Diabetic neuropathy (DN) refers to symptoms and signs of neuropathy in a patient with Figure 1 Schematic diagram showing types of diabetic neuropathy. Core tip: Diabetic neuropathic pain is a common complication of diabetes and the most common form of neuropathic pain. In this review, we will. which allows users to download, copy and build upon published articles even for . antioxidants (9) diabetic central neuropathy and its underlying mechanisms have .. form of its onset, prevention, progression, and treatment in their patients.
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license, which allows users to download, copy and build upon published articles even for Chapter 7 Clinical Cases in Pediatric Peripheral Neuropathy symptoms include foot drop, claw toe, and muscle wasting in the hands. breakdown of neuronal axon, which define primary forms of this disease, CMT type 1 and. BACKGROUND AND OBJECTIVES: Diabetic neuropathy is a major cause of neuropathy, focusing on its classification, diagnostic investigation and treatment. . form with motor involvement in specific compression sites such as wrist me-. Editorial Reviews. About the Author. I am a husband, father, grandfather and lifetime contract This autoimmune form of thyroid disease that causes destruction of the thyroid gland resulted in my also . Peripheral Neuropathy e- chart: Full illustratedKindle Edition The Best Darn Hypothyroidism Ebook Download.
Correspondence to: Although pain is one of the main symptoms of diabetic neuropathy, its pathophysiological mechanisms are not yet fully known. It is widely accepted that the toxic effects of hyperglycemia play an important role in the development of this complication, but several other hypotheses have been postulated. The management of diabetic neuropathic pain consists basically in excluding other causes of painful peripheral neuropathy, improving glycemic control as a prophylactic therapy and using medications to alleviate pain. First line drugs for pain relief include anticonvulsants, such as pregabalin and gabapentin and antidepressants, especially those that act to inhibit the reuptake of serotonin and noradrenaline.
In addition, in diabetic states methylglyoxal is also involved in the formation of AGEs[ 74 ].
Diabetic neuropathic pain: Physiopathology and treatment
Calcium channels can also be misregulated in a diabetic condition, leading to an enhanced calcium influx in sensory neurons[ 75 ], what can deflagrate both substance P and glutamate release[ 76 ].
However, there was no translation of these results to patients in clinical trials[ 80 ]. A possible future target for pharmacological intervention over calcium channels has been proposed by Orestes and colleagues , which observed that glycosilation of Cav3.
Interestingly, the deglycosylation treatment with neuraminidase inhibits native calcium currents in nociceptors and completely and selectively reverses hyperalgesia in a pre-clinical model of type 2 diabetes[ 80 ].
Regarding the currents generated by activation of these Kv channels in primary afferents there are two main types: So, this down regulation can increase neuronal excitability and peptide release[ 83 ], which might also participate in hyperexcitability of peripheral nerves of diabetic subjects.
It is becoming increasingly recognized that glial cells play an important role in the pathogenesis of many diseases of the nervous system, including chronic pain states[ 85 ]. Glia comprises both macroglia including astrocytes, radial cells and oligodendrocytes and microglia cells, which are mainly responsible for maintain homeostasis, form myelin, and provide support and protection for neurons from both central and peripheral nervous system[ 85 ].
Activation of microglia occurs right after peripheral nerve injury, lasting for less than 3 mo, and is responsible for a production of several inflammatory mediators as cytokines, chemokines, and cytotoxic substances such as nitric oxide and free radicals, prompting to a pro inflammatory milieu[ 83 ]. Diabetes has impact on all glial cells of the spinal cord since persistent microglial activation was observed in streptozotocin-induced diabetic rats lasting from 4 wk[ 87 , 88 ] to 6 or 8 mo[ 61 , 89 ].
This microglial activation has been associated with sensorial changes and up-regulation of Nav1. Conversely, diabetes is associated with a reduction in glial fibrillary acidic protein i. Considering the potential of microglial activation in driving spinal sensitization, in the near future, drugs that target these cells may become an important therapeutic alternative in chronic pain control.
As already demonstrated in different neuropathic pain states, DNP may be a consequence of both peripheral and CNS changes[ 93 , 94 ]. It was well described that during DNP, primary afferents are sensitized, inducing dorsal horn hyperactivity and neuroplastic changes in central sensory neurons[ 93 ].
Among the factors that can lead to the hyperactivity of spinal neurons in diabetic neuropathy is the increased glutamate release from primary afferents in the spinal cord[ 96 , 97 ]. Moreover, spinal N-Methyl-D-aspartate NMDA receptor expression is augmented in this condition[ 98 ], generating increased and more frequent excitatory post synaptic currents in the lamina II[ 97 ].
Thus, it is plausible that augmented NMDA expression and glutamate release might contribute to spinal cord hyperactivity.
On the other hand, GABA B receptors seem to be downregulated in the spinal cord in diabetic neuropathy[ 98 ]. Considering the importance of central sensitization in the hypersensitivity associated with DNP, strategies that aim to control spinal neurons hyperexcitability are very useful in pain control in this condition, as will be discussed bellow.
Functional changes in pain processing areas in the CNS, besides the spinal cord, have been ultimately linked with DNP[ ], in a tight relation to increased peripheral input[ 93 , ].
Among these areas, marked changes in the thalamus, cortex and rostroventromedial medulla RVM have been reported in DNP patients and or experimental models. The ventral posterolateral nucleus VPL of the thalamus is the main receiving area of nociceptive stimuli that is processed in the spinal cord[ ].
Projection neurons reach the thalamus trough the spinothalamic tract STT , which represents a major ascending nociceptive pathway.
It has been demonstrated that in diabetic rats, these neurons present increased spontaneous activity, enlargement of the receptive field and augmented responses to mechanical noxious and innocuous stimuli. The hyperexcitability of STT neurons probably accounts to hypersensitivity to external stimuli and spontaneous pain[ 93 ], increased in primary afferents activity[ 93 , ] and to plastic changes in spinal neurons[ 93 ].
In addition, in studies that assessed brain imaging in diabetic rats it was reported increased activity not only at VPL, but also in different thalamic nuclei that control sensory-motor aspects[ ]. In diabetic patients, a recent study showed increased activation of diverse brain areas, including medial thalamus after application of noxious thermal stimuli in feet[ ]. Moreover, it has been described that DNP patients has a marked reduction in the levels of N-acetyl-aspartate NAA levels in the thalamus compared to painless diabetic individuals[ ].
It is important to point out that patients with brain disorders in which neuronal loss or dysfunction are involved have consistently decreases in brain NAA concentrations[ ]. Other clinical finding related to thalamus alterations in diabetic patients is that subjects with painful type 1 diabetic neuropathy presented increased thalamus blood flow, when compared with those without pain, which was considered to reflect higher neuronal activity[ ].
Likewise, in a model of type 1 diabetes, increased glutamate transmission was reported in the anterior cingulate cortex a brain area involved in the processing of the affective-motivational dimension of pain[ ]. The consequence of higher stimulation of this area by glutamate is suggested to be a sustained negative perception of affective component of pain[ ].
Changes in the endogenous pain control system have also been described in pre-clinical and clinical studies of DNP. The RVM is a structure that receives direct influences of periaqueductal gray matter, which is, in turn, affected by other structures, such as amygdala and hypothalamus[ ].
Three different populations of cells have been describe within the RVM: In diabetic animals, there is evidence of a reduction on the OFF cells and increase on the ON cells population. In addition, basal activity is augmented in ON cells, and reduced in OFF cells, in a resultant misbalance between pain facilitatory and inhibitory descending modulation in diabetic animals[ ]. After noxious mechanical stimulation in the periphery, there was no difference between diabetic and control ON cells activity.
Thus, the mechanical hyperalgesia detected in diabetic rats could be associated with OFF cells impairment and consequently reduction on descending inhibitory tone[ ].
Some studies have also addressed the levels of the main neurotransmitters of the endogenous pain control system in different areas of the CNS in diabetic rats, but they have shown discrepant results.
While some researchers found reduced release of norepinephrine in the spinal cord in diabetic rats[ ], others have described opposite findings[ ]. There is also evidence of diminished norepinephrine levels in supra spinal areas, such as brainstem and thalamus, but higher concentration in the cortex of diabetic animals[ ].
Additionally, impaired spinal opioid-induced release of serotonin 5HT has been demonstrated in diabetic rats, and this finding may be related to opioid hyporesponsiveness in experimental DNP[ ].
Increased norepinephrine and 5HT levels in the spinal cord, as well as, augmented expression of norepinephrine and 5HT in RVM neurons was also demonstrated in diabetic rats[ ].
Considering the facilitatory role of serotoninergic and noradrenergic descending modulation during chronic pain, these changes may probably account for enhanced pain during diabetic neuropathy[ ]. There is also clinical evidence for misbalance between excitatory and inhibitory neurotransmitters in the CNS of diabetic patients with positive symptoms of neuropathy. These changes may contribute to pain development in DNP, but further studies are necessary to determine their clinical significance.
DNP continues to represent a therapeutic challenge as its pathophysiology is not yet fully understood and pain relief is still unsatisfactory. The pharmacological treatments, with exception to those targeted to the glycemic control, are symptomatic, not focused on the pathophysiological mechanisms, limited by side effects[ 3 , ] and by the development of tolerance[ ].
A wide variety of drugs, used alone or in combination, has been shown to significantly reduce neuropathic pain compared with placebo in randomized controlled trials, but pain relief remains inadequate for most patients[ ]. Thus, the management of this condition basically consists of excluding other causes of painful peripheral neuropathy, improving glycemic control as a prophylactic therapy and using medications to alleviate pain[ ].
Despite of multimodal and multidisciplinary approaches to the treatment, the primary pathway is pharmacologically based[ ]. However, as pain relief is still suboptimal and challenging for clinicians[ 95 ], drugs from various pharmacological classes have been used and some of them are included in this review.
Pregabalin was the first anticonvulsant to receive approval from the Food and Drug Administration FDA for the treatment of postherpetic neuralgia, DNP[ , ] and neuropathic pain after spinal cord injury[ ]. Several clinical trials evaluating pregabalin in DNP showed efficacy in the management of this condition[ 3 , , ] with a number needed to treat NNT of 6.
In addition to its analgesic effects, pregabalin presents anxiolytic activity[ , ] and it has a beneficial effect on sleep and quality of life[ ], contributing, therefore, to improve the general condition of the patients.
The side effects include dizziness, somnolence, peripheral edema, headache and weight gain[ 3 ]. Some guidelines have also recommended gabapentin to treat DNP[ ]. Besides pregabalin, gabapentin is the only other anticonvulsant drug that demonstrated efficacy in the treatment of this condition[ ] with an NNT of 5.
Gabapentin and pregabalin have a similar mechanism of action and the first is licensed for neuropathic pain in the United Kingdom, but not in the United States[ ]. Some clinical trials have suggested that gabapentin and pregabalin present better analgesic efficacy than tricyclic antidepressants or opioids[ ] and other important aspects of these drugs include their tolerability and lack of serious toxicity[ ].
Antidepressants represent the first line drugs in DNP management. Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is rated level A for efficacy and is approved in the United States for the treatment of this condition.
Additionally, some clinical trials have pointed out the effectiveness of duloxetine in other chronic pain conditions, such as fibromyalgia and chronic musculoskeletal pain[ , ]. Moreover, in a 2-wk open-label randomized trial in diabetic patients poorly responsive to gabapentin, duloxetine was able to reduce the pain score to levels similar to those achieved with pregabalin[ , ].
Furthermore, analgesic efficacy of duloxetine in the treatment of DNP is maintained over a 6-mo period[ ], reinforcing its importance as a treatment option for this condition. The NNT for duloxetine varies from 1. Venlafaxine is also a selective serotonin and noradrenaline reuptake inhibitor, that predominantly inhibits serotonin reuptake at low doses and noradrenaline at higher doses[ ]. Venlafaxine was also shown to be effective in reducing pain intensity in diabetic neuropathic patients[ ], with an NNT between 2.
Tricyclic antidepressants can also be an alternative to treat DNP[ ]. Amitriptyline was shown to be as effective as gabapentin in a direct meta-analysis study[ ] and as duloxetine in a randomized, double-blind, crossover trial[ ].
Likewise, nortriptyline was reported as being as effective as gabapentin in attenuating neuropathic pain in a double-blind crossover trial enrolling diabetic patients[ ]. Tricyclic antidepressants are estimated to have an NNT of 1. The most common side effects related to the use of these drugs are dry mouth, postural hypotension, arrhythmias, cognitive impairment, constipation and urinary retention, which are more frequently observed after amitriptyline than nortriptyline treatment[ ].
Opioids are recommended to be used as second or third line treatment for DNP[ 3 , ]. One multicenter, randomized, placebo-controlled study reported the tramadol effectiveness to significantly improve scores on physical and social functioning ratings in patients with DNP, but beneath some side effects such as nausea, constipation, headache and somnolence[ ]. Morphine was also shown to be effective in reducing mean daily pain scores related to diabetic neuropathy and postherpetic neuralgia[ , ].
Moreover, results of clinical trials indicated that diabetic neuropathic patients experienced a significant reduction in pain intensity and an improvement on quality of life during oxycodone treatment, compared to placebo-exposed group[ , ]. Besides, oxycodone improved gabapentin but not the pregabalin effectiveness in promoting DNP relief[ , ]. The clinical evidence for the effectiveness of opioids in the control of DNP is corroborated by some pre-clinical data, which have reported the effectiveness of morphine[ , ] and buprenorphine[ ] in reducing thermal or mechanical hypersensitivity in DNP animal models.
There is also evidence that the anti-hyperalgesic effect of opioids is improved by the association with some drugs, such as the antidepressants amitriptyline, moclobemide and reboxetine[ ].
Tapentadol has been shown to be effective in the management of different types of chronic pain, including osteoarthritis knee pain, low back pain and DNP, with a tolerable safety profile[ , ]. Similar data were obtained in a recent clinical trial in diabetic neuropathic patients with moderate to severe pain, which experienced nausea However, further studies are necessary, specially controlled clinical trials, to determine the more efficacious, safe and successful combinations to be applied in the management of DNP[ ].
Capsaicin topical cream: Topical agents may be associated with fewer and less clinically significant adverse events than systemic agents[ ]. In addition, the possibilities of drug interactions are markedly reduced with the use of local treatments, which represent good options for patients with multiple medical problems[ ].
Diabetic neuropathic pain: Physiopathology and treatment
The capsaicin cream has been shown to be effective in the treatment of neuropathic conditions[ ] and is approved for topical relief of neuropathic pain[ ]. Capsaicin is the pungent component of hot chilli peppers[ 11 ] and an agonist of the transient receptor potential vanilloid 1. This receptor is a ligand-gated, nonselective cation channel, predominantly expressed on unmyelinated C nerve fibers[ ], which, after repeated exposure to topical capsaicin, are depleted of their content of substance P and other neurotransmitters[ , ].
The C fibers depletion and desensitization reduce painful stimuli transmission from peripheral nerves to the central nervous system[ ]. Some clinical trials have demonstrated the effectiveness of low-concentration from 0. Higher concentrations are not indicated because of desensitization of nociceptive sensory nerve endings, which may increase the risk of skin injuries in DNP patients[ , ].
Some adverse effects include itching, stinging, erythema, transient burning sensation and initial pain at the application site, that diminishes with repeated use[ , ], leading many patients to withdraw from the treatment[ , ]. Lidocaine patch: Lidocaine patches act as peripheral analgesics with minimal systemic absorption and are used in combination with other analgesic drugs[ , ].
Lidocaine blocks sodium channels and counteracts the hyperexcitability of peripheral nociceptors that contributes to neuropathic pain[ , ]. The blockade reduces ectopic discharges and raises the peripheral sensory neuron discharge threshold[ ]. The few DNP clinical trials that compared topical lidocaine with other relevant interventions suggested that the effects in pain reduction are comparable to other drugs, such as capsaicin, gabapentin, amitriptyline[ ] and pregabalin[ , ].
Adverse events include local irritation[ ], contact dermatitis and itching[ ]. Alpha lipoic acid: The benefit provided by alpha lipoic acid ALA in the treatment of DNP possibly is due to its direct effects on the neuropathy, by reducing the oxidative stress, which has been defined as an important factor in the physiopatology of the diabetic neuropathy[ ]. Its antioxidant and anti-inflammatory actions may contribute to an all-round improvement of diabetic neuropathy symptoms[ ]. In some clinical trials that evaluated ALA effect in diabetic patients, pain was not a primary end point.
However, they have shown a moderate benefit in terms of pain reduction[ ]. In a randomized double-blinded trial, ALA-treated patients reported a greater reduction in neuropathic pain when compared to placebo-treated subjects[ ].
Compared to several drugs currently in use for DNP treatment, ALA has fewer side effects[ 30 ], being nausea and vomiting the most common[ ]. Isosorbide dinitrate spray: Isosorbide dinitrate is a nitric oxide-dependent vasodilator with effects on both arteries and veins[ ].
The improvement of pain and burning sensation could be associated with the increased generation of nitric oxide, improving microvascular blood flow[ ]. Final considerations about DNP treatment: Besides the fact of many diabetic complications can be reduced with improved blood glucose control and other lifestyle interventions[ , ], such as quit smoking and reducing alcohol consumption[ ], the efficacy of these measures, as well as the pharmacological treatments on DNP are not predictable.
P- Reviewer: Tian YL L- Editor: A E- Editor: Liu SQ. This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers.
Peer-review started: August 30, First decision: November 14, Article in press: February 9, National Center for Biotechnology Information , U. Journal List World J Diabetes v. World J Diabetes. Published online Apr Author information Article notes Copyright and License information Disclaimer. Author contributions: All authors contributed equally to this work.
Published by Baishideng Publishing Group Inc. All rights reserved. This article has been cited by other articles in PMC. Diabetes, Neuropathic pain, Hyperglycemia, Anticonvulsants, Antidepressants.
Polyol pathway hyperactivity Metabolic disorders are the primary cause of diabetic neuropathy. Oxidative and nitrosative stress As already mentioned, the polyol pathway activation could be the primary cause of oxidative stress associated with diabetes. Microvascular changes DNP is frequently associated with microvascular impairment[ 33 , 34 ].
Channels sprouting Damaged nerve endings are believed to contribute to pain in DNP[ 49 , 50 ]. Microglial activation It is becoming increasingly recognized that glial cells play an important role in the pathogenesis of many diseases of the nervous system, including chronic pain states[ 85 ]. Central sensitization As already demonstrated in different neuropathic pain states, DNP may be a consequence of both peripheral and CNS changes[ 93 , 94 ]. Brain plasticity Functional changes in pain processing areas in the CNS, besides the spinal cord, have been ultimately linked with DNP[ ], in a tight relation to increased peripheral input[ 93 , ].
Anticonvulsants Pregabalin was the first anticonvulsant to receive approval from the Food and Drug Administration FDA for the treatment of postherpetic neuralgia, DNP[ , ] and neuropathic pain after spinal cord injury[ ].
Antidepressants Antidepressants represent the first line drugs in DNP management. Opioids Opioids are recommended to be used as second or third line treatment for DNP[ 3 , ].
Footnotes P- Reviewer: Liu SQ Conflict-of-interest: August 30, First decision: November 14, Article in press: References 1. International Diabetes Federation. IDF Diabetes Atlas.
Brussels, Belgium: International Diabetes Federation; Diabetic neuropathies: Diabetes Care. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy.
Clinical practice. Neuropathic diabetic foot ulcers. N Engl J Med. Vascular risk factors and diabetic neuropathy. Symptomatic treatment of painful neuropathy. The intensity severity of neuropathic pain and its course should be assessed using an Point numerical rating scale Likert scale or a visual analogue scale. These questionnaires use verbal descriptors and pain qualities as a basis for distinguishing neuropathic pain from other types of chronic pain such as nociceptive pain Evaluation of pain intensity is essential for monitoring response to therapy.
With the visual analog scale the patient marks the intensity of their pain on a scale from , allowing an assessment of the response to intervention. Simultaneously, the patient should complete a quality of life tool such as the Norfolk QOL-DN which needs to include comorbidities such as anxiety, depression, and sleep interference Level 1a, Grade A 9.
Such a tool permits evaluation of the impact of the pain on quality of life QOL , anxiety and depression, all of which are known to be accompanying features of DPN. Several studies have consistently found that neuropathic pain has a negative impact on global health-related quality of life. A systematic review of 52 studies in patients with one out of 6 different disorders associated with neuropathic pain, including PDPN, established that neuropathic pain impairs physical and emotional functioning, role functioning including participation in gainful employment, sleep and, to a lesser degree, social functioning.
In addition, there is also evidence suggesting an association between neuropathic pain and depression, as for other types of pain. Also the nature of pain may be important, as Daousi et al.
Neuropathic pain is the consequence of an array of diseases or injuries to the peripheral or central nervous system. It is often chronic and if inadequately treated patients may experience anxiety, depression, catastrophising behaviour an inability to accept chronic pain , and sleep disturbances. Treatment of peripheral neuropathic pain conditions can benefit from further understanding of the impact of pain response and QOL including ADLs and sleep. Castro et al studied patients with depression, anxiety, and sleep disturbances.
As a corollary Gore et al showed that with increasing pain severity there was a linear increase in HADs pain and Depression scores.
Moreover Gupta et al showed that higher scores for anxiety, depression, and sleep disturbances predicted the development of pain. The pain circuit therefore involves not only the peripheral sensory pathways but also the central emotional and cognitive neural pathways Figure 8.
The microanatomy of pain is only beginning to evolve, and recent studies using functional MRI and CHEPS are beginning to define the role of the thalamus, limbic region, and cerebral cortex in pain manifestations.
It is becoming increasingly clear that pain has strong neuro-endocrine, autonomic, pro-inflammatory, and neuro-degenerative underpinnings Of particular note is the activation of the autonomic nervous system and the association between pain, anxiety, and autonomic nervous system dysfunction Martinez Lavin has shown that infusion of norepinephrine heightens the pain experienced, and Rainsville has shown that negative emotions exacerbate pain There is also a significant impact of chronic pain on immune function , with increases in circulating levels of IL-6, IL-8 and IL1-ra.
IL-8 is a proinflammatory cytokine which mediates sympathetic pain; IL1-ra is involved with stress; and IL-6 activates sympathetic pain and is involved with stress, fatigue, hyperalgesia, and depression. Thus, it should be recognized that pain management programmes based on cognitive behavioral principles, are the treatment of choice. Evaluation of outcomes should be standard practice, assessing distress and the emotional impact of pain. Sankar et al.
Anxiety resulted in reporting a significantly higher pain intensity score [NPS: Patients with anxiety also reported significantly higher scores in all sub-categories of Norfolk QOL 9. Subjects who were depressed were less likely to accept pain [CPAQ depression vs. ITT population comprised patients and placebo. Pearson correlations and pathway analysis were used in the analysis. The data showed a direct relationship between the reduction in pain and enhanced sleep, as well as improvement in social functioning on the SF36 scale.
Indeed, the improvement in social functioning depended on pain relief and sleep improvement equally well. In addition, the effects of pregabalin on pain relief were mediated directly and indirectly through its effects on sleep improvement about equally Level 1a Grade A. This speaks to the need for determining sleep status in the evaluation of pain and choosing an agent capable of enhancing sleep if pain relief is to be achieved.
Finally, Boyd et al have shown that relief of pain with the anti-epileptic drug topiramate is associated with improvement in subjective and objective measures of nerve function as well as intraepidermal nerve fiber regeneration Level 1b Grade A Neuropathic pain is not uncommon. Similarly a large population-based study in France showed that 6.
Perhaps a little recognized fact is that mononeuritis and entrapments were 3 times as common as diabetic peripheral neuropathy DPN , and fully one third of the diabetic population has some form of entrapment which, when recognized is readily amenable to intervention Even more salutary is the mounting evidence that even with impaired glucose tolerance IGT , patients may experience pain ,, In the general population region of Augsburg, Southern Germany , the prevalence of painful PN was The most important risk factors of DSPN and neuropathic pain in these surveys were age, obesity, and low physical activity, while the predominant co-morbidity was peripheral arterial disease, highlighting the paramount role of cardiovascular risk factors and diseases in prevalent DSPN.
Indeed, a risk factor for neuropathic pain in diabetic and non-diabetic populations is an impairment of peripheral vascular function , Pain associated with a peripheral nerve injury has several distinct clinical characteristics. In a clinical survey including patients with painful DSPN, the following locations of pain were most frequent: The average pain intensity was moderate, approximately 5. Allodynia pain due to a stimulus which does not normally cause pain, e.
The symptoms may be accompanied by sensory loss, but patients with severe pain may have few clinical signs. Pain may persist over several years , causing considerable disability and impaired QOL in some patients , whereas it may remit partially or completely in others 87, despite further deterioration in small fiber function Pain exacerbation or even acute onset of pain tends to be associated with sudden metabolic change, short duration of pain or diabetes, or preceding weight loss; it has less severe or no sensory loss, and normal strength and reflexes 87, Neuropathic pain derived from small nerve fibers is often burning, lancinating or shooting in quality with unusual, tingling or crawling sensation referred to as formication.
Some describe bees stinging through the socks while others talk of walking on hot coals. The pain, worse at night, keeps the patient awake and is associated with sleep deprivation 9.
Patients volunteer that they have allodynia or pain from normal stimuli, such as the touch of bedclothes, and may have hyperaesthesias increased sensitivity to touch , hyperalgesia increased sensitivity to painful stimuli , or even altered sensation to cold or heat. These may be paradoxical with differences in sensation to one or another modality of stimulation.
Unlike animal models of DPN, the pain is spontaneous and does not need provocation such as a hot plate or laser heat. It has a glove and stocking distribution. Small fiber neuropathies usually present with pain in the feet or hands, do not have abnormalities in sensation, lack weakness or loss of reflexes, and are electrophysiogically silent, thus often leading to the erroneous diagnosis of hysteria or conversion reactions.
Large fiber neuropathy presents with characteristic weakness, ataxia, loss of reflexes, and impaired nerve conduction. In contrast, the nociceptive pain of arthritis does not have these qualities. It is localized to the joints, starts with morning stiffness, and improves as the day wears on Fasciitis pain is localized to the fascia; entrapment produces pain in a dermatome; and claudication is made worse by walking.
The diagnosis of neuropathic pain - as opposed to pain from causes other than neuropathy - is first and foremost made by careful history taking.
The physician should ensure that all the features of pain such as distribution, quality, severity, timing, associated symptoms, and exacerbating and alleviating factors if any are recorded. A number of tools and questionnaires have been developed to quantify the pain impact on sleep, mood, and QOL, mainly to be used in clinical trials.
Responses to treatment by self-reporting using a diary can document the course of painful symptoms and their impact on daily life Level 1a, Grade A Diaries are also most useful for outcomes measures in clinical trials on drugs used for pain relief.
Control of pain is one of the most difficult management issues in DN. It often involves different classes of drugs and requires combination therapies.
In any painful syndrome, special attention to the underlying condition is essential for the overall management and for differentiation from other conditions that may coexist in patients with diabetes i. Small nerve fiber neuropathy often presents with pain but without objective signs or electrophysiologic evidence of nerve damage.
Large nerve fiber neuropathies produce numbness, ataxia and incoordination. A careful history of the nature of pain, its exact location, and detailed examination of the lower limbs are mandatory to ascertain alternate causes of pain. Figure 8 describes the pathophysiological basis for the generation of neuropathic pain. Different types of pain respond to different types of therapies Figure 9 describes the different nerve fibers affected and possible targeted treatments. Schematic representation of the generation of pain: A Normal: Central terminals of c-afferents project into the dorsal horn and make contact with secondary pain-signaling neurons.
B C-fiber sensitization: C C-fiber loss: D Central disinhibition: Sympat, sympathetic nerve Different mechanisms of pain and possible treatments. C fibers are modulated by sympathetic input with spontaneous firing of different neurotransmitters to the dorsal root ganglia, spinal cord and cerebral cortex. Sympathetic blockers e. Dextromethorphan blocks N-methyl-D-aspartate receptors in the spinal cord. Tricyclic antidepressants, selective serotonin reuptake inhibitors e.
Tramadol is a central opioid analgesic. Painful symptoms in DSPN may constitute a considerable management problem. The efficacy of a single therapeutic agent is not the rule, and simple analgesics are usually inadequate to control the pain. There is agreement that patients should be offered the available therapies in a stepwise fashion Level 1a, Grade A Effective pain treatment considers a favourable balance between pain relief and side effects without implying a maximum effect.
The following general considerations in the pharmacotherapy of neuropathic pain require attention:. The appropriate and effective drug has to be tried and identified in each patient by carefully titrating the dose based on efficacy and side effects. Potential drug interactions have to be considered given the frequent use of polypharmacy in diabetic patients. The relative benefit of an active treatment over a control in clinical trials is usually expressed as the relative risk, the relative risk reduction, or the odds ratio.
However, to estimate the extent of a therapeutic effect i. Such a practical measure is the "number needed to treat" NNT , i. This measure is expressed as the reciprocal of the absolute risk reduction, i. The NNT and NNH number needed to harm for the individual agents used in the treatment of painful diabetic neuropathy are given in Table 5 and Figure However, some authors have cautioned that summary NNT estimates may have limited clinical relevance, due to problems of heterogeneity The neuropharmacology of pain is also becoming better understood.
For example, recent data suggest that gamma-aminobutyric acid GABA , voltage-gated sodium channels, and glutamate receptors may be involved in the pathophysiology of neuropathic pain. Many of the newer agents have significant effects on these neurophysiologic mechanisms. Hyperglycemia may be a factor in lowering the pain threshold. Pain is often worse with wide glycemic excursions. Paradoxically acute onset of pain may appear soon after initiation of therapy with insulin or oral agents Adding to the confusion, it has been reported that a striking amelioration of symptoms can occur with continuous subcutaneous insulin administration, which may reduce the amplitude of excursions of blood glucose This dichotomy is not well explained.
There is a sequence in DN, beginning when Ab and C nerve fiber function is intact and there is no pain. With damage to C fibers there is sympathetic sensitization and peripheral autonomic symptoms are interpreted as painful.
Topical application of clonidine causes anti-nociception by blocking emerging pain signals at the peripheral terminals via alpha-2 adrenoreceptors , in contrast with the central actions of clonidine on blood pressure control. With the death of C-fibers there is nociceptor sensitization. Ab fibers conduct all varieties of peripheral stimuli such as touch, and these are interpreted as painful, e.
With time there is reorganization at the cord level and the patient experiences cold hyperalgesia and ultimately, even with the death of all fibers, pain is registered in the cerebral cortex whereupon the syndrome becomes chronic without the need for peripheral stimulation. Disappearance of pain may not necessarily reflect nerve recovery but rather nerve death. When patients volunteer the loss of pain, progression of the neuropathy must be excluded by careful examination as shown in Table 3.
Initially, when there is ongoing damage to the nerves, the patient experiences pain of the burning, lancinating, dysesthetic type often accompanied by hyperalgesia and allodynia. Because the peripheral sympathetic nerve fibers are also small unmyelinated C-fibers, sympathetic blocking agents clonidine may improve the pain.
C-fibers utilize the neuropeptide substance P as their neurotransmitter, and depletion of axonal substance P through the use of capsaicin will often lead to amelioration of the pain. Prolonged application of capsaicin depletes stores of substance P, and possibly other neurotransmitters, from sensory nerve endings. This reduces or abolishes the transmission of painful stimuli from the peripheral nerve fibers to the higher centers An analysis of randomized and controlled studies revealed that either a repeated application of low doses of capsaicin or single application of high doses affords pain relief Capsaicin transmethyl-N-vanillylnonenamide is an alkaloid and the most pungent ingredient in the red pepper.
It depletes tissues of substance P and reduces neurogenic plasma extravasation, the flare response, and chemically induced pain. Substance P is present in afferent neurons innervating skin, mainly in polymodal nociceptors, and is considered the primary neurotransmitter of painful stimuli from the periphery to the central nervous system.
Several studies have demonstrated significant pain reduction and improvement in quality of life in diabetic patients with painful neuropathy after 8 weeks of treatment with capsaicin cream 0. Treatment should be restricted to a maximum of 8 weeks, as during this period no adverse effect on sensory function due to the mechanism of action was noted in diabetic patients. Level Ib, Grade B. Indeed, pain relief was sustained for the duration of the study If successful, therapy can be continued with oral mexiletine.
This class of compounds targets the pain caused by hyperexcitability of superficial, free nerve endings The AAN recomendations are:. There are two possible targeted therapies. Tramadol is a centrally acting weak opioid analgesic for use in treating moderate to severe pain. Tramadol was shown to be better than placebo in a randomized controlled trial of only 6-weeks duration, but a subsequent follow-up study suggested that symptomatic relief could be maintained for at least six months Side-effects are, however, relatively common, and are similar to other opioid-like drugs.
Blockade of NMDA receptors is believed to be one mechanism by which dextromethorphan exerts analgesic efficacy The NMDA receptors play an important role in central sensitization of neuropathic pain. Their use, however, has not been widespread in part due to dose-limiting side effects Level1a Grade A Tramadol acts directly via opioid receptors and indirectly via monoaminergic receptor systems.
Because the development of tolerance and dependence during long-term tramadol treatment is uncommon and its abuse liability appears to be low, it is an alternative to strong opioids in neuropathic pain One conceivable mechanism for the favourable effect of tramadol could be a hyperpolarization of postsynaptic neurons via postsynaptic opioid receptors.
Alternatively, the reduction in central hyperexcitability by tramadol could be due to a monoaminergic or a combined opioid and monoaminergic effect. Most severe pain requires administration of strong opioids such as oxycodone. Although there is little data available on combination treatment, combinations of different substance classes have to be used in patients with pain resistant to monotherapy.
As expected, adverse events were frequent and typical of opioid-related side effects. A cross-over study examined the maximum tolerable dose of a combination treatment of gabapentin and morphine as compared to monotherapy of each drug. The maximum tolerable dose was significantly lower, and efficacy was better, during combination therapy than with monotherapy, suggesting an additive interaction between the two drugs The results of these studies suggest that opioids should be included among the therapeutic options for painful DSPN, provided that careful selection of patients unresponsive to standard treatments, regular monitoring, appropriate dose titration, and management of possible opioid-specific problems analgesic misuse or addiction, tolerance, opioid-induced hyperalgesia are ensured.
Recent recommendations have emphasized the need for clinical skills in risk assessment and management as a prerequisite to safe and effective opioid prescribing Treatment of painful DSPN with opioid agonists should generally be reserved for patients who have failed to respond to or cannot tolerate the first-line medications.
Tapentadol is a novel centrally active analgesic with a dual mode of action: Compared with placebo, tapentadol ER mg bid was associated with a statistically significant difference in the maintenance of the initial improvement of pain and was well tolerated The AAN recommendations are: Data are insufficient to recommend one agent over the other.
Therefore, combination pharmacotherapy is required in patients who have only partial response or in whom the drug cannot be further titrated due to intolerable side effects.
A recent trial showed that the combination of nortriptyline and gabapentin at the maximum tolerated dose was more effective than either monotherapy despite a lower maximum tolerable dose as compared with monotherapy Appropriate analgesic combinations include antidepressants with anticonvulsants, or each of these with opioids.
Some patients may even require a triple combination of these drug classes. Antidepressants are now emerging as the first line of agents in the treatment of chronic neuropathic pain Clinical trials have focused on interrupting pain transmission utilizing antidepressant drugs that inhibit the reuptake of norepinephrine or serotonin.
This central action accentuates the effects of these neurotransmitters, essentially activating endogenous pain-inhibitory systems in the brain that modulate pain transmission cells in the spinal cord Imipramine, amitriptyline, and clomipramine induce a balanced reuptake inhibition of both norepinephrine and serotonin, while desipramine is a relatively selective norepinephrine inhibitor.
The number needed to harm NNH in patients with neuropathic pain for one drop out of the study due to adverse events is 16 The most frequent adverse events of TCAs include tiredness and dry mouth. The starting dose should be 25 mg 10 mg in frail patients taken as a single night time dose one hour before sleep.
It should be increased by 25 mg at weekly intervals until pain relief is achieved or adverse events occur. The maximum dose is usually mg per day. Their use is limited by relatively high rates of adverse events and several contraindications. Thus, there is a continuing need for agents that exert efficacy equal to or greater than that achieved with TCAs but that have a more favourable side effect profile. Because of the relatively high rates of adverse effects and several contraindications of TCAs, it has been reasoned that patients who do not tolerate them due to adverse events could alternatively be treated with selective serotonin reuptake inhibitors SSRI.
SSRIs specifically inhibit pre-synaptic reuptake of serotonin but not norepinephrine; and, unlike the tricyclics, they lack the postsynaptic receptor blocking effects and quinidine-like membrane stabilization. Unfortunately, only weak effects on neuropathic pain were observed after treatment with fluoxetine, paroxetine, citalopram, and escitalopram.
Because of these limited efficacy data, SSRIs have not been licensed for the treatment of neuropathic pain. Level IIb, Grade B. Because SSRIs have been found to be less effective than TCAs, recent interest has focused on antidepressants with dual selective inhibition of serotonin and noradrenaline such as duloxetine and venlafaxine.
In all three studies, the average 24 hour pain intensity was significantly reduced with both doses as compared to placebo treatment, the difference between active and placebo achieving statistical significance after 1 week. Pain severity, but not variables related to diabetes or neuropathy, predicts the effects of duloxetine in diabetic peripheral neuropathic pain. Patients with higher pain intensity tend to respond better than those with lower pain levels These adverse events are usually mild to moderate and transient.
In contrast to TCAs and some anticonvulsants duloxetine does not cause weight gain, but a small increase in fasting blood glucose may occur Venlafaxine is another SNRI that has mixed action on catecholamine uptake.
At lower doses, it inhibits serotonin uptake and at higher doses it inhibits norepinephrine uptake The extended release version of venlafaxine was found to be superior to placebo in diabetic neuropathic pain in non-depressed patients at doses of mg daily, and when added to gabapentin there was improved pain, mood, and quality of life Because patients with depression were excluded, the effect of venlafaxine mg was attributed to an analgesic, rather than antidepressant, effect.
The most common adverse events were tiredness and nausea ; additionally, clinically important electrocardiogram changes were found in seven patients in the treatment arm. Duloxetine, but not venlafaxine, has been licensed for the treatment of painful diabetic neuropathy. Antiepileptic drugs AEDs have a long history of effectiveness in the treatment of neuropathic pain, dating back to case studies of the treatment of trigeminal neuralgia with phenytoin in and carbamazepine in For example, one might choose a sodium channel blocker such as lamotrigine to be used with a glutamate antagonist such as felbamate.
Furthermore, a single drug may possess multiple mechanisms of action, perhaps increasing its likelihood of success e. If pain is divided according to its derivation from different nerve fiber types e. Ad vs.
C-fiber , spinal cord or cortical, then different types of pain should respond to different therapies. In addition to providing efficacy against epilepsy, these new AEDs may also be effective in neuropathic pain. For example, spontaneous activity in regenerating small-caliber primary afferent nerve fibers may be quelled by sodium channel blockade, and hyperexcitability in dorsal horn spinal neurons may be decreased by the inhibition of glutamate release - 2 mechanisms of action possessed by the AED lamotrigine , Clinical trials, however, have not been salutary 9.
Patients who have failed to respond to one AED may respond to another or to 2 or more drugs in combination.
Level 1a, Grade A Although topiramate failed in three clinical trials due to the use of the wrong endpoint , it has been shown to successfully reduce pain and induce nerve regeneration 89, Topiramate has the added advantages of causing weight loss and improving the lipoprotein profile, both of which are particularly useful in overweight type 2 diabetic patients.
Gabapentin is an anticonvulsant structurally related to g-aminobutyric acid GABA , a neurotransmitter that plays a role in pain transmission and modulation. The exact mechanisms of action of this drug in neuropathic pain are not fully elucidated. A recent analysis of the efficacy of six agents for managing PDN found gabapentin to offer the most favourable balance between safety and efficacy , and it is now widely recommended in guidelines for the treatment of PDN despite its relatively high NNT.
The efficacy and safety of pregabalin were reported in a pooled analysis of 6 studies over weeks in diabetic patients with painful neuropathy. The evidence supporting a favourable effect in painful diabetic neuropathy is more solid and dose titration is considerably easier for pregabalin than gabapentin.
Level 1a, Grade A A Spanish cost-comparative analysis of adding pregabalin or gabapentin therapy to community dwelling patients with PDN found that pregabalin therapy generated lower total healthcare costs compared with gabapentin Although carbamazepine has been widely used for treating neuropathic pain, it cannot be recommended in painful diabetic neuropathy due to very limited data.
Its successor drug, oxcarbazepine, as well as other sodium channel blockers such as valproate, mexiletine, topiramate, and lamotrigine showed only marginal efficacy and have not been licensed for the treatment of painful diabetic neuropathy.
Lacosamide is a novel anticonvulsant which selectively enhances the slow inactivation of voltage dependent sodium channels but, in contrast to the aforementioned sodium channel blockers, does not influence the fast sodium channel inactivation. Its second putative mechanism is an interaction with a neuronal cytosolic protein, the collapsin response mediator protein 2 CRMP-2 , which plays an important role in nerve sprouting and excitotoxicity.
Lacosamide has been evaluated in several studies in painful diabetic neuropathy. However, the drug was not approved by the FDA or EMEA for painful diabetic neuropathy and a recent analysis of 6 studies concluded that lacosamide is without any useful benefit in treating neuropathic pain Voltage-gated sodium channels are crucial determinants of neuronal excitability and signaling.
After nerve injury hyperexcitability and spontaneous firing develop at the site of injury and also in the dorsal root ganglion cell bodies. This hyperexcitability results at least partly from accumulation of sodium channels at the site of injury Faber and colleagues have published two studies associating gain-of-function mutations in voltage-gated Nav1. However, genetic testing is not readily available and clinical implications are still uncertain.
Five types of voltage gated calcium channels have been identified and the L- and N-types of channels have a role to play in the neuromodulation of sensory neurons of the spinal cord.
Gabapentin and pregabalin are medications that bind at the alpha 2 delta subunits of the channels. Unlike traditional calcium channel antagonists they do not block calcium channels but modulate their activity and sites of expression. The exact mechanism of action of this group of agents on neuromodulation has yet to be clearly defined. Level 11b, Grade B. Botulinum toxin has been tried for trigeminal neuralgia and has been shown to have long-lasting anti-nociceptive effects in carpal tunnel syndrome with no electrophysiologic restoration It may provide relief of neuropathic pain in diabetes through its modulatory effects on afferent sensory fiber firing.
One small double-blind crossover trial of intradermal botulinum toxin type A in 18 patients with PDN demonstrated a significant reduction in pain and improvement in sleep quality Because there is no entirely satisfactory pharmacotherapy of painful diabetic neuropathy, non-pharmacological treatment options should always be considered.
As for the pharmacological options, considerable efforts must also be made to develop effective non-pharmacological approaches. A recent systematic review assessed the evidence from rigorous clinical trials and meta-analyses of complementary and alternative therapies for treating neuropathic and neuralgic pain.
Data on the following complementary and alternative medicine treatments were identified: The conclusion was that the evidence is not fully convincing for most complementary and alternative medicine modalities in relieving neuropathic or neuralgic pain. The evidence can be classified as encouraging and warrants further study for cannabis extract, magnets, carnitine, and electrostimulation A psychological component to pain should not be underestimated.
Hence, an explanation to the patient that even severe pain may remit, particularly in poorly controlled patients with acute painful neuropathy or in those painful symptoms precipitated by intensive insulin treatment. Thus, the empathetic approach addressing the concerns and anxieties of patients with neuropathic pain is essential for their successful management The temperature of the painful neuropathic foot may be increased due to arterio-venous shunting. Cold water immersion may reduce shunt flow and relieve pain.
Allodynia may be relieved by wearing silk pyjamas or the use of a bed cradle. Patients who describe painful symptoms on walking as comparable to walking on pebbles may benefit from the use of comfortable footwear A week uncontrolled study with a follow-up period of weeks in diabetic patients showed significant pain relief after up to 6 courses of traditional Chinese acupuncture without any side effects A single-blind placebo-controlled randomized trial of acupuncture in 45 subjects with PDN recently reported an improvement in the outcome measures assessing pain in the acupuncture arm relative to sham treatment However, Chen and colleagues warn that design flaws and lack of robust outcome measures of pain in acupuncture trials make meaningful conclusions difficult Larger controlled studies are needed to confirm these early findings.
Transcutaneous electrical nerve stimulation TENS influences neuronal afferent transmission and conduction velocity, increases the nociceptive flexion reflex threshold, and changes the somatosensory evoked potentials. In patients who only marginally responded to amitriptyline, pain reduction was significantly greater following TENS given for 12 weeks as compared with sham treatment.
Thus, TENS may be used as an adjunctive modality combined with pharmacotherapy to augment pain relief Frequency-modulated electromagnetic nerve stimulation FREMS in 2 studies, including a recent double-blind randomized placebo controlled trial with 51 weeks of follow-up, proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate but transient reduction in pain and no effect on nerve conduction velocities Level 11b, Grade B.
Pathogenesis The cause of DN though remains unknown but ischaemic and metabolic components are implicated. Management of diabetic neuropathy Disease modification The treatment of DN is aimed at preventing the progression of neuropathy and providing symptomatic relief. Glycaemic control The relation between hyperglycaemia and development of severity of neuropathy has been shown in retrospective and prospective studies. Aldolase reductase inhibitors ARIs ARIs reduce the flux of glucose through polyol pathways, inhibiting accumulation of sorbitol and fructose, and preventing reduction of redox potential.
Neurotrophic therapy In view of experimental evidence of decreased expression of nerve growth factor NGF and its receptor Trk A, several trials on trophic factors in DM have been carried out. Symptomatic treatment Painful paresthesia especially when the pain is of lancinating type can be helped by tricyclic antidepressants and anticonvulsants such as phenytoin, carbamazepine, and gabapentin.
Neuropathic pain Pain relief is one of the most challenging issues in DN. Type C The patient with DN present with lancinating, burning, dysesthetic pain because of peripheral sympathetic fibres, which are unmyelinated C type. Large fibre neuropathy The management of large fibre neuropathy is by gait and strength training, pain management as discussed above, orthopaedic devices, tendon lengthening for Achilles contracture, and immunomodulation as detailed above.
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