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Background: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, traumatic spinal cord injury, or multiple sclerosis. These syndromes are distinctly less common than peripheral neuropathic pain, and less is known regarding the underlying pathophysiology, appropriate pharmacotherapy, and long-term outcomes. The objective of this study was to determine the long-term clinical effectiveness of the management of central neuropathic pain relative to peripheral neuropathic pain at tertiary pain centers. Methods: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified for analysis from a prospective observational cohort study of patients with chronic neuropathic pain recruited from seven Canadian tertiary pain centers. Data regarding patient characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow-up. The primary outcome measure was the composite of a reduction in average pain intensity and pain interference. Secondary outcome measures included assessments of function, mood, quality of life, catastrophizing, and patient satisfaction. Results: At 12-month follow-up, 13.5% (95% confidence interval [CI], 5.6-25.8) of patients with central neuropathic pain and complete data sets (n=52) achieved a ≥30% reduction in pain, whereas 38.5% (95% CI, 25.3-53.0) achieved a reduction of at least 1 point on the Pain Interference Scale. The proportion of patients with central neuropathic pain achieving both these measures, and thus the primary outcome, was 9.6% (95% CI, 3.2-21.0). Patients with peripheral neuropathic pain and complete data sets (n=463) were more likely to achieve this primary outcome at 12 months (25.3% of patients; 95% CI, 21.4-29.5) (p=0.012). Conclusion: Patients with central neuropathic pain syndromes managed in tertiary care centers were less likely to achieve a meaningful improvement in pain and function compared with patients with peripheral neuropathic pain at 12-month follow-up.
Background: Painful diabetic neuropathy (PDN) is a frequent complication of diabetes mellitus. Current treatment recommendations are based on short-term trials, generally of ≤3 months’ duration. Limited data are available on the long-term outcomes of this chronic disease. The objective of this study was to determine the long-term clinical effectiveness of the management of chronic PDN at tertiary pain centres. Methods: From a prospective observational cohort study of patients with chronic neuropathic non-cancer pain recruited from seven Canadian tertiary pain centres, 60 patients diagnosed with PDN were identified for analysis. Data were collected according to Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials guidelines including the Brief Pain Inventory. Results: At 12-month follow-up, 37.2% (95% confidence interval [CI], 23.0-53.3) of 43 patients with complete data achieved pain reduction of ≥30%, 51.2% (95% CI, 35.5-66.7) achieved functional improvement with a reduction of ≥1 on the Pain Interference Scale (0-10, Brief Pain Inventory) and 30.2% (95% CI, 17.2-46.1) had achieved both these measures. Symptom management included at least two medication classes in 55.3% and three medication classes in 25.5% (opioids, antidepressants, anticonvulsants). Conclusions: Almost one-third of patients being managed for PDN in a tertiary care setting achieve meaningful improvements in pain and function in the long term. Polypharmacy including analgesic antidepressants and anticonvulsants were the mainstays of effective symptom management.
Segmental hyperhidrosis is an uncommon finding which is usually associated with irritation or infiltration of pre-ganglionic sympathetic fibres or the sympathetic chain.
We report two cases of segmental hyperhidrosis with striking clinical features.
In one case, a mesothelioma produced ipsilateral simultaneous underactivity and overactivity of sympathetic outflow and in the other case a thoracic central disc herniation was probably responsible for a band of sweating which clearly extended beyond the segmental level of injury.
Segmental hyperhidrosis should trigger a search for structural disease in the spinal and paraspinal region.
This chapter describes the forms of assessment of neuropathic pain (NP) currently used in neuropathic pain therapeutic trials including intensity scales, specific and non-specific pain measurement questionnaires, and quantitative sensory testing (QST), with emphasis on their advantages and limitations. The lack of specificity of the McGill Pain Questionnaire (MPQ) and SF-MPQ for neuropathic pain has led to the development of various NP measurement scales that have been designed to evaluate separately the various symptoms of neuropathic pain. QST allows an assessment of sensory detection thresholds for innocuous stimuli and pain thresholds, generally using the method of limits, less commonly the method of levels. It also includes the assessment of sensations induced by sub-threshold or suprathreshold stimuli, which may contribute to the identification and quantification of hyperalgesia. Finally, the chapter summarizes and discusses prior recommendations about the use of these measures in clinical trials.
This chapter focuses on the voltage-gated sodium (Nav) channel and voltage-gated calcium channel (VGCC), since they are essential to pain transmission. The most basic structural plan of a eukaryotic voltage-gated ion channel consists of four sub-units surrounding a central pore, through which ions pass. Sodium channel inactivation is modulated by many factors, including toxins, disease states, mutations, and therapeutic drugs. In neurons, activation of VGCC in response to depolarized membrane potential leads to calcium entry, mediating calcium-dependent enzyme activation, gene expression, or release of neurotransmitters. Two main classes of VGCC have been reported, the T-type or low voltage activated (LVA) and the high voltage activated (HVA) channels. To manage different etiologies of neuropathic pain, a variety of therapeutic targets must be available. Drugs directed at specific targets, such as those channels expressed in nociceptors, or upregulated after injury, may give the best pain management while minimizing undesirable side effects.
This chapter describes commonly used peripheral nerve injury models of neuropathic pain. It introduces the central, non-traumatic and orofacial models of neuropathic pain. Neuropathic pain of central origin is observed clinically after traumatic incidents, such as stroke or spinal cord injury (SCI). An important consideration is that the pain experience, in humans and animals, has both sensory and emotional dimensions. The focus on nociception in pain research has been associated with the clinical failure of several potential pain medicines. An understanding of both sensory and affective dimensions of pain may improve translational research. Further, interpretations made from animal nerve injury models should be considered in the context of gender, age, and species/strain studied. Finally, it appears that no animal nerve injury model is without limitations, therefore, behavioral, physiological, and biochemical studies can only speculate on the relevance of experimental findings to human neuropathic pain.
Neuropathic pain after spinal cord injury (SCI) is a type of central neuropathic pain and is a frequent complication of spinal injury which is often refractory. Studies in animal models describe a number of peripheral and central pathophysiological processes after nerve injury that would be the basis of underlying neuropathic pain mechanisms. A major inhibitory system related to pain is opioid receptor mediated analgesia. In neuropathic pain, N-methyl-d-aspartate (NMDA) receptor activation increases excitation in the pain transmitting systems. Recent advances in pain research indicate multiple mechanisms, including many components of peripheral and central sensitization mechanisms, underlying the initiation and maintenance of neuropathic pain. Neurosurgical interventions may be treatment options in patients with poor pain control despite pharmacotherapy. Besides the effectiveness of a treatment, the adverse event profiles of these analgesics have to be considered before starting therapy or combining different agents.
Over the past 150 years, regional post-traumatic pain has had various appellations, most recently complex regional pain syndrome (CRPS) and post-traumatic neuralgia (PTN). CPRS appears to be a complex endophenotype of PTN that involves neurogenic inflammation as well as pain. There is increasing evidence that peripheral and central inflammatory cascades triggered by nerve injuries contribute to CRPS and perhaps PTN as well. PTN and CRPS often spread beyond classic individual nerve territories, although when patients are asked to outline the epicenter, or most abnormal area, this frequently identifies a specific nerve injury. The most dramatic CRPS and PTN-associated movement abnormality is fixed distal dystonia. Nerve conduction studies and electromyography are useful in documenting and localizing peripheral nerve damage. Currently, four classes of medications are primary options for chronic CRPS/PTN: tricyclics and serotonin-noradrenaline reuptake inhibitors; opioids; gabapentinoids; and topical or systemic local anesthetics.
This chapter summarizes a standard approach to identifying neuropathic pain for the clinician. For neuropathic pain, and for the condition of complex regional pain syndrome (CRPS) especially, the six Ss should be queried when obtaining details regarding the affected region. A useful tool to rapidly and accurately localize sources of chronic pain and assist in the diagnosis of causes of neuropathic pain is a pain diagram. The examination of a chronic pain patient should start with an appropriate and directed general examination including a neurological examination. Quantitative sensory testing (QST) provides indirect information used to evaluate underlying sensory function abnormalities using only small, portable tools and with less time requirement than protocols developed by the German Neuropathic Research Network. In the future, bedside QST is expected to continue to play a role in determining potential pain mechanisms to help direct further evaluation and treatment.
Diabetic sensorimotor polyneuropathy (DSP) is a condition that has escaped direct management at the present time. The diagnosis of painful DSP (PDSP) is based upon important historical and clinical examination aspects, with some diagnostic assistance provided by nerve conduction studies. There is great complexity in the pathophysiology of DSP. Hyperglycemia in both humans and in animal axonal models appears to drive several metabolic pathways contributing to initiation and progression in humans and to the presence of peripheral neuropathy in animal models. Pharmacological treatment is required in a majority of patients with PDSP. Most guidelines suggest that anticonvulsants and antidepressants be used first, prior to opioids due to the risk of dependency, tolerance, dose escalation, and diverse effects. Future treatments may include better methods to modulate loss of central inhibition, better topical applications, and directed therapy against neuroinflammatory changes of microgliosis and astrogliosis.
Central or peripheral neuropathic pain can be caused by a wide range of injuries, infections and diseases such as: spinal cord injury, multiple sclerosis, stroke, herpes zoster, diabetes and cancer. Many of these pain syndromes are difficult to treat, representing a challenge for many neurologists not routinely trained in pain management. Written by an international team of experts in the field, Neuropathic Pain: Causes, Management and Understanding gives readers an in-depth understanding of the multitude of conditions causing neuropathic pain. Epidemiology, clinical diagnosis, pathophysiology, outcome measurement and the best evidence-based management of individual and general neuropathic pain conditions are also described in depth. A unique chapter, written from a patient's viewpoint, gives new insight into how chronic neuropathic pain affects the lives of those patients with the condition. This book is essential reading for all pain specialists, neurologists, psychiatrists and anesthesiologists who wish to better understand their patients' neuropathic pain.
Tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors (SNRIs) (venlafaxine, duloxetine) are recommended as the first-line agents for peripheral neuropathic pain, especially for painful polyneuropathy, the other first-line options being gabapentinoids and topical lidocaine. Tricyclic antidepressants became a mainstay in the management of neuropathic pain before their mechanisms were elucidated and before the advent of systematic ways to evaluate their efficacy. Venlafaxine and duloxetine should be used with caution in patients with a history of mania, seizures, or bleeding tendency. Due to risk of excessive serotoninergic effect, they should be used with caution in patients receiving concomitant selective serotonin reuptake inhibitor (SSRI) or tramadol treatment. When selecting the treatment for an individual patient, comorbid conditions and their medications need to be taken into account. More detailed information of the effects of pharmacological agents on various symptoms of neuropathic pain and sensory profiles may guide drug selection in the future.
Neuropathic pain occurs frequently in patients with cancer, both from direct tumor infiltration of neural structures and as a consequence of treatment of the neoplasm. Management of neuropathic pain presents a number of challenges. Such pain is often more resistant to conventional analgesic approaches than is nociceptive pain. Many of these patients will have mixed pain problems, where neuropathic pain is combined with elements of somatic or visceral nociceptive pain. Neuropathic pain also may signal progressive and often incurable disease, adding a significant suffering component to the pain problem.
Successful management of neuropathic cancer pain requires an understanding of the pathophysiologic processes that generate this type of pain and of the distinctive clinical features that identify it. In addition, a knowledge of the various clinical neuropathic pain syndromes that occur in the cancer patient and of the range of available treatments is essential.
Neuropathic pain occurs as a result of aberrant somatosensory processing in the nervous system, and as such may be sustained by peripheral mechanisms, central mechanisms, or both. Pain after peripheral nerve injury may occur through a variety of mechanisms. When a nerve is compressed or distended, nerve trunk pain may occur as a result of activation of the nervi nervorum, the normal nociceptive afferents that innervate the nerve sheaths themselves (1). Damage to primary nociceptive afferents may result in spontaneous ectopic activity, perhaps secondary to focal demyelination with exposure of sodium channels (2). Regenerating afferents may form neuromas, where sodium channels accumulate and spontaneous activity occurs (3). The dorsal root ganglion may represent an additional site of ectopic activity (3).