Pharmacotherapy for Neuropathic Pain in the Elderly: Focus on Painful Diabetic Peripheral Neuropathy

Chronic pain is common and poorly controlled in elders, with a prevalence of 50% in community-dwelling older persons.¹ In addition, between 45% and 80% of nursing home residents have daily pain that interferes with their function and quality of life (QOL).² Although pain can result in cognitive dysfunction, depression, insomnia, gait disturbances, falls, anorexia, social withdrawal, and reduced ability to perform activities of daily living (ADLs; eg, toileting, grooming, eating) and instrumental ADLs (IADLs; eg, housekeeping, using the telephone),^3,4 it often remains poorly controlled or untreated.

Numerous barriers to pain control exist, including patient and physician factors. Patient barriers to pain control include the belief that pain is a normal part of aging and the fear that complaining about it may negatively affect their care.² Physician barriers to pain control include a lack of knowledge about opioid pain relievers and fear of their side effects. Although physicians are well trained to handle medical problems such as pneumonia, they are generally not skilled in pain management. As a result, opioids are frequently prescribed as needed rather than as scheduled, despite the latter approach being more effective at controlling pain. In addition, elderly persons (≥65 years) are frequently underrepresented in pain research.

One of the most common types of pain is neuropathic pain, which affects approximately 3.8 million individuals in the United States annually.⁵ The International Association for the Study of Pain (IASP) defines neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.”⁶ Neuropathic low back pain is the leading cause of neuropathic pain, with a prevalence in the United States of 2.1 million.⁵ This is followed by painful diabetic peripheral neuropathy (DPN), which affects 600,000 people in the United States, and postherpetic neuralgia (PHN), diagnosed in 500,000 people.⁵ Although neuropathic pain can affect anyone, it is more prevalent in older people because many diseases that cause neuropathic pain increase in incidence with advancing age.

The pathophysiology of neuropathic pain is complex, partly because it involves both peripheral and central sensitizations. The goal of pharmacologic therapy in patients with neuropathic pain is to block these sensitizations by modulating sodium channels and voltage-gated calcium channels, restoring inhibitory neurotransmission, and by blocking N-methyl-D-aspartate (NMDA) receptors. However, many front-line therapies for neuropathic pain do not have a favorable safety profile in elders.^7,8 In addition, older patients have more comorbidities and nutritional deficiencies and a higher incidence of polypharmacy than their younger counterparts, making proper selection and administration of pain medications and dosages especially challenging in this population.

This article provides an update on the pharmacotherapy of neuropathic pain in the elderly, focusing on DPN. In the next issue of Clinical Geriatrics, we will examine the pharmacotherapies for PHN. The aim of these articles is to provide clinicians with a comprehensive overview of the pharmaceuticals that can be used to manage two of the most common forms of neuropathic pain in geriatric patients. Cautions regarding use of these agents in this patient population are also outlined. When treatments for DPN are properly prescribed and used, they can significantly improve the QOL in elders with neuropathic pain.

Etiology and Pathophysiology of Neuropathic Pain

There are two types of neuropathic pain: central and peripheral.^9,10 Common causes of central neuropathic pain include myelopathy (compressive, infectious, or ischemic), multiple sclerosis, postischemic stroke, and posttraumatic spinal cord injury.⁹ Causes of peripheral neuropathic pain include low back pain, painful DPN, PHN, polyradiculopathy, alcoholic polyneuropathy, entrapment neuropathies (eg, carpal tunnel syndrome), nerve compression, phantom limb pain, and trigeminal neuralgia.⁹

Diabetic-induced neuropathies that affect elders include focal neuropathy (ie, third cranial nerve palsy), entrapment syndrome (ie, carpal tunnel syndrome), proximal motor neuropathy, and chronic sensorimotor distal neuropathy (painful DPN). The latter is by far the most recognized form of diabetic neuropathy.⁹ The onset is usually insidious and mostly sensory in nature, but it can progress to motor neuropathy (pain that occurs upon movement), and it may involve small fibers, large fibers, or both.⁹ Small fiber neuropathy causes burning, dysesthetic pain, which is often accompanied by hyperalgesia (extreme pain in response to a stimulus that is normally painful) and allodynia (pain due to a stimulus that does not normally provoke pain).^5,9,10 The pain of large fiber neuropathy is usually described as deep and gnawing.¹¹ Function, balance, and ADLs are frequently compromised.¹¹

The pathophysiology of neuropathic pain is complex and includes peripheral and central sensitizations.¹² Peripheral sensitizations start with a peripheral nerve injury that leads to the increased expression of sodium and voltage-gated calcium channels, lowering of nociceptor depolarization threshold, and increased neuronal excitability.¹² Foci of neuronal excitability may act as an ectopic neuronal pacemaker along the nerves, similar to the ectopic pacemaker foci within the heart. In central sensitization, there is increased spontaneous activity of the dorsal horn neurons, reduced activation thresholds, increased response to synaptic inputs, and death of inhibitory interneurons. NMDA receptors and increased intracellular calcium play an important role in central sensitization.¹² Understanding the pathophysiology of neuropathic pain is essential to improve therapy. The goal is to block peripheral and central sensitizations by modulating sodium channels and voltage-gated calcium channels, thereby restoring inhibitory neurotransmission, and by blocking NMDA receptors.^12,13

Treatments for Painful Diabetic Peripheral Neuropathy

Antidepressants, anticonvulsants, and analgesics (opioid and topical) have been used to treat painful DPN. According to the second European Federation of Neurological Societies (EFNS) Task Force, the following medications have level A evidence for the treatment of painful DPN: duloxetine, gabapentin, tricyclic antidepressants (TCAs), oxycodone, pregabalin, tramadol alone or with acetaminophen (APAP), and venlafaxine extended-release (ER).⁸ The Neuropathic Pain Special Interest Group of the IASP⁷ has published evidence-based guidelines, which list the following medications as first-line therapy for neuropathic pain: TCAs, gabapentin, pregabalin, dual reuptake inhibitors of serotonin and norepinephrine, and topical lidocaine. Opioids and tramadol were considered second-line therapies that could be used as first-line therapies in certain clinical circumstances.⁷ Although all of the aforementioned agents have been shown to be effective in treating pain associated with DPN, the data regarding their use in elders are limited. We examine the evidence for treating painful DPN in elders with these agents and outline any caveats regarding their use in this population.   

Antidepressants
Antidepressants used for DPN primarily include TCAs and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Tricyclic antidepressants. TCAs may act by altering the central perception of pain. Double-blind, randomized controlled trials reported reduced pain severity among subjects with painful DPN after taking TCAs.^14,15 A systematic review found that TCAs were more effective for short-term pain relief than the traditional or newer generation anticonvulsants.¹⁶ The therapeutic effect usually occurs sooner (within 6 weeks) and at doses lower than those needed to treat depression.¹⁴

Amitriptyline is not recommended for use in elders because of its anticholinergic side effects, such as orthostatic hypotension and possible cardiac arrhythmias. Older adults who have neuropathy are at risk for adverse events from TCAs, especially falls and cognitive decline. Contraindications to TCAs include cardiac conduction block, long QT syndrome, myocardial infarction within 6 months, and ventricular arrhythmias or frequent premature ventricular contractions.¹⁷ Obtaining a baseline electrocardiogram (ECG) before these agents are prescribed is imperative. Nortriptyline (10-, 25-, 50-, and 75-mg capsules) or desipramine (10-, 25-, 50-, 75-, 100-, and 150-mg tablets) have the fewest side effects among this class and are preferred in geriatric patients.¹⁸ Desipramine (100 mg/day) is more cost-effective than gabapentin (2400 mg/day) and pregabalin (300 mg/day) in elders.^19-21

Serotonin-norepinephrine reuptake inhibitors. The SNRIs work by blocking reuptake of serotonin and norepinephrine in the brain. The two SNRIs that have been found to be the most useful for treating DPN are duloxetine and venlafaxine.

Duloxetine. Duloxetine is approved by the US Food and Drug Administration (FDA) for the treatment of painful DPN. It relieves pain by increasing synaptic availability of 5-hydroxytryptamine, which inhibits pain impulses in both ascending and descending pathways.

In a double-blind study, patients with painful DPN and without comorbid depression were randomly assigned to treatment with duloxetine 60 mg once daily, duloxetine 60 mg twice daily, or placebo for 12 weeks.²² The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Duloxetine 60 mg once daily and 60 mg twice daily demonstrated improvement in the management of DPN and showed rapid onset of action, with separation from placebo beginning at week 1 (P<.001). Duloxetine 60 mg once daily and 60 mg twice daily were equally effective for all primary and secondary measures. Ratings on the Clinical Global Impression of Severity scale and the Patient Global Impression of Improvement (PGI-I) scale were significantly improved in the duloxetine groups compared with the placebo group (P<.001).²² A study by Armstrong and associates²³ had similar results, with duloxetine significantly improving functional outcomes in persons with DPN pain.²³ Wu and colleagues²⁴ showed that duloxetine was more cost-effective than routine treatment in managing DPN.

In an open-label safety study of duloxetine that randomized patients to receive duloxetine 60 mg twice daily or 120 mg once daily, both doses were safely administered and well tolerated by patients with painful DPN for up to 28 weeks.²⁵ Adverse events resulted in treatment discontinuation in 20.1% of patients in the 60-mg twice daily group and 27.0% of those in the 120-mg once daily group. Sustained elevation in blood pressure was reported for 5.5% of patients in the 60-mg twice daily group and for 5.4% of patients in the 120-mg once daily group.Duloxetine treatment was not associated with significant QTc prolongation.²⁵ Because duloxetine has been associated with clinically significant hyponatremia in elders, physicians should monitor sodium levels and check blood pressure before initiating this treatment in this population.

Venlafaxine. Venlafaxine is FDA-approved for the treatment of depression. Although it does not hold an indication for the treatment of DPN, it is used off-label for this purpose in clinical practice. In a 6-week trial, venlafaxine 75 mg daily and 150 mg to 225 mg daily were compared with placebo in 244 diabetic patients with painful DPN.²⁶ There was significant pain relief in the higher dosage group but not in the lower dosage group. Treatment-emergent adverse events were reported by 75% of the patients in the placebo group, 88% in the venlafaxine-ER 75-mg group, and 89% in the 150-mg to 225-mg groups, respectively. The most commonly reported adverse events, which were mild to moderate in severity, were nausea, dyspepsia, sweating, somnolence, and insomnia. Blood pressure and cardiac rhythm changes (mainly atrial fibrillation and first-degree atrioventricular block) occurred more often in the venlafaxine treatment arms, and seven patients treated with venlafaxine demonstrated clinically important changes in their ECG findings. However, the higher dose of venlafaxine-ER showed robust analgesic efficacy but had little, if any, additional disadvantage in tolerability compared with the lower dose. Monitoring of cardiac rhythm and vital signs is indicated when starting this medication.²⁶

Another small study randomized 60 patients (47 women and 13 men) with painful DPN, determined by a minimum visual analog scale (VAS) score of 40 mm, to receive either venlafaxine hydrochloride (n=30) or placebo (n=30).²⁷ The placebo was a combination tablet of vitamins B₁and B₆. The severity of pain was measured by VAS, the short-form McGill Pain Questionnaire (SF-MPQ), and the numerical analog scale scores at admission and at weeks 2, 4, and 8 of the study. Venlafaxine hydrochloride resulted in a statistically significant decrease in pain severity, measured by both the SF-MPQ and the numerical analogue scales (P<.001). The authors concluded that venlafaxine hydrochloride is a safe and well-tolerated analgesic drug for the treatment of symptoms of painful DPN.²⁷ No specific dose adjustments of venlafaxine are considered necessary based on patient age alone; however, elderly patients are more likely to have age-related liver or kidney problems, which may require an adjustment in the dose. As a rule, when treating elderly persons, the lowest effective dose should always be used.

Anticonvulsants
Anticonvulsants, typically used to treat patients with seizures, have gained recent attention for their effectiveness in relieving pain. Over the past decade, two structurally related agents—gabapentin and pregabalin—received FDA approval for pain indications.

Gabapentin. Gabapentin was first approved by the FDA in December 1993 for the treatment of partial seizures. In 2002, an indication was added for treating painful neuropathies, including DPN and PHN.²⁸ Gabapentin works by binding to the alpha2-delta subunit of the calcium channel and reducing calcium flux, thereby reducing neurotransmitter release in hyperexcited neurons.

In a randomized controlled trial, 147 patients (mean age, 59 years) received either gabapentin-ER 3000 mg (g-ER titrated from 300 mg to 3000 mg daily over 2 weeks), or placebo for 4 weeks.²⁹ A statistically significant decrease in the average daily pain score was observed in the g-ER group compared with the placebo arm (P=.001). More people in the treatment group reported dizziness and somnolence.²⁹ In a meta-analysis, gabapentin was compared with TCAs for efficacy against painful DPN and PHN. There was no difference between gabapentin and TCAs in achieving pain relief (relative risk [RR], 0.99; 95% confidence interval [CI], 0.76-1.29).³⁰ Gabapentin improved sleep, which is often compromised in patients with chronic pain.³¹ Another meta-analysis compared the efficacy of gabapentin, duloxetine, and pregabalin against painful DPN.³² All three medications were superior to placebo on all efficacy parameters, including reduction in 24-hour pain severity, response rate (≥50% pain reduction), PGI-I scores, and the Patient Global Impression of Change (PGI-C) scores. An indirect comparison of duloxetine with pregabalin found  a nonsignificant difference of -0.248 (95% CI, -0.667 to 0.162) in the 24-hour pain scores in favor of duloxetine, but significant differences were found in PGI-I and PGI-C, favoring pregabalin, and in dizziness, favoring duloxetine. There were no statistically significant differences when comparing duloxetine with gabapentin.³²

Gabapentin is generally well tolerated by elders. Sedation is the most frequent side effect; thus, we advise starting this agent at a low dose and slowly titrating it to desired levels. Because concomitant ginkgo biloba use can reduce the activity of gabapentin, clinicians should advise their patients to discontinue this herbal supplement before initiating gabapentin therapy.

Pregabalin. Pregabalin was first approved in July 2004 by the European Medicines Agency’s Committee for Medicinal Products for Human Use for the treatment of peripheral neuropathic pain. Pregabalin received conditional approval by the FDA for the treatment of painful DPN and PHN in December 2004 and was granted final approval after controlled substance scheduling by the US Drug Enforcement Agency in August 2005.³³ Pregabalin is a schedule V–controlled substance.

The exact mechanism of action of pregabalin is unclear but is thought to be similar to that of gabapentin. Pregabalin is a structural analogue of gamma-aminobutyric acid (GABA), but is inactive at GABA_A or GABA_B receptors, is not converted into GABA or a GABA antagonist, and does not affect GABA uptake. Pregabalin is an alpha2-delta ligand; it may alter the release of several neurotransmitters by selectively binding to the alpha2-delta auxiliary protein subunit of voltage-gated calcium channels. By tightly binding to alpha2-delta protein, pregabalin reduces the influx of calcium, thereby reducing the release of neurotransmitters, including glutamate, norepinephrine, and substance P. These mechanisms are thought to result in the anticonvulsant, anxiolytic, and analgesic properties exhibited by pregabalin.³⁴

Pregabalin is recommended by EFNS as a first-line treatment for painful polyneuropathy.⁵ In clinical trials, pregabalin improved pain scores as early as 1 week following the start of treatment and sustained pain relief for 6 to 12 weeks.^35,36

In a randomized, double-blind, placebo-controlled trial, patients with painful DPN received either pregabalin 600 mg daily (300 mg twice daily) or placebo.³⁷ Pregabalin-treated patients had lower mean pain scores than controls (mean difference, -1.28; P<.001). Pain improvement was evident at week 1 and remained stable throughout the study. The percentage of patients with ≥7% weight gain was higher in the pregabalin group (11%) than in the placebo group (2%).³⁷
Peripheral edema was also common. In previous studies of pregabalin (600 mg daily fixed dose), peripheral edema ranged from 10% to 17% in the pregabalin group compared with 2% to 5% in the placebo group.^35,36 Adverse events commonly reported in clinical trials include dose-related somnolence, ataxia, confusion, peripheral edema, weight gain, and constipation.^37,38 Although there are no geriatric-specific considerations that would limit the usefulness of pregabalin in elderly persons, this population is more likely to have unwanted effects (eg, dizziness, blurred vision, confusion, or clumsiness) and age-related kidney problems, which may require dose adjustment.

Opioid Analgesics
Opioid analgesics have played a limited role in the management of DPN, partly because of concerns about the responsiveness of neuropathic pain to opioid treatment.³⁹ Opioids that can be considered include controlled-release (CR) oxycodone, fentanyl, methadone, and tramadol.

Oxycodone. Oxycodone-CR has been shown to be a safe and effective treatment for painful DPN, and to improve QOL.⁴⁰ In a 6-week, randomized, controlled trial, oxycodone-CR was effective in treating moderate to severe pain from DPN, but typical opioid-related side effects were observed.³⁹

Fentanyl. A multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of fentanyl buccal tablets (FBTs) in opioid-tolerant patients with breakthrough pain associated with chronic nonmalignant neuropathic pain.⁴¹ In the study, FBTs were shown to have a rapid onset of action (10-15 minutes) and were an effective, well-tolerated treatment for breakthrough pain among patients with chronically painful DPN, PHN, traumatic injury, or complex regional pain syndrome.⁴¹ In elderly patients, FBTs may have reduced clearance and a prolonged half-life. Fentanyl transdermal patches also should be used with caution in debilitated or cachectic elderly, as these individuals may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance.

Methadone. Methadone is both a µ-opioid receptor agonist and a potent NMDA inhibitor.⁴² NMDA antagonism produces analgesia and reverses opioid tolerance.⁴³ Data for the use of methadone in painful DPN are lacking. The half-life of methadone is long, usually about 24 hours, but can vary widely between patients, ranging from 12 hours to >150 hours.⁴³ Therefore, there is potential for accumulation of the drug over a prolonged period and patients may be at risk of late toxicity.

Caution is needed when switching to methadone from other opioids.⁴⁴ Methadone has the potential to prolong the QT interval,⁴⁴ a phenomenon that predisposes patients to torsades de pointes. Caution also should be used when prescribing high doses of methadone (>200 mg daily) or administering methadone to patients who have intrinsic heart disease or are receiving other drugs that prolong the QTc interval.⁴⁴

Methadone is extensively metabolized by three cytochrome P450-enzymes: CYP1A2, CYP3A4, and CYP2D6. As a result, the metabolism of methadone can be greatly influenced by medications whose effect is related to cytochrome enzyme activity. Most drug interactions with methadone involve inducers or inhibitors of the cytochrome P450 system. The classic antiseizure medications carbamazepine, phenobarbitol, and phenytoin are inducers of CYP3A4 and can lower the blood levels of methadone. Valproic acid and gabapentin do not interact pharmacokinetically with methadone. The selective serotonin reuptake inhibitors influence the activity of several cytochrome enzymes. If antidepressants are needed in elderly persons, then an SNRI like venlafaxine has the least potential for drug interaction with methadone. Desipramine plasma levels increase when it is administered with methadone due to competitive inhibition of CYP2D6.⁴

Tramadol. Tramadol is a weak µ-opioid agonist. It also inhibits norepinephrine and 5-hydroxytryptamine. In one study, 313 patients with painful DPN were randomized to receive a combination of tramadol plus APAP (37.5 mg/325 mg) or placebo, up to one to two tablets four times daily, for 66 days.⁴⁵ The age (mean±SD) in the tramadol/APAP group was 56.2±9.88 years. Tramadol/APAP significantly improved pain scores in 1 week compared with placebo, and it sustained pain control throughout the study (P=.001). All secondary measures of sleep interference, QOL, mood, and global impression scores were significantly improved in the tramadol/APAP group (P<.05). Nausea was a side effect in 12% of  patients in the tramadol/APAP group.

Another study randomized 163 subjects with painful DPN to receive either tramadol/APAP (37.5 mg/325 mg; n=79) or gabapentin (300 mg; n=84) for 6 weeks, but doses were titrated to achieve pain control.⁴⁶ Baseline pain severity was similar in both groups. At the end of the study, the mean doses were 1575 mg daily for gabapentin and 4.22 tablets daily for tramadol/APAP. The mean reductions in pain intensity were similar in both groups (tramadol/APAP, -3.1±2.0; gabapentin, -2.7±2.1; P=.744). The investigators concluded that tramadol/APAP treatment is as effective as gabapentin in the treatment of painful DPN in patients with type 2 diabetes.⁴⁶ Tramadol is commonly used in the geriatric setting. No dose adjustment is needed for elders between 65 and 75 years of age who are otherwise healthy. For patients older than 75 years, the maximum daily dose should be ≤300 mg daily in divided doses. In case of renal failure (creatinine clearance
<30 mL/min), tramadol should be given every 12 hours; the maximum daily dose is 200 mg.

Lidocaine Patch
The 5% lidocaine patch is effective in painful DPN.^47,48 The patch reduces the excitability of C and A delta fibers of peripheral nerves, thereby providing local pain relief through localized analgesia. It is an optimal medication for elders because it has minimal side effects and less potential for drug interactions.^49,50 Up to three patches can be applied daily for up to 12 hours.⁵¹

In a recent meta-analysis, the lidocaine patch was comparable to amitriptyline, capsaicin, gabapentin, and pregabalin at significantly reducing pain scores from baseline compared with placebo: amitriptyline, -12.58 (95% CI, -16.66 to -8.50); capsaicin, -9.40 (95% CI, -13.92 to -4.88); gabapentin, -10.22 (95% CI, -17.25 to -3.19); pregabalin, -10.53 (95% CI, -14.74 to -6.32); and 5% lidocaine patch, -9.10 (95% CI, -13.93 to -4.26).⁵² In a two-stage, adaptive, randomized, open-label, multicenter study, adults with PHN or painful DPN received either the topical 5% lidocaine patch applied to the most painful skin area or twice daily pregabalin capsules.⁵¹ The primary end point was response rate at 4 weeks, defined as a reduction in pain of ≥2 points from baseline averaged over the previous 3 days or an absolute value of ≤4 points on the 11-point Numerical Pain Rating Scale. More patients with PHN responded to the 5% lidocaine patch than to pregabalin, whereas patients with painful DPN responded comparably to both therapies. Most patients in the pregabalin arm required a daily dosage of 600 mg. Improvement in QOL scores were reported most often in the 5% lidocaine group. Side effects of the lidocaine patch were mainly mild to moderate application-site reactions, whereas pregabalin resulted in moderate to severe central nervous system side effects.^51,52

Conclusion

Uncontrolled pain in elders may cause cognitive dysfunction, depression, insomnia, gait disturbances, falls, anorexia, social withdrawal, and dependence in ADLs and IADLs. FDA-approved drugs for the treatment of painful DPN include pregabalin, duloxetine, and the 5% lidocaine patch. NMDA receptors, sodium channels, voltage-gated calcium channels, and inhibitory neurotransmission are involved in the pathophysiology of neuropathic pain and are important targets for improving treatment and developing effective drug combinations; however, research on neuropathic pain has not included enough patients 65 years and older, and more research is needed in this age group. The ultimate goal of treating elderly patients is to optimize function and mobility. Because combination therapy for neuropathic pain produces better outcomes with a smaller dose of each drug, this approach is gaining momentum and should be considered for geriatric patients.

The authors report no relevant financial relationships.

Dr. Mahmoud is Geriatric Fellow, University of Connecticut Center on Aging, Farmington; and Dr. Tampi is Associate Clinical Professor of Psychiatry, Yale University School of Medicine, New Haven, CT.

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