Neuropathic Pain in Elderly

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1		Claudia Loreti	+ 2904 word(s)	2904	2021-05-12 08:12:22	\|
2	format correction	Peter Tang	Meta information modification	2904	2021-05-19 04:52:35	\|

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics11040613

Neuropathic pain due to a lesion or a disease of the somatosensory system often affects older people presenting several comorbidities. Moreover, elderly patients are often poly-medicated, hospitalized and treated in a nursing home with a growing risk of drug interaction and recurrent hospitalization.

neuropathic pain aging personalized medicine

1. Introduction

Neuropathic pain in the elderly is a common but unrecognized clinical issue. In the general population, recent surveys reported prevalence rates of between 6.9% and 10% for neuropathic pain ^[1], while data on the prevalence among older people are scarce. Due to cognitive impairment and concurrent illnesses, older people often underreport pain, especially to primary care physicians ^[2]. Moreover, aging reveals anatomical and biological changes, such as loss of neurons in the central nervous system, increased number of abnormal or degenerating fibrers, slower conduction velocity, altered endogenous inhibition and decreased function of neurotransmitters ^[3]^[4]^[5]. These anatomical changes are involved in the altered perception of neuropathic pain among older people. Finally, difficulties in conducting questionnaires among patients with dementia or visual and hearing disorders could delay the diagnosis of neuropathic pain.

Despite the age-related organic changes, both younger and older people might be affected by the same chronic diseases which carry on the common manifestations of neuropathic pain. This explains why classification of different types of neuropathic pain and first clinical approach do not differ between all ages.

If reported, pain mostly results from the stimulation of pain receptors. This kind of pain is called nociceptive pain, and its treatment is based on common analgesic medications ^[3]^[6]. Neuropathic pain is often persistent and more difficult to treat than nociceptive pain. Sometimes more than one medication is needed to achieve pain relief ^[7]^[8]^[9]. Although persistent pain is reported more often by seniors living in nursing homes than by persons living independently ^[10]^[11], recent studies demonstrate that there is no association between chronic pain and cognitive or functional status. Perhaps pain is not a feature of aging, but it may contribute to functional deterioration ^[12].

Sometimes, there are mixed pain syndromes that include nociceptive and neuropathic pain, such as cancer-related pain. Chronic diseases related to neuropathic pain, such as diabetes mellitus, are very common in the general population. Moreover, aging is associated with a persistent inflammation state that carries high susceptibility not only to chronic morbidities but also to peripheral nerve sensitization. Considering that painful diabetic neuropathy affects one third of adults with diabetes mellitus ^[13], the prevalence of the neuropathic component of pain among older people should be higher than expected.

The pharmacological treatment of neuropathic pain in the elderly is often suboptimal ^[14]. Comorbidities may influence the correct management of chronic pain and its consequences among older people ^[3]. Some clinical conditions, such as chronic kidney disease or heart failure, require a careful evaluation of types, times and dosage of pharmacological therapies. Elderly, or persons generally affected by more than one illness, usually require chronic and multiple medications, which might interact with medication for persistent pain. This requires great attention from physicians; in fact, polypharmacy is associated with several adverse outcomes, including hospitalization, length of hospital stay and mortality. In a previous study, we described that polypharmacy (5–9 drugs) and excessive polypharmacy (≥10 drugs) are factors associated with polypharmacy status, including not only co-morbidity but also specific symptoms and age ^[15].

In literature, we classified the elderly into three groups: youngest-old, ages 65 to 74 years; middle-old, 75 to 84 years; and oldest-old, ≥85 years ^[16]. For the focus on very old people, who are often affected by malnutrition, sarcopenia and higher risk of falls, a different approach in the treatment of pain is required. In these cases, physicians should prefer lower dosages, alternative medications or nonpharmacological therapies.

Persons affected by neuropathic pain often report mood disorders and sleep disturbances as consequences of persistent pain. Lower satisfaction with life is common in patients with neuropathic pain, not only due to the symptoms of pain but also due to the impact of its consequences on the quality of life ^[17]^[18]. Neuropathic pain might affect the quality of life as much as other chronic illnesses, such as coronary artery disease or poorly controlled diabetes mellitus ^[19]. Depression is a common consequence, particularly if associated with higher pain intensity ^[17]. Concerning the elderly, untreated persistent pain is associated with poor sleep, social isolation, functional deterioration and increased risk of falls ^[20]. Anticonvulsants, such as pregabalin and gabapentin, as a first line therapy for neuropathic pain have are effective also for sleep disturbances.

2. Clinical Evaluation and Diagnosis

In order to choose the most appropriate treatment, it is important to know and identify the underlying mechanisms involved in pain perception (Table 1). Pain problems that arise from the stimulation of pain receptors give rise to nociceptive pain; generally, these receptors are stimulated as a result of trauma, inflammation and/or mechanical deformation. Examples may include ischemia, arthritis, infection, trauma and tissue distortion. Neuropathic pain results from pathophysiologic processes occurring in the central or peripheral nervous system. Some examples are diabetic neuralgia, posttraumatic neuralgia and postherpetic neuralgia. Central sensitization, a phenomenon resulting from synaptic plasticity, is important for the maintenance of chronic pain, both neuropathic and nociceptive. Increasing evidence suggests that this phenomenon is in part due to neuroinflammatory processes, involving both the peripheral and central nervous systems ^[21]. Moreover, there are other mechanisms of pain, including mixed nociceptive and neuropathic syndromes and pain syndromes of unknown mechanisms. Finally, it is important to consider the presence of psychological factors that may influence pain perception.

Table 1. Pain pathomechanism.

Type of Pain	Nociceptive Pain	Neuropathic Pain	Central Sensitization
Pathological mechanism	Results from trauma, inflammation and/or mechanical deformation	Central or peripheral nerves damage	Absence of any nerve damage, trauma or inflammation
Common syndromes	Osteoarthritis Rheumatoid arthritis Tendonitis Neck pain Back pain Inflammatory disease	Diabetic neuropathic pain (DNP) Post-herpetic neuralgia (PHN) Chemotherapy induced neuropathy (CIPN) Post-operative neuropathic pain (PONP) Complex regional pain syndrome (CRPS) Compressive neuropathic pain (CNP) Post-amputation neuropathic pain (PANP) Central post-stroke pain syndrome (CPSP) Multiple sclerosis (MS) Spinal cord injury (SCI) Trigeminal Neuralgia (TN)	Chronic fatigue syndrome Fibromyalgia Restless leg syndrome

3. Pharmacological Management

The management of neuropathic pain is based on a multidisciplinary team assessment ^[22], especially in the elderly, who are often affected by multiple diseases that require a more complex assessment than younger people. Pain relief and the improvement of the consequences derived by persistent pain should be the main goals for those who approach this issue. Guidelines for neuropathic pain management suggest a substantial drug approach with any distinctions based on different ages. In these circumstances, pharmacologic therapies represent the first step in pain treatment (Table 3).

Table 3. Pharmacological management of neuropathic pain.

Anticonvulsivant	Starting Dose	Elderly Point
Gabapentin	100 to 300 mg once to trice/day p.o.	Increased risk of serious, life-threatening and fatal respiratory depression and accidental injuries (e.g., falls).
Pregabalin	25 to 150 mg/day in 2 to 3 divided doses	Initiate therapy at the lowest dose. Increased risk of serious, life-threatening and fatal respiratory depression and accidental injuries (e.g., falls), visual impairment.
Carbamazepine	200 to 400 mg/day	Beers Criteria: potentially inappropriate medication, use with caution. Causes or exacerbates SIADH and hyponatremia. Increased risk of psychiatric effect; may activate latent psychosis, confusion, or agitation.
SNRIs
Duloxetine	60 mg once daily	Beers Criteria: potentially inappropriate medication, use with caution. Causes or exacerbates SIADH and hyponatremia. Increased fall risk, with serious consequences. Antidepressants are associated with an decreased risk of suicidal ideation and suicidal tendencies in older adults ≥65 years of age.
Venlafaxine	37.5 mg or 75 mg once daily	Beers Criteria: potentially inappropriate medication, use with caution. Causes or exacerbates SIADH and hyponatremia. Increased risk of blood pressure elevation. May be associated with an increased risk of bone fractures. Antidepressants are associated with a decreased risk of suicidal ideation and suicidal tendencies in older adults ≥65 years of age.
TCAs
Nortriptyline	10 to 25 mg/day	Beers Criteria: potentially inappropriate medication, use with caution. Causes or exacerbates SIADH, hyponatremia, sedation and orthostatic hypotension.
Amitriptyline	10 to 25 mg once daily at bedtime	Beers Criteria: potentially inappropriate medication, use with caution. Causes or exacerbates SIADH, hyponatremia, sedation and orthostatic hypotension. Antidepressants are associated with a decreased risk of suicidal ideation and suicidal tendencies in older adults ≥65 years of age.

Older people are often affected by more than one disease. Physicians should pay attention to drugs for chronic illnesses that have pharmacological interactions with pain medications. Metabolism in the elderly is compromised by physiological decrease in liver, kidney and heart function. Frailty and multimorbidity require a single-person strategy for pharmacological interventions. Starting with low doses and titrating very slowly are recommended. Some analgesic medications should be administered with caution in acute and long-term pain therapy. For example, NSAIDs (non-steroidal anti-inflammatory drugs) have several adverse reactions, including GI bleeding, renal impairment and platelet dysfunction; therefore, their use should be limited among older people.

Chronic pain is less manageable than acute pain. Patients affected by persistent pain should be aware that complete relief from neuropathic pain is difficult to achieve. For these reasons, pharmacological treatment often needs adjustments. It is necessary to review frequently the classes of medications, dosages, patterns and side effects to obtain an effective recovery. If a specific class of drugs is not efficacious, the use of an alternative one may be more favorable. Nonpharmacological strategies, such as cognitive behavior interventions, may be useful in combination with drugs or an alternative to them in long-term pain management. To avoid adverse effects of or addiction to the drugs, a nondrug intervention should be also considered as a bridge to other kinds of treatment.

Patients with persistent pain often experience sleep deprivation and mood disorders. Pain may lead to difficulties in initiating and maintaining sleep. As a result, sleep deprivation decreases the pain threshold and improves anxiety and depressed mood ^[22]. Nondrug assessment, including sleep restriction therapy, may help to improve the patient’s quality of life. Social isolation and loss of autonomy might complicate the pain assessement. Then, a mixed approach based on pharmacological interventions, cognitive behavioral therapies and rehabilitation is required. In the elderly, more so than in younger people, physiotherapists and occupational therapists assume an important role in the process of care.

4. Surgical Therapies

Radiculopathy surgery, especially lumbar surgery, is currently considered a safe and effective intervention even in the elderly population ^[23]. Indeed, age is not an independent exclusion factor, but it is important to consider preoperative risk, which considers not only age and medical comorbidities but ensures a multidimensional assessment of the elderly. Efficacy, in terms of satisfaction and pain control after therapy, is similar both in the elderly and younger people. Given the increased prevalence of degenerative spinal disease associated with the aging of the general population, it is important to consider this type of treatment in the elderly as well ^[24].

Microvascular decompression is an effective procedure in the treatment of trigeminal neuralgia; this treatment has been shown to be as effective in the elderly as in the young. It is unclear whether it is this approach is riskier in the elderly than in the young; however, an increase in cases of death, stroke and thromboembolism has been noted in the former group ^[25].

Spinal Cord Stimulation (SCS) is an invasive neuromodulatory technique that should be considered in chronic pain that does not respond to conservative approaches and in particular when it is localized to one extremity. Its mechanism of action is still unclear. It has been hypothesized that it may regulate cytokines imbalance ^[26], but further studies are needed to ascertain that. At the state of the art, a multifactorial mechanism of action seems most likely. SCS has been shown to be effective in some types of chronic neuropathic pain, primarily in failed back surgery syndrome, but also in multiple sclerosis pain and complex regional pain syndrome. However, it may be less effective in postherpetic neuralgia and phantom limb syndrome ^[27]. Recent studies have shown how important it is to consider the complexity of pain and the possible overlap of multiple pain syndromes in the elderly patient when choosing a treatment ^[28].

More recently, dorsal root ganglia stimulation (DRGS) is being increasingly used as a first-line neuromodulation technique or in cases of SCS failure. Some data seem to show better outcomes than SCS, while maintaining comparable risks and complications of both techniques ^[29]. However, further studies are needed, especially in the elderly population to evaluate any differences in terms of efficacy and safety.

Nerve decompression surgery is a technique that aims to restore the function of compressed nerves. It has been hypothesized to be effective in some cases of diabetic peripheral neuropathy and superimposed focal nerve entrapment ^[29]; however, due to the presence of conflicting data, its use is not yet recommended for DNP ^[30].

Sympathetic nerve block (SNB) is a surgical technique that requires the presence of experienced staff and can achieve partially benefit in terms of reducing neuropathic pain. At present SNB is being used effectively to reduce pain in CRPS. It is not yet clear what the role may be in PHN ^[31]. In some cases, it has been hypothesized to be involved in DNP ^[32] and in PANP treatment ^[33].

Dorsal root entry zone (DREZ) has been described in the literature as a possible treatment for patients who have failed to respond to more conservative modes of therapy; however, at present, there are no studies indicating safety and efficacy in elderly patients.

5. Other Therapies

At the state of the art, pharmacologic therapies are the mainstay of neuropathic pain management; however, some nonpharmacologic therapies may be effective in adjuvating pharmacologic co-treatment ^[34]. The main non-pharmacological strategies include lifestyle modifications, physical therapies, surgery and microsurgery, cognitive-behavioral therapy and vaccines.

5.1. Lifestyle Modifications

Lifestyle modifications can be numerous and vary depending on the specific etiologic scenario; however, they are applicable wherever it is possible to correct an inappropriate behavior or an exposure to a modifiable risk factor, such that there is a significant impact in reducing the degree of pain, disease progression or quality of life.

5.2. Physical Therapies

Physical therapies that have demonstrated efficacy in the management of neuropathic pain include the application of superficial and deep level heat and cold, fluid therapy, whirlpool therapy, physical massage, TENS, transcranial magnetic stimulation and transcranial electrical stimulation.

Transcutaneous electrical nerve stimulation (TENS) has been shown to be one of the most effective physical therapies in the treatment of neuropathic pain; for instance, it is used to treat diabetic neuropathy that does not tolerate first-line therapies. Although there are not numerous studies, it has been shown in diabetic neuropathy to reduce pain ^[35]. In addition, TENS therapy has demonstrated effectiveness in treatment following spinal cord injury, acute, subacute, and chronic postoperative pain, and radiculopathy. Currently, the efficacy of TENS is believed to depend on intensity, frequency, duration and number of sessions. In elderly patients, when applied during exercise, TENS is well tolerated and can generate short-term hypoalgesia which may have beneficial short-term effects ^[36].

Transcranial direct current stimulation has been demonstrated that in some cases there is a reduction in pain intensity in the elderly ^[37]^[38]; however, its use may be limited by practical and regulatory issues.

Transcranial Magnetic Stimulation (TMS) has been shown to be a safe procedure and may be effective in some conditions ^[39]; studies have demonstrated pain reduction in chronic unilateral neuropathic pain from thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus lesion or trigeminal nerve lesion ^[40].

5.3. Rehabilitation

Rehabilitation is a widely employed element in the management of neuropathic pain ^[6]; the goal of this therapy is to adjuvate the pharmacological treatment, potentiating it, reducing the dose necessary to achieve the effective analgesic effect and improving the functionality and quality of life of the subject ^[41]. Although a fundamental element of rehabilitation is physical exercise, there are still no conclusive data of its effectiveness in neuropathic pain; however, the most studied area is diabetic and pre-diabetic neuropathy. Further research is needed to understand the role of exercise in sensory nerve disorders. The effectiveness of exercise depends on the type of underlying neuralgia ^[42]^[43].

5.4. Acupuncture

It has been demonstrated that acupuncture can be an effective therapeutic option in reducing the pain of diabetic neuropathy and chronic low back pain; however, it is still unclear how effective it is, even though safe and generally well tolerated, in other neuropathic pain syndromes such as post-stroke and post-herpetic neuralgia ^[33]. Acupuncture has been shown to be safe in many studies, although its efficacy compared to drug therapy has not yet been unequivocally demonstrated ^[44] and in some cases has proven ineffective. In elderly patients, it appears to be a good adjuvant therapy during the rehabilitation phase following acute disease, improving pain, quality of life and sleep and overall well-being ^[45].

5.5. Cognitive Behavioral Therapy

Cognitive behavioral therapy is used in the treatment of several conditions, both in young and older adults; the strongest evidence concerns anxiety disorders, somatoform disorders and bulimia. In addition, generalized anxiety disorder is not uncommon in the elderly ^[46]. Therefore, over the years more and more attention has been paid to the role and importance of psychological and social factors in chronic pain. This has contributed to the development of approaches such as cognitive behavioral therapy. Although the efficacy of this approach in the treatment of neuropathic pain is not universally validated, it is believed that given its low cost and safety, it is still a viable alternative in the management of neuropathic pain.

5.6. Varicella-Zoster Virus Vaccine

Age is the major risk factor for the development of herpes zoster and postherpetic neuralgia. The vaccine reduces the risk of herpes zoster incidence in the elderly population ^[47]. In addition, it generates a cell-mediated immunity response comparable to exposure to the Varicella-Zoster virus itself, which in turn is associated with a lesser severity of the course and incidence of postherpetic neuralgia ^[48].

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