Efficacy, Safety, and Tolerability of Pharmacotherapy for Management of Persistent Pain in Older Persons

INTRODUCTION

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 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), as well as noncompliance due to misinformation about ADRs, and fears of addiction or dependence. In addition, because of new cardiovascular warning labels on nonsteroidal anti-inflammatory drugs (NSAIDs) and the recent withdrawal of two of the three commercially available cyclooxygenase-2 (COX-2) inhibitors, (ie, rofecoxib and valdecoxib), 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 on 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 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 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 (~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 Food and Drug Administration (FDA)-approved 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 neuropathy,⁸ and refractory neuropathic pain of various origins.⁹ It has been reported to be effective as add-on therapy in 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, or abnormal sensation) that are generally mild and transient, and resolve spontaneously within minutes to hours (Table I).⁵ Clinically significant drug interactions, systemic ADRs,⁶ and sensory loss (ie, local anesthesia)¹² have not been reported with lidocaine patch 5%. Some patients have reported breakthrough pain with the FDA-approved dose (ie, up to 3 patches for 12 h on/12 h off),⁶ and recently published pilot studies have demonstrated a similar safety profile with applications up to 18 to 24 hours.^6,8

Capsaicin
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, 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

Common ADRs include burning pain at the application site, sneezing, and coughing (Table I).¹⁶ While these effects can be decreased with use of a topical anesthetic spray¹³ and routine handwashing after contact, capsaicin has also been shown to be neurotoxic, with epidermal nerve fiber degeneration occurring as early as 3 days after beginning therapy.²² Dosed on a regular schedule—every 6 hours—it generally takes 2 to 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.

Other Local Agents
Corticosteroids, useful alternatives to NSAIDs in some clinical situations, can be administered via intra-articular or topical, as well as oral, rectal, or parenteral routes.²³ Indicated in various inflammatory disorders,²⁴ they have also been shown to provide analgesia in arthritis and relief from compressive symptoms caused by malignancies.²³ 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 I). Insufficient data exist to warrant discussion of other topical or local pharmacologic agents for treatment of pain in older adults.²⁴

ORAL NONOPIOID ANALGESICS

Oral nonopioids are generally first-line therapy for treatment of mild-to-moderate nociceptive pain.²⁵ These include acetaminophen, nonselective NSAIDs, and selective COX-2 inhibitors.

Acetaminophen
Acetaminophen has been found to be effective in a number of common pain conditions,²⁴ and is often a preferred agent for mild-to-moderate nociceptive pain because of its relative safety in older persons.²⁶ Acetaminophen is associated with less gastrointestinal and renal toxicity compared with NSAIDs, few drug interactions, and no age-related differences in drug clearance²⁴; however, since it is metabolized in the liver, caution is advised when administered concurrently with other hepatically metabolized drugs, in patients with concomitant liver disease,²⁶ and when consumed with alcohol or when fasting (Table I).²⁷

Nonselective NSAIDs
Inhibition of the enzymes cyclooxygenase-1 and -2 (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.²⁸ COX-1 is the constitutive form normally expressed in the gastrointestinal 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 central nervous system. The NSAIDs act peripherally to reduce the production of prostaglandins at site of injury through their inhibition of COX-1 and COX-2.²⁸ NSAIDs have long been considered drugs of choice for inflammatory disorders, including rheumatoid arthritis, gout, pseudogout, and bursitis.²⁴ In addition, perioperative use has been shown to reduce postoperative opioid requirements.²⁹ Headache of various etiologies³⁰ and nonspecific episodic musculoskeletal pains³¹ 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 I). In patients age 60 years or older, gastrointestinal toxicity is increased 3-fold as compared with that occurring in younger individuals.³² Although gastrointestinal complications can be partially reduced with addition of a proton pump inhibitor (PPI) or misoprostol,24 concurrent use increases the probability of drug-drug interactions.23 Further, the risk of hemorrhagic peptic ulcer disease is increased nearly 13-fold when NSAIDs are administered concurrently with warfarin.³³ Inhibition of prostaglandin synthesis affects kidney function and the cardiovascular system, leading to fluid and electrolyte disturbances, acute deterioration of renal function, and, rarely, nephrotic syndrome with interstitial nephritis and papillary necrosis.³⁴ In addition, a 2-fold increased risk for hospital admission for heart failure has been observed in older persons taking concurrent NSAIDs and diuretics.³⁵

Current data strongly suggest that all NSAIDs should be used cautiously in patients at risk of adverse cardiovascular (CV) and renal effects.³⁶ 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.²⁴ NSAIDs not recommended for use in older persons because of their toxicity potential include indomethacin, ketorolac, mefenamic acid, piroxicam, and phenylbutazone.²⁴ When indicated in older persons, short-acting agents used at the lowest effective dose and as needed versus routine administration are preferred.²³

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.³⁷ Because of minimal COX-1 inhibition, COX-2 inhibitors are associated with an improved gastrointestinal safety profile aggregation, decreased risk of bleeding complications, and low potential for interaction with warfarin, compared with nonselective NSAIDs.²⁶ Like NSAIDs, however, they are associated with adverse renal and CV effects.²⁸ Analysis of rofecoxib studies revealed an increased incidence of ischemic cerebrovascular events, heart failure, pulmonary edema, and/or myocardial infarction (MI),³⁸ prompting its removal from the market. Subsequently, an increased incidence of CV events following coronary artery bypass surgery was reported in patients receiving either valdecoxib or parecoxib, compared with placebo.³⁹ Valdecoxib has also recently been withdrawn from the market. 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 heart failure) with celecoxib as compared with placebo.⁴⁰

These data strongly suggest that the CV risk reported with COX-2 inhibitors is a class effect,⁴¹ 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 congestive heart failure).⁴² 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 gastrointestinal risk factors, a nonselective NSAID with a gastrointestinal 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.

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ADJUVANT DRUGS

Adjuvant drugs are used alone or in combination with analgesics to treat persistent (especially neuropathic) pain conditions.⁴³ Before FDA approval of the topical lidocaine 5% patch for postherpetic neuralgia, 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 required for primary indications,²⁴ interindividual variability in therapeutic effects and inconsistent dose-response relationships necessitate slow titration and close monitoring for therapeutic effects and ADRs.^6,43

Anticonvulsants
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.⁴⁴ 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 ADRs that are potentially troublesome in older patients (Table I).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.²⁴ 

A substituted analog of gamma-amino butyric acid (GABA), pregabalin, was recently FDA-approved for management of pain associated with diabetic peripheral neuropathy and PHN.^45,46 Because of limited experience in older adults, however, its place in therapy is currently unclear. Other anticonvulsant agents used for neuropathic pain conditions include carbamazepine, valproic acid, lamotrigine, topiramate, gabitril, oxcarbazepine, and levetiracetam.

Antidepressants
The analgesic mechanism of action of tricyclic antidepressants (TCAs) is not known; however, it is believed to be related to their serotonin reuptake blockade,⁴⁷ and blockade of voltage-gated sodium channels.⁴⁸ While TCAs have been found to be effective in placebo-controlled trials for treatment of neuropathic pain,⁴⁹ their clinical usefulness in older patients is limited by their potential for drug interactions and ADRs (Table I).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.²⁴ Lower starting doses followed by slow titration are recommended.²³

Duloxetine, a serotonin and norepinephrine reuptake inhibitor antidepressant, was recently approved by the FDA for management of pain associated with diabetic peripheral neuropathy.⁵⁰ Like pregabalin, there has been little experience with this agent in older adults, and its place in therapy is not yet determined. 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

Tramadol has a dual mechanism of action: inhibition of norepinephrine and serotonin reuptake, and a weak affinity for mu-opioid receptors.⁵¹ 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.⁵²

Tramadol has a low abuse potential compared with opioids, lacks gastrointestinal and renal toxicity, and has no precautions for use in patients with heart failure, hypertension, or renal insufficiency—offering an advantage over many other nonopioid analgesics for persons at risk of drug-disease interactions due to CV risk factors⁵²; however, it should be used with caution in patients with a seizure history or in those taking medications that lower the seizure threshold.⁴³ 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. Similar precautions with regard to bowel effects, nausea, ataxia, and confusion typical of all opioids and monoamine reuptake inhibitors should be taken when prescribing tramadol.

PURE MU-OPIOID AGONIST ANALGESICS

Opioids are used for treatment of moderate-to-severe pain that is poorly responsive to other pharmacotherapy,⁵³ including neuropathic pain.²⁴ Chronic administration of opioids for persistent pain may have fewer potential life-threatening risks than long-term use of NSAIDs²³; common ADRs associated with opioid analgesics that may be troublesome in older patients are summarized in Table I. 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.⁵⁴ Few long-term studies have been conducted, however, and some recent 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.⁵⁵

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.²⁶ 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.⁵⁶ 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, methadone, and the mixed agonist-antagonist agents (eg, pentazocine, buprenorphine).^26,43

SUMMARY

The recent 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 gastrointestinal 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, 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 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, and 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.

This article is made possible by an educational grant from Endo Pharmaceuticals Inc. Dr. Fine has served as an advisor for Alpharma, Cephalon, Eli Lilly, and Endo Pharmaceuticals. Dr. Herr is a member of the speaker’s bureau for Endo Pharmaceuticals, Alpharma, Purdue, and Pfizer.