Pharmacological Management Of Neuropathic Pain Research Articles

Neuropathic Pain Referrals to a Multidisciplinary Pediatric Cancer Pain Service

Neuropathic pain (NP) in children with cancer is not well characterized. In a retrospective review of patient data from a 3.5-year period, we describe the prevalence of NP and the characteristics, duration of follow-up, and interventions provided for NP among patients referred to a pediatric oncology center's pain management service. Fifteen percent (66/439) of all referrals to our pain service were for NP (56/323 patients [17%]; 34 male, 22 female). The NP patient group had 1,401 clinical visits (778 inpatient visits [55.5%] and 623 outpatient visits [44.5%]). Patients with NP had a significantly greater mean number of pain visits per consultation (p = .008) and significantly more days of pain service follow-up (p < .001) than did other patients. The most common cause of NP was cancer treatment rather than the underlying malignancy. Pharmacologic management of NP was complex, often comprising three medications. Nonpharmacologic approaches were used for 57.6% of NP referrals. Neuropathic pain is less frequently encountered than non-NP in children with cancer; nevertheless, it is more difficult to treat, requiring longer follow-up, more clinical visits, complex pharmacologic management, and the frequent addition of nonpharmacologic interventions.

The pharmacological management of neuropathic pain

Neuropathic pain has recently been defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system". Neuropathic pain is a debilitating chronic condition that remains very difficult to treat and challenging to manage. Tricyclic antidepressants (amitryptiline, nortriptyline, imipramine), selective serotonin and norepinephrine reuptake inhibitors (duloxetine, venlafaxine), anticonvulsants (gabapentin, pregabalin), and 5% lidocaine patches have demonstrated efficacy in neuropathic pain and are recommended as first-line medications. In patients who fail to respond to these first-line medications alone and/or in combination, opioid analgesics or tramadol can be used as a second-line treatment alone or in combination with one of the first-line medications. Opioid analgesics and tramadol can also be considered for first-line use in selected clinical circumstances. Other pharmacological therapeutic options include selective serotonin reuptake inhibitors, antiepileptic drugs (levetiracetam, lacosamide, lamotrigine, valproic acid), cannabinoids, high concentration capsaicin patch, and botulinum toxin A. Medication selection should be individualized, with side effects taken into consideration as well as potential beneficial or deleterious effects on comorbidities, and whether or not prompt onset of pain relief is necessary.

Evidence-based guideline for neuropathic pain interventional treatments: spinal cord stimulation, intravenous infusions, epidural injections and nerve blocks.

The Special Interest Group of the Canadian Pain Society has produced consensus-based guidelines for the pharmacological management of neuropathic pain. The society aimed to generate an additional guideline for other forms of neuropathic pain treatments. To develop evidence-based recommendations for neuropathic pain interventional treatments. A task force was created and engaged the Institute of Health Economics in Edmonton, Alberta, to survey the literature pertaining to multiple treatments. Sufficient literature existed on four interventions only: spinal cord stimulation; epidural injections; intravenous infusions; and nerve blocks. A comprehensive search was conducted for systematic reviews, randomized controlled trials and evidence-based clinical practice guidelines; a critical review was generated on each topic. A modified United States Preventive Services Task Force tool was used for quality rating and grading of recommendations. Investigators reviewed four studies of spinal cord stimulation, 19 studies of intravenous infusions, 14 studies of epidural injections and 16 studies of nerve blocks that met the inclusion criteria. The task force chairs rated the quality of evidence and graded the recommendations. Feedback was solicited from the members of the task force. There is sufficient evidence to support recommendations for some of these interventions for selected neuropathic pain conditions. This evidence is, at best, moderate and is often limited or conflicting. Pain practitioners are encouraged to explore evidence-based treatment options before considering unproven treatments. Full disclosure of risks and benefits of the available options is necessary for shared decision making and informed consent.

Pain responsiveness to opioids: Central versus peripheral neuropathic pain

Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system. Neuropathic pain is composed of peripheral neuropathic pain (with a primary lesion or dysfunction in the peripheral nervous system) and central neuropathic pain (CNP; with a primary lesion or dysfunction in the central nervous system). CNP may be further subdivided into supraspinal central neuropathic pain and spinal central neuropathic pain. Opioids have a role in the pharmacologic management of neuropathic pain; however, there is a scarcity of literature on the treatment of CNP with opioids. One of the few statements in the literature regarding the analgesic efficacy of opioids for CNP suggests that despite limited data, the opioid responsiveness for neuropathic pain of central and peripheral etiologies is similar. After reviewing the extremely limited data, it is proposed that although there may be a subpopulation of patients with CNP who have a reasonable analgesic response to opioids, overall, when sensory pain rating is used as the yardstick, CNP appears to respond less well to opioids than peripheral neuropathic pain. Thus, opioids should be considered a second- or third-line agent in any algorithm of the pharmacologic treatment of CNP. Also within CAP, it appears that supraspinal central neuropathic pain may respond less well to a trial of opioids than spinal central neuropathic pain. Moreover, under close monitoring for side effects (eg, constipation), it is suggested that clinicians may want to consider titrating to higher doses of potent opioids before the trial is judged to be unsuccessful for refractory supraspinal central neuropathic pain.

Recent advances in pharmacological treatment of neuropathic pain

Recent studies investigating the pharmacological management of neuropathic pain support the efficacy of certain antidepressants, anticonvulsants, and opioids. Novel directions in drug applications include topical applications of patches with either lidocaine or capsaicin and intradermal injections of botulinum toxin. In cases of partial pain relief, drug combinations may be considered.

Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update

The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

Treatment of Neuropathic Pain: An Overview of Recent Guidelines

A number of different treatments for neuropathic pain have been studied, but the literature is sizable, rapidly evolving, and lacks important information about practical aspects of patient management. Under the auspices of the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group (NeuPSIG), a consensus process was used to develop evidence-based guidelines for the pharmacologic management of neuropathic pain that take into account clinical efficacy, adverse effects, impact on health-related quality of life, convenience, and costs. On the basis of randomized clinical trials, medications recommended as first-line treatments for neuropathic pain included certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel α 2-δ ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in selected clinical circumstances. Other medications that generally would be used as third-line treatments include certain other antidepressant and antiepileptic medications, topical capsaicin, mexiletine, and N-methyl- d-aspartate receptor antagonists. Two other national and international associations recently published pharmacologic treatment guidelines for neuropathic pain, which are summarized and contrasted with the NeuPSIG recommendations. Recent guidelines for the use of neurostimulation for the treatment of neuropathic pain also are summarized. For all treatments for neuropathic pain, long-term studies, head-to-head comparisons, and studies of treatment combinations are a priority for future research.

Pharmacological Management of Neuropathic Pain in Older Adults: An Update on Peripherally and Centrally Acting Agents

The burden of neuropathic pain in older adults is great and the practitioner is challenged to reduce symptoms and improve quality of life. Many common neuropathic pain syndromes are more prevalent in the older population, and older adults also carry greater sensitivity to certain side effects. The health care professional should have a thorough familiarity with all medications available to treat this difficult group of disorders.

Pharmacologic Management of Neuropathic Pain in Patients with Advanced Illness (333)

Pharmacologic Management of Neuropathic Pain in Patients with Advanced Illness (333)

Pharmacological Management of Neuropathic Pain Following Spinal Cord Injury

Spinal cord injury (SCI) has a number of severe and disabling consequences, including chronic pain, and around 40% of patients develop persistent neuropathic pain. Pain following SCI has a detrimental impact on the patient's quality of life and is a major specific healthcare problem in its own right. Thus far, there is no cure for the pain and oral pharmaceutical intervention is often inadequate, commonly resulting in a reduction of only 20-30% in pain intensity. Neuropathic pain sensations are characterized by spontaneous persistent pain and a range of abnormally evoked responses, e.g. allodynia (pain evoked by normally non-noxious stimuli) and hyperalgesia (an increased response to noxious stimuli). Neuropathic pain following SCI may be present at or below the level of injury. Oral pharmacological agents used in the treatment of neuropathic pain act either by depressing neuronal activity, by blocking sodium channels or inhibiting calcium channels, by increasing inhibition via GABA agonists, by serotonergic and noradrenergic reuptake inhibition, or by decreasing activation via glutamate receptor inhibition, especially by blocking the NMDA receptor. At present, only ten randomized, double-blind, controlled trials have been performed on oral drug treatment of pain after SCI, the results of most of which were negative. The studies included antidepressants (amitriptyline and trazodone), antiepileptics (gabapentin, pregabalin, lamotrigine and valproate) and mexiletine. Gabapentin, pregabalin and amitriptyline showed a significant reduction in neuropathic pain following SCI. Cannabinoids have been found to relieve other types of central pain, and serotonin noradrenaline reuptake inhibitors as well as opioids relieve peripheral neuropathic pain and may be used to treat patients with SCI pain.

Pharmacologic management of neuropathic pain

The mechanisms underlying the pathogenesis of neuropathic pain are complex but are gradually coming to light. Agents that have been found effective in a variety of neuropathic pain conditions include drugs that act to modulate (a) sodium or calcium channels, (b) N-methyl-D-aspartate receptors, (c) norepinephrine or serotonin reuptake, (d) opioid receptors, and (e) other cellular processes. Clinical trials have primarily evaluated these treatments for postherpetic neuralgia and painful diabetic neuropathy, the two most common types of neuropathic pain. Nonetheless, the identification of effective treatment regimens remains challenging, often because multiple mechanisms may be operating in a given patient giving rise to the same symptom. Alternatively, a single mechanism may be responsible for multiple symptoms. Currently available diagnostic tools are inadequate to determine the best treatment using a mechanism-based model. Clinically, drug treatment of neuropathic pain is often a matter of treatment trials. This article presents a summary of available clinical information on first-line and lesser-known treatments for neuropathic pain.

New and emerging pharmacological targets for neuropathic pain.

Increasing knowledge of the molecular consequences of nerve injury and the availability of genome databases has greatly increased the range of potential targets for the pharmacological management of neuropathic pain. Controlling neuronal sensitization and the associated alterations in gene expression, protein modification, and neuronal excitability is the key to managing neuropathic pain. Control of neuronal sensitization can occur through inhibition of nerve injury-associated production of cytokines, activation of glial cells, modulation of potassium channel subtypes, mitogen-activated protein kinases, the ubiquitin-proteasome system, or the protection and amplification of spinal cord dorsal horn inhibitory systems. These new and already established targets promise unparalleled opportunities for the prevention, management, and resolution of persistent pain states following nerve injury.

The pharmacologic management of neuropathic pain

N reuropathic pain intrinsically differs from nociceptive pain. Nociceptive pain is mediated by activation of nociceptors (transduction) a~d transmission of electrochemical impulses along defined pathways to higher rostral centers. Modulation of afferent noxious input occurs at the level of the spinal cord. In contrast, neuropathic pain cannot occur de novo. By definition, the genesis of neuropathic pain implies damage to neural tissue. There are no predefined pathways, but pre-existent pathways may be damaged. Spontaneous discharge of damaged neurons or higher order neurons is responsible for the genesis of neuropathic pain. These changes become permanent because of the plasticity of the central nervous system. Despite these basic differences, nociceptive and neuropathic pain do share certain aspects of the physiologic processes of transduction, transmission, and modulation. While it is not the purpose of this article to exhaustibly review the neuroscience of neuropathic pain, it would be worthwhile to discuss some basic concepts. Nociceptors (nerves that transmit noxious impulses throughout the nervous system) differ from non-nociceptors in two discrete ways: ( I ) they are stimulated at higher threshaids than non-nociceptors, and (2) they have the ability to be sensitized. Sensitization refers to a decrease in the stimulation threshold as well as an increase in the magnitude of the response to that stimulation. Both peripheral and central nociceptors may become sensitized. Much has been written with respect to the central sensitization or wind-up of dorsal horn neurons. Release of excitatory amino acids (glutamate and aspartate) and neuropeptides (substance P, cal-

The evolving role of antiepileptic drugs in treating neuropathic pain. (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) Neurology 2000;55(Suppl 1): S41-S46.

For many years, tricyclic antidepressants (TCAs) were used as initial therapy for the pharmacologic management of neuropathic pain. First-generation antiepileptic drugs (AEDs) are also used for the treatment neuralgia and migraine headache, respectively. Although TCAs are associated with side effects that limit their usefulness, particularly in the elderly or in patients with multiple problems, comparative meta-analyses show their tolerability to be greater than that of the first-generation AEDs. Recently, newer AEDs with more favorable side-effect profiles have been tested in placebo-controlled clinical trails for the treatment of neuropathic pain, including painful diabetic neuropathy and postherpetic neuralgia. The results of these trials, together with advances in understanding the pathophysiology of neuropathic pain, provide the basis for reevaluating some of the commonly accepted paradigms that guide approaches to treatment.

Treatment options in postherpetic neuralgia.

Postherpetic neuralgia (PHN) is a separate disease entity that represents a complication of acute herpes zoster. PHN, involving aberrant somatosensory processing in the peripheral and/or central nervous system, is considered to be a chronic neuropathic pain, frequently unresponsive to all treatment modalities. Despite the clinical trial data demonstrating successful pain relief with several drug regimens, the pharmacologic management of neuropathic pain is difficult, particularly in PHN. Response to therapy is generally inhomogeneous. Some patients experience long-term pain control with either topical or oral monotherapy with antidepressants, anticonvulsants, or opioids. Other PHN patients, such as those suffering pain due to central nervous system lesions, are extraordinarily refractory to all measures. This article will review current treatments--tricyclic antidepressants, anticonvulsants, local anesthetics, clonidine, N-methyl-D-aspartate (NMDA)-antagonists, and opioids and focus on mechanism-based pharmacologic interventions. Pharmacologic approaches can be classified into three groups: 1) drugs that act topically in the affected skin area; 2) drugs that act on nerve excitability and conduction in sensory axons; and 3) drugs that act on neural damage related synaptic changes. This last group is the only pain treatment option related to central denervation. To date, the treatment of PHN has relied on the use of tricyclic antidepressants (TCAs), which represent the most comprehensively studied medications for this pain syndrome. Clinical data indicate that TCAs are effective analgesics in approximately 50% of patients; these drugs have been recommended as first-line agents for all neuropathic pain syndromes except trigeminal neuralgia, but are frequently contraindicated or poorly tolerated in elderly patients with PHN. If monotherapy fails, a mechanism- and/or symptom-based multidrug regimen can be used. There is also consistent support for intravenous and topical lidocaine, intravenous ketamine, carbamazepine, and opioids. Gabapentin, a new anticonvulsant, can be considered a first-line oral medication for PHN based on the efficacy and safety results of a recently completed double-blind trial. In addition to positive effects on PHN, sleep, mood, and overall quality of life were significantly improved.