A Delphi consensus statement of the Neuropathic Pain Special Interest Group of the Italian Neurological Society on pharmacoresistant neuropathic pain.

To improve patient care and help clinical research, the Neuropathic Pain Special Interest Group of the Italian Neurological Society appointed a task force to elaborate a consensus statement on pharmacoresistant neuropathic pain. The task force included 19 experts in neuropathic pain. These experts participated in a Delphi survey consisting of three consecutive rounds of questions and a face-to-face meeting, designed to achieve a consensus definition of pharmacoresistant neuropathic pain. In the three rounds of questions, the participants identified and described the main distinguishing features of pharmacoresistance. In the face-to-face meeting the participants discussed the clinical features determining pharmacoresistance. They finally agreed that neuropathic pain is pharmacoresistant when "the patient does not reach the 50% reduction of pain or an improvement of at least 2 points in the Patient Global Impression of Change, having used all drug classes indicated as first, second, or third line in the most recent and widely agreed international guidelines, for at least 1 month after titration to the highest tolerable dose." Our consensus statement might be useful for identifying eligible patients for invasive treatments, and selecting patients in pharmacological trials, thus improving patient care and helping clinical research.

How to diagnose neuropathic pain? The contribution from clinical examination, pain questionnaires and diagnostic tests.

Patients with peripheral and central nervous system diseases may suffer from different types of pain, namely nociceptive, neuropathic and mixed pain. Although in some cases, the distinction between these types of pain is clinically evident, yet in some patients an accurate differential diagnosis requires dedicated clinical examination, screening questionnaires and diagnostic techniques some of which are available only in specialized pain centres. This review briefly addresses the currently agreed definitions of the different types of pain and shows how clinical examination, pain questionnaires and diagnostic tests can help the clinicians in identifying neuropathic pain.

Prevalence and features of peripheral neuropathy in Parkinson's disease patients under different therapeutic regimens.

BACKGROUND: Recent reports suggest increased frequency of peripheral neuropathy (PN) in Parkinson's disease (PD) patients on levodopa compared with age-matched controls particularly during continuous levodopa delivery by intestinal infusion (CLDII). The aim of this study is to compare frequency, clinical features, and outcome of PN in PD patients undergoing different therapeutic regimens. METHODS: Three groups of consecutive PD patients, 50 on intestinal levodopa (CLDII), 50 on oral levodopa (O-LD) and 50 on other dopaminergic treatment (ODT), were enrolled in this study to assess frequency of PN using clinical and neurophysiological parameters. A biochemical study of all PN patients was performed. RESULTS: Frequency of PN of no evident cause was 28% in CLDII, 20% in O-LD, and 6% in ODT patients. Clinically, 71% of CLDII patients and all O-LD and ODT PN patients displayed a subacute sensory PN. In contrast, 29% of CLDII patients presented acute motor PN. Levodopa daily dose, vitamin B12 (VB12) and homocysteine (hcy) levels differed significantly in patients with PN compared to patients without PN. CONCLUSIONS: Our findings support the relationship between levodopa and PN and confirm that an imbalance in VB12/hcy may be a key pathogenic factor. We suggest two different, possibly overlapping mechanisms of PN in patients on CDLII: axonal degeneration due to vitamin deficiency and inflammatory damage. Whether inflammatory damage is triggered by vitamin deficiency and/or by modifications in the intestinal micro-environment should be further explored. Proper vitamin supplementation may prevent peripheral damage in most cases.

Painful peripheral neuropathies.

Peripheral neuropathies are a heterogeneous group of diseases affecting peripheral nerves. The causes are multiple: hereditary, metabolic, infectious, inflammatory, toxic, traumatic. The temporal profile includes acute, subacute and chronic conditions. The majority of peripheral neuropathies cause mainly muscle weakness and sensory loss, positive sensory symptoms and sometimes pain. When pain is present, however, it is usually extremely intense and among the most disabling symptoms for the patients. In addition, the neurological origin of the pain is often missed and patients receive inadequate or delayed specific treatment. Independently of the disease causing the peripheral nerve injury, pain originating from axonal pathology or ganglionopathy privileges neuropathies affecting smaller fibres, a clinical observation that points towards abnormal activity within nociceptive afferents as a main generator of pain. Natural activation of blood vessels or perineurial nociceptive network by pathology also causes intense pain. Pain of this kind, i.e. nerve trunk pain, is among the heralding symptoms of inflammatory or ischemic mononeuropathy and for its intensity represents itself a medical emergency. Neuropathic pain quality rekindles the psychophysical experience of peripheral nerves intraneural microstimulation i.e. a combination of large and small fibres sensation temporally distorted compared to physiological perception evoked by natural stimuli. Pins and needles, burning, cramping mixed with numbness, and tingling are the wording most used by patients. Nociceptive pain instead is most often described as aching, deep and dull. Good command of peripheral nerve anatomy and pathophysiology allows timely recognition of the different pain components and targeted treatment, selected according to intensity, type and temporal profile of the pain.

Pain in diabetic neuropathy case study: whole patient management.

Painful diabetic peripheral neuropathy (DPN) is described as a superficial burning pain associated with other positive and/or negative sensory systems affecting the feet and lower extremities. It is one of the most commonly encountered neuropathic pain syndromes in clinical practice. Presentation may be complicated by multiple symptoms, including allodynia, hyperalgesia, other less well characterized dysesthesias, and serious disruption of social functioning and mood. Peripheral nerve function may deteriorate, which can account for patient reports of diminution of pain after several years of follow-up. Although current understanding holds that the pathogenesis of DPN is multifactorial in nature, long-term studies have shown that rigorous glycemic control is the most relevant factor in clinical intervention and can delay the onset and slow the progression of neuropathy. In addition to glycemic control, other treatment approaches must be examined in order to restore quality of life for patients experiencing painful DPN. Differential diagnosis is required to isolate DPN from other unexplained chronic pain. Neurologic testing in painful DPN is an area of active research and is used to assess the neurologic pathways giving rise to the pain, the degree of neural damage and the degree of subclinical damage. Current treatment options for DPN include mainly antidepressants and anticonvulsants, with other agents such as tramadol, dextromethorphan and memantine being employed or studied. This review article includes a case study of a patient with painful DPN to demonstrate the current management strategies for this neuropathic pain syndrome.

Iatrogenic painful neuropathic complications of surgery in cancer.

It is estimated that at least one out of four patients with cancer complains of pain originating from nerve injury. Nerve injury may result from direct invasion/compression by tumour, or by remote effect of the cancer such as paraneoplastic polyneuropathy. In many cases, the nerve injury is caused by medical therapy, or surgical interventions. Pain generated by drugs or medical acts is called iatrogenic. A common iatrogenic neuralgia is chemotherapy induced painful polyneuropathy. This neuropathy typically affects mostly the small myelinated and unmyelinated nerve fibres. Surgical and anaesthesiological interventions also frequently cause direct nerve stretch or section. Some interventions, particularly those requiring extended resection, have a higher incidence of painful sequelae. Limb and colon amputation, nerve dissection, mastectomy and thoracotomy are the most common interventions for cancer known to cause nerve injury. As pain clinicians, we focus attention on the painful consequences of surgical interventions because there is evidence that a more accurate surgical approach and possibly a prophylactic prevention of the neuralgia may reduce the painful sequelae of nerve injury.

Disappearance of central pain following iatrogenic stroke.

An exceptional case of long-standing central pain temporarily relieved by a focal stroke in the primary somatosensory area is reported. This case highlights the focal nature of central pain mechanisms and the possible value of selective subparietal leukotomies in the management of central pain.

Sympathetically maintained pain.

Reflex sympathetic dystrophy (RSD) is a controversial condition, redefined in 1996 by an ad hoc International Association for the Study of Pain (IASP) task force. One of the strongest critiques against the entire concept of sympathetic-dependent pain is that patients labeled as having RSD harbor in reality a somatoform disorder. Here clinical cases are described to prove that other organic medical conditions may exist other than RSD and still present the clinical picture of pain, sensory, and vasomotor disorders and trophic changes. The analysis of each patient illustrates how the inappropriate diagnosis of RSD may lead to increased worsening of pain intensity, or delay the proper diagnosis, and consequently the appropriate treatment.

Injured nerve block alters adjacent nerves spinal interaction in neuropathic rats.

Baseline activity and responses to simultaneous saphenous stimulation of pairs of neurones recorded from sciatic (L5-6) and saphenous (L2) spinal cord segments, in rats with thermal hyperalgesia following sciatic constriction, were analysed before, during and after a sciatic nerve block with a local anaesthetic. In sciatic neurones, during the block, reductions of baseline activity (p < 0.001), increases in threshold of saphenous electrical stimulation (p < 0.01) and reductions of responses to electrical and to natural noxious saphenous stimuli (p < 0.001) were consistently found. The neuronal baseline and evoked activities remained unmodified in saphenous neurones. The contribution of input from injured periphery to central neurone circuitry mechanisms underlying the unmasking of improper afferents is discussed.

Evidence of peripheral axonal neuropathy in primary restless legs syndrome.

Restless legs syndrome (RLS) is a well-defined clinical entity characterized by an unpleasant creeping sensation arising in the legs with an irresistible need to move them. The trouble is more pronounced when the affected people lie in a prolonged rest position and try to fall asleep. It is known that RLS may be consequent to systemic disorders and to diseases affecting the central or peripheral nervous system. The International Classification of Sleep Disorders states that peripheral neuropathy should be ruled out by medical history and clinical grounds before diagnosing primary RLS (pRLS). The present study extended peripheral nerve investigation in eight consecutive pRLS patients with normal neurological examination results and showed that all patients exhibited two or more electrical, psychophysiological, and/or morphological features of peripheral axonal neuropathy. Morphometric analysis of sural nerve showed a significant reduction in myelinated fiber density and g ratio (axon diameter/fiber diameter) in the pRLS group compared with eight control biopsy specimens. These results suggest that axonal neuropathy is often present in patients with RLS. A comprehensive peripheral nerve investigation should be considered in RLS patients.

Different time-courses of i.v. lidocaine effect on ganglionic and spinal units in neuropathic rats.

The effect of intravenous lidocaine (4 mg kg-1) on ganglionic and spinal neuronal hyperactivity following sciatic chronic constriction injury (CCI) was studied in anaesthetized and curarized rats. A significant difference in the time course and magnitude of the lidocaine effect on the two neuronal populations was found. Longer lasting and more potent inhibitory effects on the dorsal horn neurones in comparison with ganglionic neurones were observed. By contrast the magnitude and time course of the inhibitory effects were highly comparable in dorsal horn neurones before and after acute rhizotomy. The results indicate that peripheral and central effects of lidocaine are not sequentially related. The likelihood that lidocaine inhibition at central sites may have a role in its analgesic effect, at least in the neuropathic model, is discussed.

Sensory disorder of the chest as presenting symptom of lung cancer.

Four patients with pancoast's syndrome had burning pain in the axilla and abnormal sensation in the intercostobrachial nerve territory. The intercostobrachial nerve is the first component of the brachial plexus to be invaded by lung tumours.

Diverse modulation by systemic lidocaine of iontophoretic NMDA and quisqualic acid induced excitations on rat dorsal horn neurons.

The effects of systemic lidocaine (3-4 mg/kg) on the responses of 60 wide dynamic range neurons (WDR) to iontophoretically applied N-methyl-D-aspartic acid (NMDA) and quisqualic acid (QUIS) were studied in anesthetized, paralysed rats. The results show that lidocaine induced (i) potentiation of the NMDA excitation, reversible by 7-chloro-kynurenate (7-Cl-KYNA), a selective antagonist of the glycine binding site on the NMDA receptor; (ii) reduction of the QUIS excitation, reversible by strychnine (STRYCH), a glycine antagonist at its receptor. These findings, supporting a glycine-like action of lidocaine, are discussed together with data on the role of excitatory amino acids (EAAs) and the analgesic effect of lidocaine on neuropathic pain.

Effect of systemic lidocaine on dorsal horn neuron hyperactivity following chronic peripheral nerve injury in rats.

Systemic lidocaine (3-4 mg/kg) was tested for its effect on identified spinal cord wide-dynamic-range (WDR) neurons in rats with a unilateral chronic neuropathy induced by two different peripheral nerve injuries (section or compression by ligatures). In both cases, neurons on the side ipsilateral to the injuries showed a spontaneous firing frequency higher than that of the opposite intact side (23.5 +/- 3.4 vs 4.2 +/- 1.5 spikes/sec). The hyperactivity was not affected by a sensory block of the peripheral receptive field. It was consistently found that lidocaine suppressed or reduced the spontaneous neuronal hyperactivity on the ipsilateral side, whereas it had no effect on the normal spontaneous activity of the neurons on the intact side. In all recordings, the hyperactivity returned to the prelidocaine injection rates within 20 min. These results indicate a preferential action of subanesthetic doses of lidocaine on the hyperactive WDR neurons. Such preferential action is related to a susceptibility acquired by WDR neurons of the peripherally injured side and is not simply attributable to the increased frequency of firing.

Selective inhibition by systemic lidocaine of noxious evoked activity in rat dorsal horn neurons.

The effect of systemically injected lidocaine (3-4 mg kg-1) on the responses to noxious and non-noxious stimuli on 28 wide dynamic range (WDR) neurons in the dorsal horn was studied in anesthetized and curarized rats. It was consistently found that lidocaine reduced or suppressed the responses to noxious stimuli whereas it did not act on the responses to non-noxious stimulation and on the spontaneous activity. Furthermore the noxious stimuli were completely ineffective from 10-15 min following the lidocaine injection while the non-noxious stimuli maintained their efficacy. The control responses, in all the cases, returned within 20 min. The results suggest that lidocaine exerts a selective inhibitory effect on nociceptive transmission at the spinal level.

Sensitized nociceptors in reflex sympathetic dystrophies.

Painful neurogenic syndromes commonly diagnosed as reflex sympathetic dystrophy (RSD) may not be the consequence of sympathetic dysfunction. Recent experimental data on the mechanism of hyperalgesia indicate that the primary pathophysiological mechanism of RSD may be sensitization of either peripheral nociceptors, or central neurons, or both. The sympathetic system might be involved in maintaining this condition, but this is not always the case. This presentation is an attempt to interpret clinical neuropathic syndromes on the basis of new scientific knowledge.

The objective assessment of visual contrast sensitivity by pattern reversal visual evoked potentials in diabetes.

Recent studies have described abnormalities of visual evoked potentials and pattern electroretinography in diabetics without retinopathy. The visual contrast sensitivity, determined by psychophysical tests, has proved to be abnormal in diabetic patients with and without clinical retinopathy. In this study we evaluated contrast sensitivity function using both electrophysiologic and psychophysical methods. The objective assessment of functional visual contrast sensitivity was superior to psychophysical evaluation in the detection of contrast sensitivity alterations. No relationships were found between contrast sensitivity dysfunction and abnormalities of pattern electroretinography or fluorescein angiography. Our data suggest that functional visual deficits might precede background retinopathy and that the involvement of foveal function is early and very frequent in diabetic patients, even if they have normal visual acuity.