Clinical Geriatrics

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.