The Treatment of Neuropathic Pain in the LTC Setting

This article addresses the most current data to help clinicians make up-to-date decisions regarding the management of neuropathic types of pain in LTC residents. For example, diabetic peripheral neuropathy (DPN), postherpetic neuralgia, and trigeminal neuralgia are recognized causes of neuropathic pain. Common symptoms associated with neuropathic pain include allodynia, paresthesias, hyperalgesia, and dysesthesia. Among published guidelines and literature reviews, antidepressants and antiepileptics are consistently touted as first-line agents. Ultimately, it is the tolerability profile, determined on a patient-by-patient basis, that should dictate which agent to invoke. The neuronal dysfunction that leads to neuropathic pain likely occurs during the acute portion of the primary illness; thus, early initiation of therapy is advisable, no matter what drug is chosen. (Annals of Long-Term Care: Clinical Care and Aging 2010;18[9]:37-40)
__________________________________________________________________________________________________________

Introduction

The term pain conjures up imagery and meanings that differ from individual to individual. To the person in pain, it can describe a state of depression, lack of enjoyment of events, or loss of freedom to engage in previously enjoyable activities. To the healthcare professional, it may mean a chronic, often frustrating, phenomenon that we have no objective way to monitor, and an ominous portent of the consequences of tissue damage. Moreover, clinicians are now confronted with an expanding array of potential therapeutics with numerous side-effect profiles. As the clinician weighs these various issues, he or she must not forget the impact of chronic pain on long-term caregivers, for whom the witnessing of persistent pain may bring about bystander suffering.

In the long-term care (LTC) population, underappreciation, and subsequent undertreatment, of pain by clinicians is a well-recognized phenomenon. It usually occurs via one or both of two distinct mechanisms: (1) impaired cognition with an inability to communicate pain by the patient; and (2) the misguided belief by the older patient that pain is an expected or inevitable part of aging.¹ The former poses a challenge that is addressed by pain scales and questionnaires designed to elicit pain symptoms from a cognitively impaired group.¹ For example, scales with pictures/cartoons is one method to obtain accurate data from such a population. The latter mechanism (misguided belief) is addressed by efforts to increase awareness among healthcare providers. Healthcare providers are encouraged to inquire about pain at every geriatric encounter. Indeed, it has been said that pain should be the fifth vital sign because suffering and the subsequent cascade of negative psychological as well as physiological impacts can adversely affect the quality of life of elderly and LTC patients.

Unfortunately, the complexity of this issue is potentiated by multiple underlying diseases and the very real concern for adverse drug interactions with any concurrent pharmacotherapy already in place for these other diseases.² Additionally, aging physiology and the potential for suboptimal drug clearance are two other key concerns. Fear of toxicity due to these issues, as well as regulatory concerns, have contributed to undertreatment of chronic neuropathic pain in the elderly.³

Pain is a physiological phenomenon important to our well-being. It illuminates internal derangements and protects us from external sources of harm. One type of pain is a perturbation in neural pathways that can lead to chronic hyperexcitability. Two mechanisms by which we feel such pain include nociceptive activation of receptors and neuropathic derangement of the peripheral and central nervous system (CNS). The former occurs due to activation of either internal or external pain receptors. Two common examples of this mechanism include musculoskeletal injury and end organ inflammation.⁴ Damage to sensory neurons may also occur via various diseases or drugs. Over time, adjacent normal neural fibers may become affected by neuropathic fibers, thereby generalizing the hyperexcitability in a process termed peripheral sensitization (a process thought to be self-sustaining).⁴

Diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), and trigeminal neuralgia are recognized causes of neuropathic pain. Common symptoms associated with neuropathic pain include allodynia, paresthesias, hyperalgesia, and dysesthesia.⁴ Management entails indirect measures such as optimizing the therapy of underlying contributing disease states, (ie, maintaining target blood sugar levels in patients with DPN) and direct pharmaceutical interventions such as the targeting of neurological transmitters.^5,6

This article addresses the most current data to help clinicians make up-to-date decisions regarding the management of neuropathic types of pain in older patients. Two broad categories of medications, anticonvulsants and antidepressants, are typically first-line agents utilized for alleviating neuropathic pain.^1,4,7,8 Unfortunately, studies that specifically target the elderly population are relatively sparse. That being said, many individuals with chronic neuropathic pain, such as trigeminal neuralgia (which usually affects patients > age 65 yr), are included in randomized controlled trials (RCTs) of the management of neuropathic pain. Thus, while conclusions concerning data from these studies may be extrapolated to the LTC setting, caution must be exercised, for example, in order to take into account drug metabolism variations and coexisting medical conditions.

Anticonvulsants

Treatment of neuropathic pain with antiepileptic drugs (AEDs) can be traced back to the early 1940s when agents such as phenytoin and carbamazepine were utilized to treat trigeminal neuralgia with notable success.⁶ Mechanisms such as the blockade of sodium channels, enhanced gamma-aminobutyric acid (GABA) activity, and antagonism of glutamate at N-methyl-D-aspartate (NMDA) receptors are central to how many of the AEDs exert their therapeutic effects.⁶ Gabapentin and pregabalin, two effective and newer neuropathic pain treatments, are believed to work on alpha-2-delta subunits of voltage-gated calcium channels.^6,9 The specific mechanism of action is still under investigation. However, Hayashida et al⁹ describe bulbospinal noradrenergic-cholinergic pathway activation as a mechanism leading to alleviation of pain by these agents.

Carbamazepine (beginning at 200 mg/d) has Food and Drug Administration (FDA) approval for the treatment of trigeminal neuralgia. It has therapeutic efficacy in other types of neuropathic pain such as peripheral diabetic neuropathy (PDN).^1,6 Here, it is important to note that agranulocytosis and aplastic anemia have been observed with this agent. Therefore, it is necessary to monitor patients with appropriate blood tests on a regular basis.¹ Special care in the Asian population (who have genetic polymorphisms in the cytochrome P450 system that can alter drug metabolism) and in individuals taking drugs that either induce or inhibit the CYP450 enzyme system is also required.

Gabapentin (beginning at 300 mg at bedtime and adjusted for renal impairment) has FDA approval for the treatment of PHN.⁶ Furthermore, it has been shown to improve sleep in patients with chronic pain. Common side effects include dizziness and somnolence, along with weight gain and peripheral edema.¹⁰ At doses greater than 1200 mg per day, gabapentin results in pain improvement of greater than 50% in patients with DPN.¹¹ Based on Cochrane reviews, no significant difference in therapeutic efficacy has been demonstrated between gabapentin and amitriptyline.¹¹ Alcohol, certain nutraceuticals, and other CNS depressant medications may adversely impact upon concurrent gabapentin use.

Pregabalin (beginning at 150 mg/d and adjusted for renal impairment) has FDA approval for DPN and PHN.⁸ The risk-benefit profile of this drug is similar to gabapentin, with the added benefit of sleep improvement. Common side effects include dose-dependent somnolence, dizziness, and peripheral edema.⁶Its potency is greater than that of gabapentin so lower dosages are prescribed; however, actual symptom alleviation typically occurs at around 300 mg.¹² In the instance of PHN, patients may respond to lower dosages (eg, 150 mg/d).¹² Monitoring the complete blood count is reasonable owing to the potential for a lowering of the platelet count with this agent.

In a 2007 Cochrane review of lamotrigine for neuropathic pain, only seven RCTs were designed such that they could be included in the analysis.¹³ The conclusion of this review was that there is not a sufficient volume of evidence to support the use of this drug for the treatment of neuropathic pain.13 Furthermore, a rare but serious skin rash associated with lamotrigine is another deterring factor from further study of this agent.⁶

Antidepressants

The use of antidepressants to treat neuropathic pain predates the introduction of AEDs, and, historically, they often have been the first agent prescribed. Given some of the side-effect profiles, discussed below, extra vigilance is necessary in elderly patients using these medications.

Tricyclic antidepressants (TCAs) have been studied most and are known to produce significant neuropathic pain relief.¹⁴ TCAs inhibit norepinephrine and serotonin reuptake, thus affecting the transmission of pain. Furthermore, their agonistic effects on H1 receptors are thought to augment sedation and analgesia.¹⁵ TCAs are often associated with anticholinergic side effects such as dry mouth, urinary retention, and constipation, rendering the drugs difficult, and sometimes unsafe, for use in the elderly population. Furthermore, TCAs are contraindicated in the setting of cardiac conduction abnormalities or recent adverse cardiac events. Hence, a baseline electrocardiogram is recommended prior to starting TCAs in the elderly.¹⁵

In trials using newer-generation serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine, these agents have been found to be effective in the treatment of neuropathic pain.^1,14,16 Furthermore, these agents are generally believed to be safer than TCAs in the elderly population.¹ One particularly worrisome adverse effect associated with SNRIs is the potential for hyponatremia. Therefore, older patients must be aggressively monitored for signs of altered mental status, including confusion or lethargy. In addition, routine electrolyte checks are advised throughout the duration of SNRI therapy.1 Of the two SNRIs, the risk for drug-drug interaction appears to be lowest with venlafaxine.¹ In contrast, limited data exist on the role of selective serotonin reuptake inhibitors (SSRIs) and their benefits, if any, for treating neuropathic pain.¹⁴

Overall, it appears that there is good evidence for the effectiveness of antidepressants in treating neuropathic pain, especially in the cases of amitriptyline and venlafaxine.¹⁴ In the older individual, lower starting and lower maintenance dosing schedules should be targeted. It should be noted that in the case of amitriptyline, there is a small increased risk of sudden cardiac death when prescribed at doses greater than 100 mg daily.¹ On the other hand, it is encouraging that if a patient does not respond to one type of antidepressant, he/she can often effectively be switched to another type with success.¹⁴

In summary, if the practitioner decides to prescribe amitriptyline or related agents for the treatment of neuropathic pain in an elderly patient, then minimal possible dosing should be employed. If, after a few weeks, there is no alleviation of symptoms, switching to venlafaxine could be considered.¹⁴ Alternatively, given the more benign side-effect profile and less drug-drug interaction of SNRIs, which are key issues in the elderly, then the practitioner may want to consider starting therapy by prescribing a SNRI and only switching to a TCA as a last resort. Ultimately, DPN and PHN are the two types of peripheral neuropathy that respond best to antidepressants.¹⁴ On the other hand, HIV-related neuropathy has not shown improvement with any of the antidepressants.¹⁴

Antidepressants versus Anticonvulsants

Previously, it was widely held that TCAs are more efficacious than anticonvulsants, primarily as determined by indirect comparisons.⁷ However, in a meta-analysis in 2008 by Chou et al⁵ (when using an end point of neuropathic pain relief), head-to-head comparison trials revealed no difference between the two drug classes.

Clinical Guidelines

The neuronal dysfunction that leads to neuropathic pain likely occurs during the acute portion of the primary illness, so early initiation of therapy is advisable, no matter what drug is chosen.¹⁰ The characteristics and intensity of neuropathic pain in the elderly patient should not dictate which class of drugs to prescribe.¹ Rather, paramount in the decision-making process should be the goal of minimizing adverse effects and maximizing the overall tolerability of the drug.¹

Other Alternatives

No RCTs of AEDs and antidepressants have reported 100% resolution of symptoms. In fact, most data approximate an average of 35-65% alleviation of symptoms. This observation emphasizes the large variability to be expected in patient response. Thus, when optimal pain relief has not been achieved on monotherapy with one of the first-line therapeutic options, then other agents may need to be added to the treatment regimen.1 In the case of PHN, either topical nonsteroidals or topical lidocaine have been shown to provide relief.¹⁰ Furthermore, topical lidocaine 5% patches appear to have no systemic side effects when restricted to no more than four patches in a 24-hour period.¹⁰ The inhibition of cyclo-oxygenase by nonsteroidal anti-inflammatory drugs (NSAIDs) makes them attractive adjuncts, especially when used in the topical formulations.¹⁰ However, given the risk of gastrointestinal bleeding, renal impairment, edema, and hypertension, long-term oral NSAIDs are relatively contraindicated in the elderly population. Tramadol is a centrally acting analgesic that binds to mu-opioid receptors. It may also inhibit reuptake of norepinephrine and serotonin.¹⁷ The adverse-effect profile of tramadol is reminiscent of opioid agents and includes dizziness, constipation, nausea, and somnolence.

Future Directions

A recent RCT evaluated smoked medicinal cannabis for end-stage HIV neuropathy and concluded that there is a clinically significant reduction in pain symptoms in patients who smoked cannabis.¹⁸ Nabilone and dronabinol are two cannabinoids approved by the FDA for clinical use. Nabilone has shown modest benefit in neuropathic pain, but CNS depression and addiction are key issues to be worked out prior to endorsing their use.¹⁷ Another drug that appears to work by promoting regeneration of peripheral nerves and enhancing vibratory perception is L-acetylcarnitine.¹⁹ Its analgesic effects, along with relative lack of side effects, make it an attractive long-term adjuvant to first-line therapeutics. Similarly, alpha lipoic acid demonstrates a significant reduction in neuropathic pain when provided intravenously at a dose of 600 mg daily for 3 weeks.²⁰ Unfortunately, the long-term evaluation of efficacy of any of these compounds is yet to be published.²⁰

Conclusion

The goal of this article is to discuss neuropathic pain with a focus on interventions for the LTC population. Among published guidelines, literature reviews, algorithms, and meta-analyses, antidepressants and antiepileptics are consistently touted as first-line agents. Hence, it is the tolerability profile determined on a patient-by-patient basis that should dictate which agent to invoke. Furthermore, other agents such as opioids, topical NSAIDs, topical capsaicin, topical lidocaine, and cannabinoids may be considered as adjuvant therapies with some potential promise.

Dr. Katz has been an investigator in a rheumatoid arthritis study funded by UCB Pharma. Dr. Tehrani reports no relevant financial relationships.

Drs. Tehrani and Katz are in the Division of Rheumatology, The George Washington University, Washington, DC.

References

1. Haslam C, Nurmikko T. Pharmacological treatment of neuropathic pain in older persons. Clin Interv Aging 2008;3(1):111-120.

2. Bustacchini S, Corsonello A, Onder G, et al. Pharmacoeconomics and aging. Drugs Aging 2009;26(suppl 1):75-87.

3. Planton J, Edlund BJ. Regulatory components for treating persistent pain in long-term care. J Gerontol Nurs 2010;25:1-8.

4. Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc 2007;107(10 suppl 6):ES39-ES48.

5. Chou R, Carson S, Chan BK. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: Discrepencies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med 2008;24(2):178-188. Published Online: December 17, 2008.

6. Vinik A. Clinical review: Use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Endocrinol Metab 2005;90(8);4936-4945. Published Online: May 17, 2005.

7. Moulin DE, Clark AJ, Gilron I, et al; Canadian Pain Society. Pharmacological management of chronic neuropathic pain-consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12(1):13-21.

8. Quilici S, Chancellor J, Löthgren M, et al. Meta-analysis of duloxetine vs pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol 2009;9:6.

9. Hayashida K, Eisenach JC. Multiplicative interactions to enhance gabapentin to treat neuropathic pain. Eur J Pharmacol 2008;598(1-3):21-26. Published Online: September 17, 2008.

10. Galluzzi KE. Managing herpes zoster and postherpetic neuralgia. J Am Osteopath Assoc 2009;109(6 suppl 2):S7-S12.

11. Wiffen PJ, McQuay AJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2005;(3):CD005452.

12. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009;(3):CD007076.

13. Wiffen PJ, Rees J. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev 2007;(2):CD006044.

14. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007;(4):CD005454.

15. Maizels M, McCarberg B. Antidepressants and antiepileptic drugs for chronic non-cancer pain. Am Fam Physician 2005;71(3):483-490.

16. Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: Systematic review of randomised trials. BMC Neurol 2008;8:29.

17. Staud R. Pharmacological treatment of fibromyalgia syndrome: New developments. Drugs 2010;70(1):1-14.

18. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: A randomized, crossover clinical trial. Neuropsychopharmacology 2009;34:672-680. Published Online: August 6, 2008.

19. Chiechio S, Copani A, Nicoletti F, Gereau RW 4th. L-acetylcarnitine: A proposed therapeutic agent for painful peripheral neuropathies. Curr Neuropharmacol 2006;4(3):233-237.

20. Mijnhout GS, Alkhalaf A, Kleefstra N, Bilo HJ. Alpha lipoic acid: A new treatment for neuropathic pain in patients with diabetes? Neth J Med 2010;68(4):158-162.