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New perspectives on the management of diabetic peripheral neuropathic pain TROELS S JENSEN, MISHA-MIROSLAV BACKONJA, SERGIO HERNÁNDEZ JIMÉNEZ, SOLOMON TESFAYE, PAUL VALENSI, DAN ZIEGLER

P

Department of Neurology, Danish Pain Research Center, Faculty of Health Sciences, University of Aarhus, Denmark. Troels S Jensen, Professor UW-Neurology Pain Clinic, H6/5 Clinical Science Center, Madison, Wisconsin, USA. Misha-Miroslav Backonja, Associate Professor of Neurology and Anesthesiology

Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México. Sergio Hernández-Jiménez, Consultant Physician

Diabetes Research Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK. Solomon Tesfaye, Consultant Physician/Honorary Professor of Diabetic Medicine Department of Endocrinology, Diabetology and Nutrition, Hôpital JeanVerdier APHP, Paris-Nord University, Bondy, France. Paul Valensi, Professor of Nutrition and Diabetology German Diabetes Clinic, German Diabetes Center, Leibniz Center at the Heinrich Heine University Düsseldorf, Germany. Dan Ziegler, Professor Correspondence to: Professor Troels S Jensen Department of Neurology, Danish Pain Research Center, Faculty of Health Sciences, Aarhus University Hospital, Building 1A, Norrebrogade 44, DK-8000 Aarhus C, Denmark. Tel: +45 8949 3380; Fax: +45 8949 3269 E-mail: [email protected]

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Table 1. Classification of diabetic neuropathy. Adapted from Boulton et al.6

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Abstract eripheral neuropathy affects about 30% of people with diabetes mellitus. Between 16% and 26% of diabetes patients experience chronic pain. This may be referred to as diabetic neuropathic pain (DNP) or diabetic peripheral neuropathic pain (DPNP). Minimum requirements for diagnosis of DPNP should include assessment of pain and symptoms and neurological examination, with the accent on sensory examination. Given that depression and other co-morbidities are commonly associated with this condition, a broad approach to management is essential. Lifestyle intervention and optimisation of glycaemic control are recommended as initial steps in management. An evidence-based treatment algorithm for DPNP has been proposed, recommending initial use of either a tricyclic antidepressant, selective serotonin noradrenaline reuptake inhibitor or alpha-2-delta agonist, depending on patient co-morbidities and contra-indications. Addition of an opioid agonist may be required in the event of inadequate pain control. Irrespective of which treatment is offered, only about one third of patients are likely to achieve more than 50% pain relief. Further research to improve the diagnosis and management of DPNP is needed.

Polyneuropathy

Mononeuropathy

Sensory ● Acute sensory ● Chronic sensorimotor

Isolated peripheral Mononeuritis multiplex Truncal

Motor

Autonomic Cardiovascular ● Gastrointestinal ● Genitourinary ● Other ●

Proximal Truncal

Diabetes Vasc Dis Res 2006;3:108–19 Key words: diabetic peripheral neuropathic pain, management, pathogenesis, serotonin noradrenaline reuptake inhibitor, treatment algorithm.

Introduction Peripheral neuropathy is estimated to affect about 30% of patients with diabetes mellitus.1,2 The condition represents an important cause of morbidity and premature mortality.3 About 16–26% of the diabetic population experience chronic neuropathic pain. Due to large inter-subject variability in symptoms and in the absence of established diagnostic criteria, it is not surprising that diabetic neuropathic pain is under-reported and under-treated.4,5 In the management of this condition it is important to discriminate between the treatment of pain and the treatment of neuropathy per se. Several unmet clinical needs relating specifically to assessment and management warrant urgent attention. This review summarises key findings from a recent meeting of diabetologists and neurologists, held to address these needs.

Epidemiology Prevalence Diabetic neuropathy is classified as either polyneuropathy or mononeuropathy (table 1).6 Painful diabetic neuropathic conditions are listed in table 2.7 The most important painful

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Table 2. Classification of painful diabetic neuropathy. Adapted from Boulton7

peripheral neuropathy will have severe symptoms that require treatment.7

Focal and multifocal painful neuropathy ● Cranial (e.g. N.III mononeuropathic pain) ● Focal limb (e.g. entrapment neuropathic pain) ● Amyotrophy (proximal motor) ● Truncal radiculo neuropathic pain

Predictive risk factors Traditional cardiovascular risk factors for macrovascular disease in patients with diabetes are also associated with an increased risk of neuropathy. In the European Diabetes Complications Prospective Study (EURODIAB), involving 1,101 patients with type 1 diabetes followed for a mean of 7.3 years, smoking, glycosylated haemoglobin (HbA1C), diabetes duration, and components of the metabolic syndrome (including hypertension, obesity, triglycerides and cholesterol) were all associated with an increased risk of polyneuropathy.14 Interestingly, female gender appears to be an independent risk factor for the development of painful neuropathy. In addition, painful neuropathy is associated with less macro/microalbuminuria, which may reflect an early neuropathy with less peripheral nerve dysfunction and less endoneurial microangiopathy.15 Data from the MONICA/ KORA Project, although consistent with those from EURODIAB, also indicate that diabetic polyneuropathy in the general population is associated with increasing age and waist circumference, as well as peripheral arterial disease.2 Risk factors for DPNP are less well defined and warrant further investigation.

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Generalised symmetrical painful neuropathy ● Acute sensory (always painful) ● Chronic sensorimotor (DPNP) ● Chronic predominantly sensory Key: DPNP = diabetic peripheral neuropathic pain

diabetic neuropathy, and the one that is considered in this review, is the pain associated with chronic sensorimotor polyneuropathy (i.e. diabetic peripheral neuropathic pain [DPNP]). Although estimates of the prevalence of diabetic neuropathy vary substantially, depending on diagnostic criteria and the extent of investigation, most studies suggest that about one third of diabetic patients are affected.1,8 This is consistent with a recent report from the MONICA/KORA Augsburg Surveys and Myocardial Infarction Registry, a population-based study in which the prevalence of distal symmetrical polyneuropathy, as assessed by the Michigan Neuropathy Screening Instrument, was 28% in diabetic subjects.2 A proportion of these subjects had DPNP. This compares with prevalences of 9% and 13% in subjects with normal and impaired glucose tolerance, respectively.2 Epidemiological data indicate that the prevalence of peripheral diabetic neuropathy is higher in type 2 than type 1 diabetes; in one study, nearly one third of patients with type 1 diabetes and more than half of patients with type 2 diabetes had evidence of peripheral neuropathy.9 In a study in subjects with newly diagnosed type 2 diabetes, 6% reported pain at diagnosis (vs. 3% of controls), and this had increased to 20% 10 years later.10 In another study, 5.3% of subjects with type 2 diabetes (vs. 1.4% of controls) had symptoms or signs suggestive of neuropathy.11 Data on the prevalence of DPNP are limited, however. In one population-based study involving 350 patients with diabetes (and 344 age- and sex-matched controls), the prevalence of painful diabetic neuropathy, as assessed by structured questionnaire and examination, was estimated at 16%. Of these patients, 12.5% had never reported symptoms to their doctor and 39% had never received treatment for their pain.5 In a subsequent cross-sectional study in which DPNP was assessed by a survey of symptoms, neurological history and examination, 26% of patients with type 2 diabetes were shown to have DPNP. Of these patients, 80% reported moderate to severe pain.12 In the US, the prevalence of painful diabetic neuropathy has been estimated at 20–24% of patients with peripheral neuropathy.13 More recently, it has been suggested that 10–20% of type 2 diabetes patients with

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Aetiology and pathogenesis A detailed description of the systems involved in transducing and transmitting information on noxious stimuli is beyond the scope of this paper. Central pathways implicated in pain perception include the spinothalamic tract, which signals the sensory discriminative part of the pain experience, and the spino-parabrachial-amygdaloid pathway, which contributes information about the emotional and affective component.16 Peripheral pathways are the main site of pathology of painful diabetic neuropathy. Neuropathic pain is caused by lesions or dysfunction of the peripheral and/or central nervous system and does not require receptor stimulation.17 Painful sensations are most commonly relayed via small primary afferents, the A-δ fibres, and unmyelinated C fibres to the dorsal horn of the spinal cord; there is a synaptic junction in the outer part of the dorsal horn and subsequently sensations are relayed to the spino-parabrachial-amygdaloid pathway and spinothalamic tract.17 Pain is not processed in a passive manner in transit to the brain, but is exposed to various types of modulations at different synaptic relays in the nervous system. Current consensus indicates that both facilitation and inhibition throughout the neural axis are involved in modulating the pain experience. Neuropathic pain is in fact a paradox, in that there is development of pain in the area where the patient experiences sensory deficit due to nerve injury. Neuropathic pain results from plastic changes in the nervous system of some, although not all, patients, which leads to increased excitability of the remaining and surrounding neurons and results in the experience of pain. Thus, to establish a diagnosis of neuropathic pain, it is necessary to show that there is some loss of input; also, the pain itself must reflect some

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Figure 1. The monoaminergic systems are implicated in diabetic neuropathic pain, although the contribution of the dopaminergic system is relatively minor Ascending systems Noradrenergic

Serotoninergic

Raphe nuclei

Locus coeruleus

Dopaminergic

DA nuclei

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sort of neuronal changes that result in hyperexcitability. Recent studies indicate that markers of neuronal function at the level of the thalamus are functional in patients with DPNP but impaired in those with painless neuropathy, indicating that these markers need to be intact if the patient is to perceive pain.18 A number of mechanisms have been proposed for DPNP,19-21 and full discussion of all of them is beyond the scope of this paper. Current ideas about neuropathic pain indicate that the underlying mechanism driving DPNP is a neuronal hyperexcitability which arises in the primary afferent fibres and spreads more centrally. Following such an injury to the nervous system, there is an accumulation of new and abnormal sodium and potassium channels in the periphery, as well as the generation of new sodium channels that give rise to an excessive input into the central nervous system, causing central sensitisation in second-order neurons in the spinal cord. Monoaminergic pathways, including the serotonergic, noradrenergic and to some extent dopaminergic systems originating in the raphe nuclei, locus coeruleus and dopaminergic nuclei in the mesencephalon, are implicated in DPNP (figure 1). Current thinking is that monoamines, either serotonin (5-hydroxytryptamine, 5-HT) or noradrenaline, are released and act on second-order neurons in the spinal cord, resulting in inhibitory modulation. The modulating effect exerted by the monoaminergic system may not only involve release from the descending projecting system but also be related to an effect by ascending projecting pathways. There is also some evidence to suggest that apoptosis of inhibitory neurons in the dorsal horn or spinal cord, which normally exert some inhibitory effect on second-order transmission neurons, results in spontaneous hyperexcitability in second-order neurons and in the descending inhibitory pathways. It is, however, difficult to dissect the effects of diabetes on the peripheral and central nervous system. Evidence suggests that the impact of diabetes on the nervous system is far more generalised than previously thought.20 There is a clear need for further information on mechanisms involved in the development of DPNP. One study looked at patients with ‘insulin neuritis’, who developed severe painful symptoms with rapid improvement in HbA1C.22 On sural nerve in vivo photography a fine network of blood vessels resembling the new vessels of the retina was found in a patient who also developed proliferative retinopathy,22 a well-recognised complication of rapid improvement in glycaemic control.23 Haemodynamic factors may therefore have a role in the pathogenesis of pain in diabetic neuropathy. There is also supportive evidence from a recent study of increased epineurial blood flow in patients with painful, compared with painless, diabetic neuropathy: this could be implicated in symptoms.24 Additionally, the role of hyperglycaemia requires further investigation. In a recent pilot study,25 in which blood glucose was monitored over 24 hours, there was evidence of very high excursions of blood glucose in patients with diabetes who had painful neuropathy, whereas blood glucose was much more stable in those with painless neuropathy. These

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Descending systems

data suggest that the increased glucose flux, or at least the increased oscillation of glucose flux, could be important in the causation or aggravation of painful neuropathic pain. Diagnosis and assessment Diagnostic criteria It is necessary to distinguish between criteria for the presence of neuropathy and criteria for painful neuropathy. There are several screening tools available for diagnosing diabetic neuropathy, such as the Michigan Neuropathy Screening Instrument.26 Current evidence supports the use of either the Neuropathic Pain Questionnaire (NPQ)27 or the Neuropathic Pain Symptoms Inventory28 for assessment of painful neuropathy. Screening using simple neuropathic pain-specific questionnaires such as the NPQ27 can be performed to identify patients with symptoms suggestive of DPNP that warrant clinical assessment. At the same time, other causes of pain (such as myofascial pain and ischaemic and arthrogenic types of pain) should be excluded, and possible other causes of neuropathy (for example, vitamin B12 and folate levels, thyroid function and alcohol intake) should be evaluated. Minimum requirements for a diagnosis of painful peripheral neuropathy are medical and pain history and assessment of symptoms by questionnaire, preferably using a numerical rating scale as assessment using visual analogue scales has shown less reproducibility.29 Neurological examination, with the accent on sensory examination, should be carried out (table 3). Evidence of sensory neuropathy in the painful area would be consistent with the presence of DPNP. Several procedures are available for further specialist assessment and research, including measurement of sensitivity to von Frey hair monofilaments and thermorollers; however, most of these are not suitable for prediction and assessment of DPNP.30 Additional aids for diagnosis of painful neuropathy are needed, looking specifically at the density of small intra-epidermal nerve fibres obtained from small skin punch biopsies in the affected areas. Such skin biopsies may also be used in the diagnosis of subclinical neuropathy in patients

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Table 3. Diagnostic methods for assessment of diabetic peripheral neuropathic pain Primary care clinician

● ●

● ● ●

Quantitative sensory testing Neurography/EMG Nerve/skin biopsies, surgical exploration

Positive symptoms and signs ●

Persistent distal burning or dull pain in feet

●

Persistent proximal aching pain in legs

●

Paroxysmal electric, shooting, stabbing pain

●

Dysaesthesias (painful paraesthesias)

Negative signs (i.e. deficits) ●

Hypoalgesia, analgesia

●

Hypoaesthesia, anaesthesia

●

Decrease in thermal, vibration and pressure sensation, abolition of reflexes

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Pain specialist/ neurologist and/or research

History with symptom assessment Neurological examination including at least ankle reflexes and sensory examination

Table 4. Symptoms and signs associated with diabetic polyneuropathy

Assessments highlighted are the minimum requirements for diagnosis. Key: EMG = electromyography

with impaired glucose tolerance, in whom there is a high risk of conversion to diabetes with subsequent loss of small fibres specifically in the distal portions of the lower extremities.31 Quantitative sensory testing is not practicable in primary care or for all patients. From the perspective of primary care, a simple questionnaire for DPNP is essential. In clinical practice, three symptoms are commonly considered suggestive of DPNP – numbness, tingling and pain (these are also included in the NPQ-short-form)32 – and should prompt further investigation. Symptom questionnaires should also include assessment of the impact of symptoms on quality of life and sleep.33 The symptoms described by patients can vary considerably. Attempts have been made to classify pain reported by patients as neuropathic or non-neuropathic in origin on the basis of the symptoms that they report.34,35 However, it is difficult to differentiate the predominant causes of pain in patients with diabetes with complex clinical presentations including other co-morbidities that can result in pain, such as arterial disease or osteoarthritis. Reliance on symptoms alone is not advisable and clinical evaluation is critical. Clinicians should also assess causes of pain other than neuropathic (e.g. pain due to peripheral vascular disease). There is clearly an unmet need to identify the specificity of symptom questionnaires, in particular to assess their predictive accuracy for pain of neuropathic origin.

Definition of neuropathic pain Neuropathic pain is defined by the International Association for the Study of Pain as ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’.36 In all types of neuropathic pain there is a combination of sensory loss, giving rise to negative signs, and pain, causing a variety of positive symptoms and signs19 (table 4). Pain may include dysaesthesia, an abnormal, unpleasant and disagreeable but not painful sensation (e.g. tingling), or allodynia, which is pain caused by a normal non-painful stimulus such as touch, or warm or cool temperatures. Hyperpathia also occurs. This is a phenomenon in which patients initially have an increased

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●

Evoked pain (hyperalgesia, allodynia)

threshold to a stimulus because of their loss of afferent input but this is followed by an increased stimulus response, where patients suddenly perceive an explosion of pain. The extent of this condition is unclear. Quite often, patients experience more than one type of pain at the same time. Neuropathic pain can be categorised as spontaneous (continuous or intermittent) or provoked. Provoked pain can be further categorised as allodynia or hyperalgesia (i.e. an exaggeration of the pain experienced in response to a noxious or painful stimulus). Provoked pain can also be categorised by the type of eliciting modality (i.e. mechanical, thermal or chemical) and by the way in which the stimulus is applied (whether a static, dynamic or stretch stimulus). This classification may assist categorisation into some of the underlying mechanisms of the pain itself. Clinically, it is important to distinguish between negative signs (indicative of sensation loss) and positive symptoms and signs (i.e. pain)37 (table 4). It is possible that because neuronal hyperexcitability manifesting with hypersensitivity is associated with DPNP, hypersensitivity in the presence of the loss of sensation might mask sensory loss. In principle, however, the clinician needs to establish sensory loss to confirm a diagnosis. Quality and frequency of symptoms What patients report as pain varies widely. In a study involving 105 patients with diabetes, commonly reported descriptors of symptoms (reported by more than 50% of patients) included 'burning', 'electric', 'sharp', and 'dull/ache'; for most patients the pain was worse at night time and when they were tired or stressed. The most prevalent descriptor was burning, reported in about two-thirds of patients.38 In other studies in patients with both non-diabetic and diabetic polyneuropathy, the most frequent symptom reported was a deep aching type of pain, more proximally located.39 In the EURODIAB cohort, 'deep burning pain' appeared to be a better discriminator of the presence of painful neuropathy than a ‘pricking sensation’, which was a less specific symptom.15 Further investigation is required to categorise the type

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Figure 2. Principles of pharmacological therapy of painful diabetic neuropathy

Table 5. Pharmacological treatments for neuropathic pain Drug class

Antidepressants ● Tricyclic antidepressants Amitriptyline, imipramine, (TCA) desipramine, nortriptyline, clomipramine ● SNRI Duloxetine, venlafaxine Anticonvulsants

Gabapentin, pregabalin, valproic acid, topiramate, carbamazepine, oxcarbazepine, lamotrigine

Opioids

Morphine, oxycodone, tramadol

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• Reduce peripheral sensitisation • Reduce ectopic activity • Decrease central sensitisation • Reduce central facilitation • Increase central inhibition

Treatments

Key: SNRI= selective serotonin and noradrenaline re-uptake inhibitor

and frequency of different pain qualities, whether spontaneous sensations manifesting as symptoms or elicited in examination as clinical signs, and to determine the frequency of hyperalgesia and allodynia in painful peripheral diabetic neuropathy. Clinical experience suggests that these latter symptoms are relatively rare. Co-morbidities Co-morbidities associated with DPNP include those commonly associated with chronic pain, such as depression and sleep disturbances,33,40-42 and those associated with diabetes, such as vascular disease.2,8 Diagnosis and assessment of patients’ co-morbidities is very important because they influence treatment planning and the choice of therapeutic options.8

Management The management of DPNP poses a challenge to clinicians.43 A broad, holistic approach to management is generally considered essential. Patients often feel misunderstood because there are no obvious signs of pain. Listening to and supporting patients, particularly those with severe pain, can in itself be therapeutic. Educating patients about pain mechanisms can help to allay fears about undiagnosed disease or amputation. Patients should also be informed about the benefits and limitations of treatment, and should be made aware that treatment is likely to achieve less than complete pain relief. Management of the patient with DPNP should encompass lifestyle intervention, glycaemic control and pharmacological therapy for pain relief. In addition, risk factors for macrovascular disease, specifically hypertension, dyslipidaemia, obesity and smoking, should be managed effectively. There is also a need to assess and treat co-morbidities, in particular depression, anxiety and insomnia, which are common in the patient with DPNP and influence pain perception.42

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Lifestyle intervention Just as lifestyle intervention has an integral role in reducing the risk of macrovascular diabetic complications, it might also improve nerve pathology and pain, even in patients with impaired glucose tolerance. In a preliminary report,44 treatment with diet and exercise for 12 months according to the Diabetes Prevention Program (DPP) in 32 patients with impaired glucose tolerance produced a significant (p 50% reduction in symptoms, as assessed by a visual analogue scale.67 This treatment is no longer in development for treatment of DPNP because of its relatively weak effect (NNT value approximately 6.0). Lamotrigine at doses of 50–400 mg has been shown to have a pain-relieving effect in a relatively small parallel study of DPNP.68

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or 120 mg/day for 12 weeks produced significantly greater improvement in the 24-hour average pain score relative to placebo, beginning one week after randomisation and continuing throughout the trial.53 The two following studies confirmed these results.55 Pooled analysis of all three trials, including a total of 1,139 patients, showed that between 45% and 55% of patients achieved > 50% pain reduction over 12 weeks’ treatment compared with between 25% and 28% for placebo.55 In terms of the number of patients needed to treat (NNT) to achieve 50% pain reduction, there was evidence of a dose-response effect (4.9 for 120 mg, and 5.2 for the 60 mg dose).56 Commonly reported side effects were nausea, somnolence, dizziness, decreased appetite and constipation. In one study, discontinuation due to adverse effects was more frequent among patients receiving duloxetine 120 mg/day than those receiving placebo (12.1% vs. 2.6%).54 Mild increases in blood pressure have been reported,54 suggesting caution when using this agent in patients with hypertension. Among patients who completed one study, continuation of duloxetine 60 mg/day for a further 52 weeks was safe and well tolerated compared with routine care (gabapentin, amitriptyline or venlafaxine). Treatment-emergent adverse events reported by > 10% of duloxetine-treated patients included nausea; for patients treated with conventional therapy they included peripheral oedema, somnolence and dizziness.57 Venlafaxine has been studied to a lesser extent. In one six-week trial comparing venlafaxine 75 mg/day or 150225 mg/day and placebo in 244 patients with diabetes and painful neuropathy, the extent of pain relief achieved in the higher-dose group was similar to that observed with duloxetine. Side effects included nausea, somnolence and elevated blood pressure, and seven patients treated with venlafaxine had clinically important ECG changes.58 In a double-blind, three-way crossover four-week study comparing venlafaxine 225 mg/day, imipramine 150 mg/day and placebo in painful polyneuropathy (in patients with and without diabetes) there was no significant difference in the pain-relieving effect of imipramine and venlafaxine,59 suggesting that the dual inhibitors may be equally effective in terms of pain relief.

Anticonvulsants Anticonvulsants act via two main mechanisms, either by blocking sodium channels or by binding to calcium ion channels. The anticonvulsants gabapentin and pregabalin act by binding to the alpha-2-delta sub-unit of the calcium channel, in turn reducing neurotransmitter release. These effects reduce peripheral excitability. There is also an indication of a central action. The efficacy of gabapentin for treatment of painful diabetic neuropathy has been evaluated in a number of studies.60-63 In one large study comparing gabapentin (titrated from 900 mg/day to 3,600 mg/day over four weeks) with placebo, 59.5% of patients treated with gabapentin (67% of whom received the highest dose) achieved > 50% reduction in pain compared with 32.9% on placebo.61 In a head-tohead study, the percentages of patients who achieved at least moderate pain relief with gabapentin (900–1,800

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Opioid agonists Opioid agonists modulate pain via a number of mechanisms, acting at the peripheral nociceptor, presynaptic receptor, enkephalin interneurons and post-synaptic receptors, as well as on the descending systems. These agents are efficacious in improving painful diabetic neuropathy.69-71 The opioid agonists are generally used as an add-on to other therapy, although clinical evidence to support this approach is somewhat limited. In one crossover study in 40 treatment-naïve patients with painful diabetic neuropathy, low-dose combination therapy with gabapentin and morphine was significantly more effective than either agent given alone at a higher dose.72 However, in clinical practice, patients would usually receive pain treatment before an opioid was added.73 Moreover, the combination was associated with a higher frequency of adverse effects than either monotherapy.72 Other treatments There is evidence that α-lipoic acid, an antioxidant which prevents experimental diabetic neuropathy, is effective in patients with diabetes who have symptomatic polyneuropathy. A meta-analysis including 1,258 patients from four prospective trials showed that treatment with α-lipoic acid (600 mg/day) for three weeks was associated with significant and clinically meaningful improvement in positive neuropathic symptoms (pain, burning, paraesthesia and numbness) as well as neuropathic deficits. The relative geometric mean difference in favour of α-lipoic acid versus placebo was 24.1% (95% CI 13.5% to 33.4%) for the total symptom score and 16.0% (95% CI 5.7% to 25.2%) for the neuropathy impairment score of the lower limbs.74

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Figure 3. Comparison of the relative efficacy of treatments for painful neuropathic pain (including painful diabetic neuropathy), based on the number of patients needed to treat (NNT).a Adapted with permission from Finnerup et al.49 including data for duloxetine53-55 397

Tricyclic antidepressants

83

Valproate

109

Carbamazepine/lamotrigine/phenytoin

149 150

Opioids Tramadol Gabapentin/pregabalin

1057

SNRI: Duloxetine

778

Mexiletine*

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calculated as the reciprocal of the absolute risk difference.77 In this review, the NNH is defined as the number of patients that need to be treated for one patient to drop out due to adverse effects.49 Comparison of the relative efficacy of different treatments investigated for neuropathic pain (including DPNP) (figure 3) shows that the TCAs are the most effective agents. However, it is clear that the TCAs are also associated with an increased risk of adverse effects, such as dry mouth, sweating, dizziness and sedation (table 7), as well as contra-indications for use in certain heart diseases, epilepsy and glaucoma.49 With regard to other treatments studied in large numbers of patients, duloxetine, pregabalin and gabapentin appear to have almost similar intermediate efficacy (figure 3). Dizziness and somnolence are more common for pregabalin and gabapentin than duloxetine, whereas nausea is more common for duloxetine (table 7). The cost of treatment with a TCA is lower than that for treatment with the SNRIs and the alpha-2-delta binding agents. There is a large degree of heterogeneity, which may be a reflection of the crossover design used especially in the TCA trials. A key message from these data is that regardless of the treatment offered to patients with painful diabetic peripheral neuropathy, only one third obtain more than 50% pain relief, based on NNT data. There appear to be no specific differences in efficacy associated with the diabetic condition or antidiabetic therapy.49

466

NMDA antagonists*

389

Capsaicin

81

SSRI: paroxetine, citalopram, fluoxetine

214

Topiramate*

0

2

4

6

8

10

NNT

aNNT was defined as the number of patients needed to treat (NNT) to obtain one patient with 50% pain relief * At least half of the conducted trials showed no significant effect

Key: SNRI = selective serotonin and noradrenalin re-uptake inhibitor; NMDA = N-methyl-D-aspartate; SSRI = selective serotonin re-uptake inhibitor

Recent evidence also suggests that high-frequency external muscle stimulation75 and frequency-modulated electromagnetic neural stimulation76 may have potential in treating DPNP.

Comparison of the efficacy and safety of the available treatments Estimation of the NNT and number needed to harm (NNH) provides a useful approach for comparing the relative efficacy and tolerability of the different treatments for neuropathic pain (including DPNP). In the current context, the NNT is defined as the number of patients needed to treat with a certain drug to obtain one patient with 50% pain relief,49 and is

Treatment algorithm The ideal characteristics of a treatment for DPNP are effective and sustained pain relief, as supported by evidence from high-quality trials, good tolerability and low cost. Additionally, treatment should not be associated with negative effects on quality of life, mood, functionality or sleep. Lifestyle intervention and control of glycaemia, hypertension and dyslipidaemia, as well as other risk factors for diabetes, are important first steps that may help to alleviate symptoms in some patients, although this approach is not substantiated by data from controlled studies. Optimising control of these risk factors may delay initiation of specific pain treatment.

Table 7. Comparison of the relative safety of different treatments for painful diabetic neuropathy (daily dose), based on the number of patients needed to harm (NNH)* for common side effects Pregabalin Pregabalin Gabapentin Duloxetine (300 mg) (600 mg) ( to 3,600 mg) (60 mg) Lesser64 Lesser64 Backonja61 Goldstein53 Dizziness Somnolence

4.5

2.9

5.3

> 20

Duloxetine Venlafaxine Tramadol Oxycodone (120 mg) (150–225 mg) (200–400 mg) (10–120 mg) Goldstein53 Rowbotham58 Harati71 Gimbel70 6.3

NR

> 20

4.5

5.2

4.4

6.1

8.1

4.9

7.1

16.7

2.6

Nausea

> 20

NR

> 20

14.0

5.6

20.0

5.0

3.6

Constipation

> 20

13.3

NR

8.8

14.1

NR

5.3

3.6

Key: NR = not reported; *NNH defined as the number of patients that need to be treated for one patient to drop out due to the specific adverse effect

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Figure 4. Proposed treatment algorithm for painful diabetic neuropathy Painful diabetic neuropathy

Depending on contra-indications and co-morbidities

Alpha-2-delta agonist (pregabalin or gabapentin)

TCA

First-line treatment Comparison of the relative efficacy and safety of treatments for painful diabetic neuropathy, based on the available NNT for neuropathic pain and NNH data (figure 3, table 7), indicates that a TCA, SNRI or alpha-2-delta agonist should be considered for first-line pain treatment (figure 4). On the basis of the evidence to date, pregabalin would be the preferred anticonvulsant and duloxetine the preferred SNRI. Which treatment is selected initially depends largely on the patient’s other contra-indications and co-morbidities, although cost is also an important issue. Although the TCAs have conventionally been regarded as first-line treatment for painful diabetic neuropathy, as they are relatively inexpensive and more effective than other treatments, they are also less well tolerated and there are a number of contra-indications which would be pertinent for the typical diabetic patient. In particular, the TCAs are contra-indicated in patients with cardiac decompensation and cardiac conduction disturbances. Furthermore, due to the risk of postural hypotension associated with treatment, TCAs should probably also be avoided in older patients, particularly those on diuretics. Following initiation of therapy, patients should be asked at each visit whether their pain has improved, worsened or changed in any way. At the same time, given the association of painful diabetic neuropathy and depression, patients should also be asked about their physical and social life and whether this has improved, worsened or remained unchanged. A simple questionnaire or numeric rating scale may assist in monitoring treatment response, although these tools are subjective and may be influenced by the patient's experience on the day of the visit. It should be emphasised that painful diabetic neuropathy is not simply related to pain intensity, but also to quality of life, and changes in the latter may therefore impact on the patient's perception of pain. It has been proposed that if a treatment provides at least 30% pain relief it is worth maintaining, based on con-

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SNRI (duloxetine)

If pain is inadequately controlled and depending on contra-indications

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Depression is commonly associated with chronic pain conditions such as DPNP. The reported prevalence of depression in chronic pain patients ranges from 65% to nearly 100%; variation in prevalence is attributable to methodological issues such as differences in patient selection criteria.78,79 Compared with chronic pain patients who do not suffer from depression, those with depression typically report less control of their lives, greater pain intensity, and more interference from pain. Emphasising once again the approach of holistic management, it is essential that healthcare professionals address all the needs of patients with chronic pain. Pain management, to be effective, must incorporate attention to mood disorders.80 Thus, it is essential to develop and maintain a good relationship between the clinician and patient, in order to achieve an appropriate clinical outcome. When to initiate pharmacological treatment for pain is largely subjective and dependent on the patient's perception of symptoms. In borderline cases, a simple neuropathic pain questionnaire may assist in clinical decision-making. However, if the patient still reports pain despite optimisation of risk factors, then it is time to treat him.

TCA or SNRI

SNRI or alpha-2-delta agonist

TCA or alpha2-delta agonist

If pain is still inadequately controlled

Opioid agonist as monotherapy, followed by combination therapy if pain control is still inadequate

Key: TCA = tricyclic antidepressant; SNRI = selective serotonin noradrenaline re-uptake inhibitor

sideration of the patient's co-morbidities.81 However, the Panel recognises that this management issue requires further evaluation. If the pain is inadequately controlled, and depending on contra-indications, another first-line agent may be considered (TCA, duloxetine or pregabalin/ gabapentin) (figure 4).

Combination therapy Combination therapy may be considered if the patient still reports pain despite a change in first-line therapy. Currently, there are no clinical trial-based data or guidelines on which to base decisions for combination therapy. Clinical experience suggests that the combination of either a TCA, duloxetine or pregabalin/gabapentin and an opioid agonist is an appropriate option, as indicated in the proposed treatment algorithm (figure 4). The Panel recognises that there needs to be some rationale for multi-drug therapy of painful diabetic neuropathy, which would offer some guidance in clinical decision-making. Additional treatments that provide at least the same level of pain relief could be prescribed, depending on the severity of pain.82 Given that the newer treatments, duloxetine, pregabalin and gabapentin are relatively well tolerated, these could be safely combined, although contraindications should also be borne in mind. Tailoring treatment to the patient Although the proposed treatment algorithm provides guid-

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ance for the clinician treating painful diabetic neuropathy (including DPNP), treatment needs to be tailored to the patient, taking into account his co-morbidities. For example, TCAs should be avoided if the patient has glaucoma, cardiovascular disease or static phenomena; duloxetine should be avoided if the patient has hepatic insufficiency; and pregabalin should be avoided if the patient has a problem with weight gain. Additionally, opioids should be avoided in patients with depression or a history of substance abuse.

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Conclusions Painful diabetic neuropathy is an important complication of diabetes, with implications for patient morbidity and mortality. Although estimates suggest that the condition affects about 10–20% of patients, further prevalence data are required, in particular for DPNP. There is a clear need for further research into the mechanism of DPNP. Additionally, there are a number of issues relating to diagnosis, assessment and treatment of DPNP that contribute to deficiencies in its management. This Expert Panel considers that initial screening, by the use of a simple questionnaire, will aid the identification of patients with symptoms suggestive of DPNP for further investigation. The minimum requirements for diagnosis of painful peripheral neuropathy are history and assessment of symptoms by simple questionnaire, together with neurological examination, including sensory examination. These assessments should be manageable in the primary care setting. Given that DPNP is a chronic pain condition, closely associated with mood disturbances, a holistic approach to management is important. Clinicians should inform patients about DPNP and the benefits and limitations of treatment. Lifestyle intervention and optimisation of glycaemia and other risk factors such as hypertension and dyslipidaemia are important first steps and may help to delay initiation of pain treatment. Recent developments have resulted in the availability of new, effective treatments for painful diabetic neuropathy, with improved tolerability compared with the TCAs. Cost is an issue, however. An evidence-based treatment algorithm has been proposed (figure 4), indicating a role for new agents such as duloxetine and pregabalin as treatment alternatives in the first-line setting. The Panel has identified a number of deficiencies in the available clinical data that warrant attention: ● The lack of understanding of the underlying mechanisms of painful diabetic neuropathy ● The lack of specific measurement tools for painful diabetic neuropathy ● The lack of direct head-to-head comparative trials ● The need for standardised study end points ● The need for studies to investigate treatment effects on different symptoms ● The need to investigate the effect of co-morbidities on treatment efficacy ● The need for further long-term efficacy and safety data ● The need for investigation of the efficacy and safety of different combination therapies ● The need for further trials to investigate non-pharmacological modes of therapy

A sobering key message emerging from this review is that irrespective of which treatment is offered, fewer than one third of patients achieve 50% or more pain relief. Although the proposed treatment algorithm provides guidance to the clinician treating painful diabetic neuropathy, treatment needs to be tailored to the patient, taking into account his co-morbidities. Treatment should encompass relief of pain, as well as improvement in quality of life. This International Expert Panel believes that the evidence discussed and presented in this report, which is consistent with a recently published consensus paper in the US,83,84 will offer a current perspective on the management of painful diabetic neuropathy, including DPNP, for clinicians.

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Acknowledgement This report was prepared following a round table discussion meeting, sponsored by Boehringer Ingelheim and Eli Lilly and Company. Professor Clifford Bailey, Head of Diabetes Research, School of Life and Health Sciences, Aston University, Birmingham, UK, acted as a mediator at the meeting. References

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