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.

Are there different predictors of analgesic response between antidepressants and anticonvulsants in painful diabetic neuropathy?

BACKGROUND: To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP). METHODS: Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes. RESULTS: A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use. CONCLUSIONS: Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms.

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.

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.

A comparison of hetastarch and peritoneal dialysis solution for intraperitoneal chemotherapy delivery.

AIM: Intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. We compared the pharmacokinetics of paclitaxel infused intraperitoneally in two isotonic carrier solutions, 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution. METHODS: Twenty patients with peritoneal carcinomatosis were randomized into one of two groups to receive early postoperative intraperitoneal chemotherapy with paclitaxel for 5 consecutive days following cytoreductive surgery. One group (8 patients) received paclitaxel in one litre of peritoneal dialysis solution; the other group (12 patients) received paclitaxel in one litre of hetastarch. Samples of peritoneal fluid and venous blood were taken during the 23 h dwell time. Volumes of chemotherapy solution were recorded and concentrations of paclitaxel determined by high performance liquid chromatography. RESULTS: Hetastarch clearance from the peritoneal cavity was reduced when compared to peritoneal dialysis solution. The mean volume of fluid remaining in the peritoneal cavity at 23 h was 900 ml +/-373.7 (SD) with hetastarch, and 285 ml (+/-157.5) with peritoneal dialysis solution (P=0.0022). The mean total amount of paclitaxel in the peritoneal cavity at 23 h was 2.597 mg (+/-1.57) with hetastarch and 0.772 mg (+/-0.667) with peritoneal dialysis solution (P=0.0152). CONCLUSION: These data show that hetastarch increased the exposure of peritoneal surfaces to paclitaxel by increasing the volume of solution with no decrease in drug concentration. Residual tumour cells within the peritoneal cavity may show an increased response to paclitaxel with hetastarch as a carrier solution.

Mucinous adenocarcinoma of the small bowel with peritoneal seeding.

AIMS: Small bowel adenocarcinoma has an extremely poor prognosis because of delayed diagnosis and the presence of advanced disease. Carcinomatosis associated with a small bowel primary cancer has not been reported to be successfully treated in the past. METHODS: The clinical information prospectively recorded on six patients with carcinomatosis from small bowel adenocarcinoma was reviewed. All of these patients were treated with an aggressive local--regional strategy that utilized cytoreductive surgery plus peri-operative intraperitoneal mitomycin C and 5-fluorouracil. RESULTS: Disease control in the abdomen and pelvis was achieved in four of these patients. Their median survival was 12 months with one patient alive and well at 4.5 years. CONCLUSIONS: Small bowel adenocarcinoma continues to provide a surgical challenge. Complete resection of all visible disease combined with intraperitoneal chemotherapy to eradicate microscopic residual disease should be considered as an option in patients with carcinomatosis.

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.

Sleep arousal response to experimental thermal stimulation during sleep in human subjects free of pain and sleep problems.

Although the interaction between sleep and pain is generating considerable interest (NIH Technology Assessment Panel, 1996), it is still unknown if chronic pain is the cause or effect of poor sleep. To further this understanding, subjects free of pain and sleep problems need to be studied in order to assess their response to pain during sleep, defined as a behavioral and a physiological state in which sensory processing is altered. (For example, while auditory perception remains active, other sensory inputs are facilitated, attenuated, or suppressed (Velluti, 199746 degrees C) was statistically greater in the lighter sleep stage 2 (48.3%) than in the deeper stages 3&4 (27.9%). A nocifensive behavioral-motor response was associated with only 2.5% of the 351 heat pain stimuli. Two other markers of sleep quality-sleep stage shift and awakening-were not influenced by the thermal stimuli. None of the subjects demonstrated any burns in the morning following the thermal stimulations applied during sleep. We conclude that the processing of nociceptive inputs is attenuated across sleep stages.

Hypnosis with conscious sedation instead of general anaesthesia? Applications in cervical endocrine surgery.

Between April 1994 and June 1997, 197 thyroidectomies and 21 cervical explorations for hyperparathyroidism were performed under hypnosedation (HYP) and compared to the operative data and postoperative courses of a closely-matched population (n = 121) of patients operated on under general anaesthesia (GA). Conversion from hypnosis to GA was needed in two cases (1%). All surgeons reported better operating conditions for cervicotomy using HYP. All patients having HYP reported a very pleasant experience and had significantly less postoperative pain while analgesic use was significantly reduced in this group. Hospital stay was also significantly shorter, providing a substantial reduction of the medical care costs. The postoperative convalescence was significantly improved after HYP and full return to social or professional activity was significantly shortened. We conclude that HYP is a very efficient technique providing physiological, psychological and economic benefits to the patient.

Ectopic impulse generation and autoexcitation in single myelinated afferent fibers in patients with peripheral neuropathy and positive sensory symptoms.

Microneurographic studies were performed using cutaneous nerves of 8 patients with documented peripheral neuropathy who expressed positive sensory symptoms. Intraneural recordings in single myelinated fibers revealed: (i) ectopic generation of bursts of spontaneous action potentials; (ii) ectopic generation of ongoing repetitive discharges transiently interrupted by natural stimulation of the receptive field; and (iii) repetitive discharges triggered by a preceding action potential. These results provide direct evidence of a peripheral pathophysiological basis for spontaneous and stimulus-induced paresthesias and dysesthesias in patients with peripheral neuropathy.

Central effect of ketorolac involving NMDA receptors activity.

Possible central mechanisms underlying the analgesic action of Ketorolac, a non-steroidal antiinflammatory drug (NSAID) have been investigated using an iontophoretic approach. We found that the excitation induced by N-methyl-d-aspartate (NMDA) on spinal wide dynamic range (WDR) neurons was prevented, or reduced, by Ketorolac applied before or after the start of the NMDA ejection. The data suggest that Ketorolac can achieve its central analgesic effect by interfering with the NMDA receptor activity on the spinal neurons.