by malignancies.25 However, clinicians should be aware of the potential for serious toxicities that can appear shortly after initiating therapy, and of multiple contraindications to conditions commonly occurring in older patients (Table). Insufficient data exist to warrant discussion of other topical or local pharmacologic agents for treatment of pain in older adults.26
Oral Nonopioid Analgesics
Oral nonopioids are generally first-line therapy for treatment of mild-to-moderate nociceptive pain.27 These include acetaminophen, nonselective NSAIDs, and selective COX-2 inhibitors.
Acetaminophen has been found to be effective in a number of common pain conditions,26 and is often a preferred agent for mild-to-moderate nociceptive pain because of its relative safety in older persons.28 Acetaminophen is associated with less GI and renal toxicity, as compared with NSAIDs, few drug interactions, and no age-related differences in drug clearance26; however, since it is metabolized in the liver, awareness of concurrently used medications that also undergo hepatic metabolism and use in patients with concomitant liver disease28 is important (Table).29
Inhibition of the enzymes COX-1 and COX-2 results in decreased prostaglandin synthesis that produces the analgesic, antipyretic, anti-inflammatory, and (COX-1 only) platelet-inhibitory effects of NSAIDs.30 COX-1 is the constitutive form normally expressed in the GI tract, kidney, and vascular system, which regulates gastric cytoprotection and vascular homeostasis. COX-2 is induced by inflammatory mediators and expressed in parts of the kidney and other organ systems, including the CNS. The NSAIDs act peripherally to reduce the production of prostaglandins at the site of injury through their inhibition of COX-1 and COX-2.30 NSAIDs have long been considered drugs of choice for inflammatory disorders, including rheumatoid arthritis, gout, pseudogout, and bursitis.26 In addition, perioperative use has been shown to reduce postoperative opioid requirements.31 Headache of various etiologies32 and nonspecific episodic musculoskeletal pains33 often respond to NSAIDs.
Despite widespread use of NSAIDs in older persons, caution is warranted due to the potential for serious ADRs and drug-drug and drug-disease interactions (Table). In patients age 60 years or older, GI toxicity is increased threefold, as compared with that occurring in younger individuals.34 Although GI complications can be partially reduced with addition of a proton pump inhibitor (PPI) or misoprostol,26 concurrent use increases the probability of drug-drug interactions.25 Further, the risk of hemorrhagic peptic ulcer disease is increased nearly 13-fold when NSAIDs are administered concurrently with warfarin.35 Inhibition of prostaglandin synthesis affects kidney function and the CV system, leading to fluid and electrolyte disturbances, acute deterioration of renal function, and, rarely, nephrotic syndrome with interstitial nephritis and papillary necrosis.36 In addition, a twofold increased risk for hospital admission for heart failure (HF) has been observed in older persons taking NSAIDs undergoing treatment for control of HF.37
Current data strongly suggest that all NSAIDs should be used cautiously in patients at risk of adverse CV and renal effects.38 Nonacetylated salicylates and NSAIDs with a short half-life (eg, ibuprofen) may be preferable in older adults due to a lower risk of peptic ulcer disease.26 NSAIDs not recommended for use in older persons because of their toxicity potential include indomethacin, ketorolac, mefenamic acid, piroxicam, and phenylbutazone.26 When indicated in older persons, short-acting agents used at the lowest effective dose and as needed versus routine administration for the shortest continuous period of time possible, are preferred.25
Selective COX-2 Inhibitors
COX-2 inhibitors are NSAIDs that exert analgesic activity primarily through selective inhibition of the COX-2 enzyme. In comparative trials, COX-2 inhibitors have been shown to be as effective as comparator nonselective NSAIDs for management of arthritis pain.39 Because of minimal COX-1 inhibition, COX-2 inhibitors are associated with an improved GI safety profile aggregation, decreased risk of bleeding complications, and low potential for interaction with warfarin, as compared with nonselective NSAIDs.28 As with NSAIDs, however, they are associated with adverse renal and CV effects.30 Analysis of rofecoxib studies revealed an increased incidence of ischemic cerebrovascular events, HF, pulmonary edema, and/or myocardial infarction (MI),40 prompting its removal from the market in 2004. Subsequently, an increased incidence of CV events following coronary artery bypass graft (CABG) surgery was reported in patients receiving either valdecoxib or parecoxib, as compared with placebo.41 Valdecoxib was withdrawn from the market in 2005. Although previous celecoxib study results provided inconsistent information regarding CV risk, results from the Adenoma Prevention with Celecoxib (APC) study also revealed a significantly increased incidence of CV events (death from CV causes, MI, stroke, or HF) with celecoxib, as compared with placebo.42
These data strongly suggest that the CV risk reported with COX-2 inhibitors is a class effect,43 particularly with prolonged therapy and high doses, and these agents should not be prescribed for persons with cardiac risk factors (ie, prior MI, hypertension, or HF).44 In selected individuals with altered platelet function (eg, postoperatively, receiving cancer chemotherapy), a short-term benefit may be provided with use of a COX-2 inhibitor. In patients with both CV and GI risk factors, a nonselective NSAID with a GI-protective agent (eg, PPI) is recommended; however, this combination should be used with extreme caution and for the shortest possible duration. The currently available COX-2 inhibitor, celecoxib, is a sulfonamide and is contraindicated both in persons with a sulfa allergy and those with salicylate sensitivity.
Adjuvant drugs are used alone or in combination with analgesics to treat persistent (especially neuropathic) pain conditions.45 Before FDA approval of the topical lidocaine patch 5% for PHN, adjuvant drugs and opioids were the only options for management of neuropathic pain.6 Although lower doses in each drug class are typically used for pain management than those required for primary indications,26 interindividual variability in therapeutic effects and inconsistent dose–response relationships necessitate slow titration and close monitoring for therapeutic effects and ADRs.6,45
Among the anticonvulsants used to treat neuropathic pain, gabapentin is considered a first-line agent.7 FDA-approved for treatment of neuropathic pain associated with PHN, gabapentin’s efficacy has been evaluated in double-blind, placebo-controlled, randomized clinical trials for other neuropathic pain syndromes, including complex regional pain syndrome, diabetic neuropathy, trigeminal neuralgia, and poststroke pain.46 Although gabapentin is generally well tolerated and lacks significant drug interactions, as compared with other systemic agents used for treatment of neuropathic pain, it is associated with several that are potentially troublesome in older patients (Table).7 Gabapentin should be started at a low dose and gradually titrated to achieve pain relief to minimize these effects. Administration of a single bedtime dose may decrease ADRs while taking advantage of sedation. A reduced dose is required in patients with renal insufficiency.26
A substituted analog of gamma-amino butyric acid (GABA), pregabalin, is FDA-approved for management of pain associated with diabetic peripheral neuropathy, PHN, and fibromyalgia.47-49 Post-marketing and phase 4 studies will yield important information about long-term effectiveness and safety in older patients. Other anticonvulsant agents used for neuropathic pain conditions include carbamazepine, valproic acid, lamotrigine, topiramate, tiagabine, oxcarbazepine, and levetiracetam.
The analgesic mechanism of action of tricyclic antidepressants (TCAs) is not known; however, it is believed to be related to their serotonin reuptake blockade,50 and blockade of voltage-gated sodium channels.51 While TCAs have been found to be effective in placebo-controlled trials for treatment of neuropathic pain,52 their clinical usefulness in older patients is limited by their potential for drug interactions and ADRs (Table).7 When indicated, secondary amines (eg, nortriptyline, desipramine) are preferred over tertiary amines (eg, amitriptyline, imipramine) because of a decreased incidence of troublesome anticholinergic effects. Pain reduction often occurs with 30% to 50% of the antidepressant dose.26 Lower starting doses followed by slow titration are recommended.25
Duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant, was approved by the FDA for management of pain associated with diabetic peripheral neuropathy and fibromyalgia.53,54 Like pregabalin, data on long-term use in older patients are not yet available. Other antidepressants that have been evaluated and found effective in clinical trials for treatment of various peripheral and central neuropathic pain syndromes include bupropion, citalopram, paroxetine, and venlafaxine.7
Tramadol has a dual mechanism of action: inhibition of norepinephrine and serotonin reuptake, and a weak affinity for mu-opioid receptors.55 For management of mild-to-moderate pain of osteoarthritis, tramadol has been shown to have efficacy comparable to ibuprofen and to permit dose reduction of naproxen. It has also been found effective for treatment of low back pain, diabetic neuropathy, and fibromyalgia.56
Tramadol has a low abuse potential, as compared with opioids, lacks GI and renal toxicity, and has no precautions for use in patients with HF, hypertension, or renal insufficiency—offering an advantage over many other nonopioid analgesics for persons at risk of drug-disease interactions due to CV risk factors.56 However, it should be used with caution in patients with a seizure history or in those taking medications that lower the seizure threshold.45 Dosing should generally start low with gradual increases, and reduced doses are recommended in patients with renal or hepatic failure and in those over age 75 years. This careful approach should also help to mitigate other potential adverse effects, including bowel effects, nausea, ataxia, and confusion typical of all opioids.
Pure Mu-Opioid Agonist Analgesics
Opioids are used for treatment of moderate-to-severe pain that is poorly responsive to other pharmacotherapy,57 including neuropathic pain.26 Chronic administration of opioids for persistent pain may have fewer potential life-threatening risks than long-term use of NSAIDs25; common ADRs associated with opioid analgesics that may be troublesome in older patients are summarized in the Table. The incidence of addictive behavior among older persons taking opioid drugs for chronic pain conditions is extremely low, and fears of psychologic dependency and addiction surrounding the use of opioid analgesics are generally unfounded.58 Few long-term studies have been conducted, however, and some evidence indicates that caution should be used when prescribing opioid therapy over several years, both in terms of long-term efficacy and potential for misuse.59
Opioids are available in transdermal, oral, transmucosal (buccal), rectal, parenteral, and neuraxial (epidural/intrathecal) formulations. Opioids are often started in older patients at doses too low to provide adequate pain relief, with the expectation of titrating to achieve relief at a minimum dose, necessitating rapid upward titration.28 Appropriate dosing can generally be achieved by beginning with a short-acting agent and switching to a controlled-release formulation administered on a regular dosing schedule, avoiding as-needed dosing except for breakthrough pain. Among the various agents, fentanyl is available in a transdermal patch. Unlike a topical delivery system, the transdermal patch leads to systemic absorption, and therefore has an inherent potential for systemic ADRs and drug-drug and drug-disease interactions.60 Opioids that should be avoided because of an increased incidence of ADRs in older adults—except by highly experienced clinicians and with appropriate monitoring—include meperidine, propoxyphene, and the mixed agonist-antagonist agents (eg, pentazocine, buprenorphine).28,45
Methadone has a very long and unpredictable half-life (up to 150 hr), nonlinear pharmacodynamics—especially when switching from another opioid to methadone—and potential for QT interval prolongation, creating substantial risks of dose-accumulation, overdose, and cardiotoxicity in at-risk patients. Nonetheless, methadone has the advantages of being a relatively long-acting analgesic that can be made available in a liquid form for ease of administration and very low-dose titration (eg, 1 mg per 5 mL), and it is relatively inexpensive. Therefore, if these considerations warrant prescription of methadone, it should be used under the advisement of someone with extensive clinical experience in its use, and only when its administration and use can be carefully monitored by a reliable caregiver.61
The withdrawal of two COX-2 inhibitors and new CV warning labels on NSAIDs have limited the options for safe treatment of many pain conditions in older adults. Among the currently available pharmacologic agents, the topical route of administration offers the lowest risk of ADRs, drug-drug interactions, and drug-disease interactions in high-risk patients with comorbidities taking concurrent medications. Among the oral nonopioid analgesics, acetaminophen remains the best choice for first-line therapy of mild-to-moderate nociceptive pain. Both nonselective NSAIDs and COX-2 inhibitors should be used with caution in all older adults; however, in persons without CV risks, a nonselective agent with or without a GI protectant, as indicated, can be used as needed for short-term relief. For neuropathic pain conditions, rational polypharmacy is often necessary, taking advantage of lower doses of mechanistically different drugs to provide additive, complementary, and synergistic mechanisms of action with lower toxicity, as compared with higher doses of any given class of agent.
This review has focused on pharmacotherapy, but quality pain management in older persons requires not only thorough and ongoing assessment, but also comprehensive therapy to optimize outcomes. While pharmacotherapy is usually required in cases where persistent pain interferes with functional capacities, sleep, mood, and other quality-of-life measures, pain management should incorporate nonpharmacologic therapies, including rehabilitative and cognitive-behavioral interventions whenever possible. If timely and seemingly appropriate therapy does not lead to improvement, or analgesic adverse effects predominate, referral for specialty evaluation and care is recommended.
Dr. Fine has served on the speakers bureaus of Eli Lilly and Company and Wyeth Pharmaceuticals; as a consultant or advisor for Cephalon, Ortho McNeil Pharmaceutica/Pricaral, Endo Pharmaceuticals, King/Alpharma, Inc, and Abbott Laboratories; and as an expert witness for Janssen Pharmaceutica.
Dr. Herr has served on the speakers bureau of Wyeth Pharmaceuticals; and as a consultant/advisor for Cephalon, Endo Pharmaceuticals, King/Alpharma, Inc, Purdue Pharma, and Wyeth Pharmaceuticals.
Author Affiliations: Dr. Fine is Professor of Anesthesiology, Pain Research Center, School of Medicine, University of Utah, Salt Lake City; and Dr. Herr is Professor and Chair, Adult & Gerontological Nursing, University of Iowa, and Academic Staff Associate, Department of Nursing and Patient Service, University of Iowa Hospitals & Clinics, Iowa City.