Painful diabetic neuropathy: A practical guide for primary care providers

Transcription

1 Painful diabetic neuropathy: A practical guide for primary care providers Abstract Painful neuropathy is one of the more common and difficult to manage complications of diabetes encountered in primary care. The incidence of painful neuropathy associated with diabetes is expected to parallel the dramatic projected prevalence in diabetes over the next 40 years. This irreversible pain process inflicts a heavy burden on the quality of life and functional status of

2 patients, and frustrates the provider-patient relationship. This is due to the heterogeneous and evolving presentation of painful diabetic neuropathy, the poor response to current treatment options, and failure to individualize and adjust treatment plans. A thorough understanding of the scope, diagnosis, and management of painful diabetic neuropathy is essential for primary care providers. 1

3 Introduction Painful diabetic neuropathy (PDN) is a common chronic disorder encountered in primary care. Defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system, neuropathic pain raises the burden of caring for diabetic patients. 1 Being subjective, the nature of pain is heavily influenced by a patient s individual educational, cognitive, and emotional traits. Additionally, co-morbidities, advanced age, and poly-pharmacy commonly found in diabetic patients complicate the diagnosis and management of PDN. This condition is challenging to manage and carries significant morbidity, which is why providers should be familiar with its presentation, burden, and management. Scope of the problem Diabetes mellitus is one of the most common metabolic disorders in the United States and is increasing in incidence. If interventions are not undertaken to reduce the risk of developing diabetes the prevalence of this condition is expected to rise from 14%, estimated in 2010, up to as most as 33% of the adult population by Further, it is estimated that more than 50% of people who suffer from diabetes have or will develop some form of peripheral neuropathy. 3 Development of painful neuropathy may be independent of other symptoms (numbness, light touch distinction, etc.) and may not correlate with current blood glucose control. With a reported incidence of PDN at 16.2%, asking about extremity burning, stabbing, or pins and needles sensation should be routine questions to screen for painful neuropathy in diabetic patients. 4 Coupled with the projected incidence of diabetes, the incidence rate of PDN means that this condition will become commonplace in primary care. Awareness and recognition of PDN is essential because, once generated, neuropathic pain is irreversible. 2

4 Pain is not only an unwanted sensory perception for patients with diabetes, but also a cause of frustration and suffering. Alteration in the processing and regulation of neuropathic pain sensation is known to negatively affect the patient s overall health-related quality of life, and physical and emotional functioning. 5 Depending on severity and timing, PDN may impair a patient s performance at work, cause sleep disturbance, negatively affect activities of daily living, and lead to social isolation and lower emotional health. More than 60% of patients with poorly controlled PDN in a cohort study reported moderate to severe interference with daily activities. 6 Patients with chronic pain commonly suffer from major depression and anxiety disorders, which contribute to the morbidity of PDN and make pain management more challenging. Poorly controlled pain is known to affect medication compliance, increase the number of visits to clinicians, negatively impact the provider-patient relationship, lead to selfmedication and doctor-shopping, and misuse and abuse of pharmacologic and recreational drugs. Neuropathic pain also has a high societal cost accounting for nearly one fourth of the annual healthcare, disability and related costs spent on chronic pain in the United States. 7 Pathophysiology Pain is dependent on a complex sensory system that includes not only the generation of action potentials by the altered peripheral nerves but also on the inhibitory system, the patient s conscious perception of pain and emotional status. Neuropathic pain in diabetes ranges from being intermittent, persistent, or independent of stimulus, and is associated with abnormal sensory perception. It is characterized by progressive destruction primarily of peripheral small non-myelinated (C-type) and thinly myelinated (A-delta-type) fibers responsible for pain and temperature sensation. Although the genesis of pain during the different stages of diabetes is not completely understood, elevated plasma glucose levels are implicated in nerve injury and loss. 8 3

5 The ensuing release of inflammatory chemicals (e.g. histamine, prostaglandings, and bradykinin) around surrounding small non-myelinated and myelinated fibers and the upregulation of sodium and calcium channels by injured afferent nociceptors result in easily excitable fibers, an increased response to stimulus, continued sensitization, and spontaneous ectopic action pontentials. 9 These changes and the partial denervation of peripheral tissues are believed to account for most of the positive signs of neuropathy such as ongoing pain, allodynia (pain evoked by a non-painful stimulus) and hyperalgesia (increased pain evoked by a painful stimulus). 10 Chronic dysfunction of these ascending pain pathways is further complicated by decreased effectiveness of spinal dorsal horn inter-neurons, which release serotonin and norepinephrine integral in modulating the concentration and activity of gamma amino butyric acid by second-order neurons responsible for descending analgesic messages. Therefore, chronic PDN is a result of problems of the transmission and inhibition of pain. Detection and Diagnosis The diagnosis of neuropathic pain is based primarily on detailed history and physical examination findings. Pain is typically polymorphous and usually occurs with the onset of sensory deficits. Thus, in describing the quality of pain, patients use positive and negative adjectives such as tingling, shooting, stabbing, shock-like crushing, burning, searing, cold or numb. These symptoms of PDN (Table 1) are diverse, spontaneous or evoked, varied in intensity, intermittent or continuous, and disabling. Depending on the degree of C-fiber density, PDN can present with or without sensory deficit or primarily as sensory loss. Over 80% of patients complaining of stocking-glove pattern sensory symptoms have reduced intra-epithelial nerve fiber densities, which correlate with the duration of diabetes. 11 4

6 The most common and long-lasting presentation of PDN is a spontaneous, superficial burning sensation in the feet, which typically increases in severity at night and is partially relieved by movement. The longest nerve fibers are affected distally first in this condition, with pain symptoms initially affecting the lower extremities symmetrically and progressing upwards to later involve the upper limbs and trunk. Patients who at first complain of an inability to have anything touch their feet may report pain or sensory deficits in their upper legs or hands. Furthermore, since the nervous system s perception and inhibition of pain is dynamic, the signs and symptoms of neuropathic pain may change over time. Noting the progressive nature of diabetes and the fact that patients often have multiple morbidities means that patients may experience a number of different symptoms. This may result in confusion for the clinician and frustration for the patient. For example, patients often have difficulty understanding why their feet are numb and burn at the same time. Providers caring for diabetic patient should also be aware of conditions that mimic PDN and recognize signs and symptoms not typical of this condition. In taking a careful history, providers should ask about familial neuropathic disorders, metabolic and autoimmune disorders, HIV status and testing, current and past alcohol and intravenous drug use, medications that may cause neuropathies (e.g. isoniazid, fluoroquinolones, and vincristine), cancers and treatments for them, and vitamin excesses and deficiencies. This is important because diabetic patients may also have treatable causes of neuropathic pain. At the same time, providers should be wary of attributing atypical signs and symptoms to diabetic changes and refer patients for further neurology workup. Following are complaints unlikely to be due to PDN: sudden, asymmetric focal deficit (e.g. foot drop); rapid progression of pain severity; cranial nerve involvement, 5

7 although this can occur very late in PDN; and radiating pain from osteoarthritis or rheumatoid arthritis. To assess the type and degree of neuropathic changes in diabetic patients, providers should perform a thorough physical examination. This may reveal concurrent conditions responsible for pain, such as swollen painful joints of arthritis. Patients with diabetic neuropathies are typically, but not always, grossly weaker distally than proximally. Providers should take into consideration the fact that strength examination may be limited by pain and be aware of how much pressure they are exerting and where they touching the patient. Deep tendon reflexes are expected to be normal or decreased as nerve damage progresses. So findings of hyperreflexia or sudden areflexia are incompatible with diabetic neuropathy and warrant a neurology referral for possible spinal cord lesions or amyotrophic lateral sclerosis. Sensory examination is critical in assessing pain distribution and response to innocuous and painful stimulus. Monofilament testing has been shown to be an effective way of assessing sensory loss secondary to diabetic nerve damage and can be used as an indirect marker of PDN in patients complaining of burning sensation. However, it is important to note that pain may be independent of numbness. Along with allodynia and hyperalgia findings, providers can document whether light touch, pin prick, vibration sense and propioperception are diminished or absent. Although quantitative sensory testing to assess cold and warm sensation thresholds and a skin biopsy to quantify somatic intra-epidermal nerve fiber density have been shown to be useful in diagnosing PDN, these techniques are not accessible to most primary care providers and are not necessary for a clinical diagnosis. More practical is identifying the quality and intensity of pain and accounting for clinical findings that may affect patient functional status such as concurrent sensory loss, abnormal gait and reflexes, foot drop, and distal muscle weakness. 6

8 Management and Treatment Currently there are no approved treatments shown to be effective in restoring nerve function or regressing PDN. Overall, PDN is challenging to manage, and many patients have debilitating pain that may become refractory to existing treatments. As such, the main goals in the care of patients with PDN are pain control and improving quality of life. To do this, clinicians need to first determine the type and extent of pain and associated deficits that patients have. The commonly used 11 point ordinal pain scale is useful in establishing a baseline from which response to treatment can be assessed. Most patients present with moderate pain, and current medications on average reduce severity by 30% to 40%, often in less than 50% of patients. 7 Thus, a reduction of 2 points from baseline may provide a clinically meaningful reduction. Reassessing pain and health-related quality of life frequently is vital after an appropriate treatment plan has been undertaken. In individualizing a treatment plan, providers need to consider multiple factors (Table 2), including patient expectations, the functional impact of PDN (e.g. degree of disability and depression), as well as ongoing evaluation, patient education and reassurance, and specialty referral. Providers should start by asking patients what medications they have tried before and what has or has not helped. There are many herbal and alternative therapies advertised in the internet and shared among patients. Asking about these is important because the use of alternative therapies may affect compliance and potentially interact with recommended treatments. Noting the impact that PDN has on independent functioning, measuring and monitoring functional status at baseline and during treatment should be integrated into a management plan. This is particularly important for older adults who may depend on caregivers for emotional support and help with activities of daily living. Finally, providers may need to 7

9 incorporate caregiver perceptions and stress as these may have a major effect on treatment decisions and patient provider interactions. The heterogeneous presentation of PDN and patient co-morbidities and expectations should be used by providers to guide treatment selection. Commonly used approved or recommended pharmacologic agents include amitriptyline, nortriptyline, gabapentin, pregabalin, duloxetine, tramadol, topical lidocaine, and opioids. Clinical studies typically use the number needed to treat (NNT) to relieve at least 50% of pain intensity as the measure of treatment efficacy. Although a meta-analysis of clinical trials evaluating current treatment options show that tricyclic antidepressants (TCAs) and opioids have the lowest NNTs, providers should be cautious in using this measure to base their treatment recommendations because it fails to account for quality of life measures and side effects. 12 For example, a recent meta-analysis indirectly comparing duloxetine vs. pregabalin and gabapentin failed to show significant differences between them in reducing the physical and emotional toll of PDN. 13 This finding and the lack of direct head-to-head comparison of different medications makes it difficult for providers to prioritize therapies based on efficacy, safety, and tolerability. Therefore, in selecting an agent for an individual patient with PDN providers should rely on their clinical experience, consider medications individually depending on a number of factors, including potential adverse effects, adequate trial time, treatment of co-morbidities (e.g. depression, sleep disturbances), drug-drug interactions, risks of misuse and abuse, and costs. Antidepressants A large number of clinical trials have found TCAs, which include amitriptyline and nortriptyline, to be efficacious and these agents have an established role in treating PDN. In addition, TCAs are useful in treating co-morbid depression and sleep disturbance, which are common in patients 8

10 with chronic pain. These agents modify the generation and sensation of pain by inhibiting serotonin and norepinephrine reuptake and blocking sodium channels. Low cost and once daily administration make these agents appealing for both clinicians and patients. However, anticholinergic adverse reactions (e.g. orthostatic hypotension, constipation, urinary retention, and dry mouth), sedation and confusion are common and may limit their use, especially in the elderly and patients with dementias. These side effects can be reduced by starting at a low dose of milligrams (mg) at nighttime. Clinicians should obtain a screening electrocardiogram for patients older than 40 years and be familiar with their patient s cardiovascular health because cardiac toxicity and conduction abnormalities are a concern with TCAs. Doses can be increased by mg every three to seven days, as tolerated, up to a maximum 150 mg dose. An adequate trial of TCA treatment can take upwards of six to eight weeks. Serotonin and norepinephrine reuptake inhibitors (SNRIs) have recently gained an inroad in PDN treatment plans because of lower adverse reactions. Like TCAs, SNRIs increase synaptic levels of these neurotransmitters enhancing the effect of descending analgesia signals. Duloxetine is the only agent in this class to have gained specific approval by the United States Food and Drug Administration (FDA) for the treatment of PDN. With a simple dosing schedule of 60 mg once daily, this agent is a good option for patients with PDN and concurrent major depression and generalized anxiety disorder. The most common side effects of duloxetine are nausea and an increase in blood pressure, which can be minimized by starting treatment at 30 mg/day for one week before increasing to 60 mg/day up to a maximum of 120 mg/day divided twice daily. Typically, two to four weeks at the maximum dose is required to assess treatment response. Gabapentinoids 9

11 Gabapentin and pregabalin have both been shown to be effective and common treatment options for patients with PDN symptoms. These drugs bind to voltage-gated calcium channels inhibiting the presynaptic neurotransmitter release implicated in ectopic peripheral pain. Although drug interactions are not common with gabapentin and pregabalin, dose-dependent dizziness and sedation are a concern due to their central nervous system effects. Careful titration of gabapentin starting at mg at bedtime with an increase of mg three times daily every three to seven days (maximum of 3600 mg/day) is required to reduce side effects and monitor response to treatment. Dosing for pregabalin, also approved by the FDA for PDN, is simpler, starting at 75 mg twice daily increasing to 300 mg/day every three to seven days as tolerated for a maximum of 600 mg divided into two or three doses. Both medications require dose reduction in patients with renal insufficiency. An adequate trial of treatment with pregabalin is shorter than with gabapentin, which can require two months or more. Providers and patients should be aware of the fact that gabapentinoids are not recommended to be taken within two hours after antacids because of reduced bioavailability. Topical Lidocaine A five percent lidocaine patch can be very useful in treating patients with localized allodynia neuropathy. Without substantial systemic absorption, the most common side effect of this option is local irritation. This topical treatment may be an ideal option for elderly or patients with multiple co-morbidities, in which adverse reactions and toxicities are concerning. Lidocaine blocks peripheral nerve sodium channels involved in spontaneous action potentials. There is no titration schedule and the maximum dose is three patches daily for a maximum of 12 hours. Four weeks is an adequate treatment trial for this option. Tramadol and Opioid Analgesics 10

12 Tramadol and oral and transdermal opioids have been proven efficacy in modulating neuropathic pain similar to TCA and antidepressants. However, because of their increased adverse reaction profile and risk of misuse and abuse, opioids are typically reserved as second line options primarily prescribed by neurologists and pain specialists. They offer relatively rapid pain relief, which makes them ideal for patients with constant pain, episodic exacerbations, or cases of severe PDN waiting for proper titration of another medication. Tramadol, with less risk of abuse, is a weak opioid µ-receptor agonist that also inhibits serotonin and norepinephrine, so caution should be used with concurrent SNRI use due to the risk of serotonin syndrome. Treatment with this drug typically starts at 50 mg once or twice daily and is increased by mg/day in divided doses every three to seven days, as needed, to a maximum of 400 mg/day. A 300 mg/day dose or lower should be maintained for patients older than seventy five years and those with liver dysfunction. Along with risks of misuse and abuse, concerns regarding long-term safety, including risk of compromised immune function (e.g. decreased lymphocyte macrophage progenitor proliferation and leukocyte migration) and hypogonadism, typically limit the use of opioids (e.g. morphine, oxycodone, methadone, levorphanol, and fentanyl) to refractory cases traditionally managed by pain specialists. Major adverse reactions of opioids include constipation, nausea, sedation and respiratory depression. Of these, constipation is a common problem necessitating stool softeners and close monitoring. All patients on long-term treatment develop physical dependence, so tapering dosages is important when discontinuing treatment. The usual starting dose in morphine equivalents is mg every four hours, as needed, and can be increased by mg/day in divided doses every three to seven days. By understanding the potential adverse reactions, cautions and required trial periods of the diverse treatment options for PDN, clinicians can select patient-specific single or 11

13 combination treatments. An appreciation of the severity and presentation of this condition in individual patients is critical when initiating symptomatic treatment. Frequent reassessment is required to monitor response to treatment, side effects, reaffirm realistic expectations, and ensure that patients remain partners in their care. This process will help reduce patient frustration, help with medication compliance, and assist primary care providers in determining when to consult neurologists or pain specialists on refractory or difficult to manage cases. Conclusion Despite the availability of multiple treatment options PDN is challenging to manage and on average the expected reduction in pain is limited to 30% to 40%, often in less than 50% of patients. Poorly controlled PDN is a significant source of morbidity and is associated with decreased quality of life, and physical and emotional functioning. The varied physical and emotional signs and symptoms of PDN require that providers be versed in diagnosing this condition and ruling out potentially treatable causes of peripheral pain. This is particularly important noting the projected prevalence of diabetes and the risk of developing PDN. Thus the impact of co-morbidities and the importance of frequently assessing response to treatment should be integrated into tailored treatment plans to ensure quality care. Recognizing the negative impact that uncontrolled pain has on the quality of life of patients, primary care providers have an opportunity to offer compassionate tailored care to patients with diabetes who develop painful neuropathy. References 1. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):

14 2. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: Dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Helath Metr. 2010;8: Aring AM, Jones DE, Falko JM. Evaluation and prevention of diabetic neuropathy. Am Fam Physician. 2005; 71(11): Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred PE, Benbow SJ. Chronic painful peripheral neuropathy in an urban community: A controlled comparison of people with and without diabetes. Diabet Med. 2004;21(9): Attal N, Lanteri-Minet M, Laurent B, Fermanian J, Bouhassira. The specific disease burden of neuropathic pain: Results of a French nationwide survey. Pain. 2011;152(12): Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai KS, Stacey B. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression and sleep. J Pain Symptom Manage. 2005;30(4): Turk DC. Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain. Clin J Pain. 2002;18: Perkins BA, Greene DA, Bril V. Glycemic control is related to the morphological severity of diabetic sensorimotor polyneuropathy. Diabetes Care. 2001;24(4): Devor M. Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res. 2009;196(1): Backonja MM, Stacey B. Neuropathic pain symptoms relative to overall pain rating. J Pain. 2004;5: Shun CT, Chang YC, Wu HP, et al. Skin denervation in type 2 diabetes: Correlations with diabetic duration and functional impairments. Brain. 2004;127:

15 12. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150(3): Quilici S, Chancellor J, Lothgren M, et al. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol. 2009;9:6. 14

16 Symptoms of Neuropathic Pain Trigger Spontaneous Pain Evoked pain Timing Permanent Paroxysmal Allodynia Hyperalgesia Quality Superficial = Burning Deep = Pressure-like Electric Shock Shooting-like Sharp/Stabbing Dynamic (soft skin brushing) Static (light pressure) Thermal (warm, cold) Table 1. Guide to understanding neuropathic pain phenomena. Hot Cold Pinprick Individualizing care of Painful Diabetic Neuropathy - Assess patient specific signs and symptoms and functional status - Determine patient goals and expectations - Consider co-morbidities and current medications - Initiate first-line therapy and set up titration schedule - Monitor adverse reactions and treatment response - Re-assess functional status and patient expectations - Switch/add-on therapy and refer to specialist if warranted Table 2. Guide of factors to consider when individualizing management of PDN 15