Current Approaches to the Management of Peripheral Neuropathic Pain.

Symptoms and signs of neuropathic pain can be both positive and negative. Tricyclic antidepressants are the first-line treatment option for neuropathic pain. Opioid agonists have demonstrated efficacy in patients with neuropathic pain. Combination therapy in the management of neuropathic pain is not well researched.-- This report is adapted from paineurope 2015: Issue 1, ©Haymarket Medical Publications Ltd., and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, Ltd., and is distributed free of charge to health care professionals in Europe. Archival issues can be viewed via the Web site: www.paineurope.com , at which health professionals can find links to the original articles and request copies of the quarterly publication and access additional pain education and pain management resources.

Intrathecal drug administration in chronic pain syndromes.

Chronic pain may recur after initial response to strong opioids in both patients with cancer and patients without cancer or therapy may be complicated by intolerable side effects. When minimally invasive interventional pain management techniques also fail to provide satisfactory pain relief, continuous intrathecal analgesic administration may be considered. Only 3 products have been officially approved for long-term intrathecal administration: morphine, baclofen, and ziconotide. The efficacy of intrathecal ziconotide for the management of patients with severe chronic refractory noncancer pain was illustrated in 3 placebo-controlled trials. A randomized study showed this treatment option to be effective over a short follow-up period for patients with pain due to cancer or AIDS. The efficacy of intrathecal opioid administration for the management of chronic noncancer pain is mainly derived from prospective and retrospective noncontrolled trials. The effect of intrathecal morphine administration in patients with pain due to cancer was compared with oral or transdermal treatment in a randomized controlled trial, which found better pain control and fewer side effects with intrathecal opioids. Other evidence is derived from cohort studies. Side effects of chronic intrathecal therapy may either be technical (catheter or pump malfunction) or biological (infection). The most troublesome complication is, however, the possibility of granuloma formation at the catheter tip that may induce neurological damage. Given limited studies, the evidence for intrathecal drug administration in patients suffering from cancer-related pain is more compelling than that of chronic noncancer pain.

Elucidation of pathophysiology and treatment of neuropathic pain.

Neuropathic pain, pain arising as a direct consequence of a lesion or disease affecting the somatosensory system, is relatively common, occurring in about 1% of the population. 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 mechanism. Additionally, neuro-imaging (positron emission tomography and functional magnetic resonance imaging) provides insights in brain mechanisms corresponding with mechanistic processes including allodynia, hyperalgesia, altered sensation, and spontaneous pain. A change in function, chemistry, and structures of neurons (neural plasticity) underlie the production of the altered sensitivity characteristics of neuropathic pain. Peripheral processes in neuropathic pain involve production of mediators (cytokines, protons, nerve growth factor), alterations in calcium channels, sodium channels, hyperpolarisation-activated nucleotide-gated ion channels, and potassium channels, phenotypic switches and sprouting of nerves endings, and involvement of the sympathetic nervous system. Stimulation of the N-Methyl-D-Aspartate receptor, activation of microglia, oligodendrocytes, and astrocytes, increased production of nerve growth factor and brain-derived neurotrophic factor together with loss of spinal inhibitory control are responsible for central neuron hyperexcitability and maintenance of neuropathic pain. Recent advances, including functional imaging techniques, in identification of peripheral and central sensitization mechanisms related to nervous system injury have increased potential for affecting pain research from both diagnostic as well as therapeutic view. Key brain regions involved in generating pharmacologically induced analgesia may be identified. Despite the progress in pain research, neuropathic pain is challenge to manage. Although numerous treatment options are available for relieving neuropathic pain, there is no consensus on the most appropriate treatment. However, recommendations can be proposed for first-line, second-line, and third-line pharmacological treatments based on the level of evidence for the different treatment strategies. Available therapies shown to be effective in managing neuropathic pain include opioids and tramadol, anticonvulsants, antidepressants, topical treatments (lidocaine patch, capsaicin), and ketamine. Tricyclic antidepressants are often the first drugs selected to alleviate neuropathic pain (first-line pharmacological treatment). Although they are very effective in reducing pain in several neuropathic pain disorders, treatment may be compromised (and outweighed) by their side effects. In patients with a history of cardiovascular disorders, glaucoma, and urine retention, pregabalin and gabapentine are emerging as first-line treatment for neuropathic pain. In addition these anti-epileptic drugs have a favourable safety profile with minimal concerns regarding drug interactions and showing no interference with hepatic enzymes. Alternatively, opioids (oxycodone and methadone) and tramadol may alleviate nociceptive and neuropathic pain. Despite the numerous treatment options available for relieving neuropathic pain, no more than half of patients experience clinically meaningful pain relief, which is almost always partial but not complete relief. In addition, patients frequently experience burdensome adverse effects and as a consequence are often unable to tolerate the treatment. In the remaining patients, combination therapies using two or more analgesics with different mechanisms of action may also offer adequate pain relief. Although combination treatment is clinical practice and may result in greater pain relief, trials regarding different combinations of analgesics (which combination to use, occurrence of additive or supra-additive effects, sequential or concurrent treatment, adverse-event profiles of these analgesics, alone and in combination) are scarce. If medical treatments have failed, invasive therapies such as intrathecal drug administration and neurosurgical stimulation techniques (spinal cord stimulation, deep brain stimulation, and motor cortex stimulation) may be considered.

Prostate cancer pain management: EAU guidelines on pain management.

CONTEXT: The first publication of the European Association of Urology (EAU) guidelines on Pain Management in Urology dates back to 2003. Since then, these guidelines have been revised several times with the most recent update achieved in 2010. OBJECTIVE: Given the scope of the full text guidelines, condensing the entire document was no option in this context. This paper presents a summary of the section of pain management in prostate cancer, a topic considered of direct relevance for the practicing urologist. EVIDENCE ACQUISITION: A multidisciplinary expert panel (urologists, anaesthesiologists, radio-oncologists) compiled this document based on a comprehensive consultation of the literature. Data were identified through a structured search, covering the time frame 2000 through 2010, using Medline and Embase as well as the Cochrane Library of systematic reviews. The scientific papers were weighed by the expert panel and a level of evidence (LE) assigned. Recommendations have been graded as a means to provide transparency between the underlying evidence and the guidance provided. Pain can occur in each stage of prostate cancer. It could be caused by the cancer itself (77%), be related to the cancer treatment (19%) or be unrelated to either (3%). The incidence of pain rises to 90% as patients enter the terminal phase of their illness. The physician's task is to discover and treat the cause of pain and the pain itself, to determine whether or not the underlying cause is treatable, to provide pain relief and palliative care. These tasks more often than not require a multidisciplinary team. Pain management involves mainly pharmacotherapy, including direct anticancer therapy such as androgen deprivation and chemotherapy, as well as analgetics, for instance non-steroidal anti-inflammatory drugs (NSAIDs) or opioids. In case of local impairment due to the cancer or its metastases, primary treatments like surgery, radiotherapy or radionuclides can provide adequate pain relief. In addition, in palliative care, functional, psychosocial and spiritual support are essential components. The EAU guidelines on Pain Management in Urology are available in a number of different formats through the EAU Central Office and the EAU website ( http://www.uroweb.org/guidelines/online-guidelines/ ). CONCLUSION: The mainstay of pain management in prostate cancer is involvement of and collaboration between experts from a number of disciplines to be able to achieve a complete pain evaluation and to offer the full range of treatment options. Prostate cancer-related pain can, in most cases, be managed effectively, but it requires careful monitoring where a balance should be found between pain relief and potential side effects of treatment and quality of life (QoL).

Mechanisms and treatment of neuropathic pain.

Neuropathic pain (pain associated with lesions or dysfunction of nervous system) is relatively common, occurring in about 1% of the population. 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 mechanism. A change in function, chemistry, and structures of neurons (neural plasticity) underlie the production of the altered sensitivity characteristics of neuropathic pain. Peripheral sensitization acts on the nociceptors, and central sensitization takes place at various levels ranging from the dorsal horn to the brain. In addition, abnormal interactions between the sympathetic and sensory pathways contribute to mechanisms mediating neuropathic pain. Despite recent advances in identification of peripheral and central sensitization mechanisms related to nervous system injury, the effective treatment of patients suffering from neuropathic pain remains a clinical challenge. Although numerous treatment options are available for relieving neuropathic pain, there is no consensus on the most appropriate treatment. However, recommendations can be proposed for first-line, second-line, and third-line pharmacological treatments based on the level of evidence for the different treatment strategies. Beside opioids, the available therapies shown to be effective in managing neuropathic pain include anticonvulsants, antidepressants, topical treatments (lidocaine patch, capsaicin), and ketamine. Tricyclic antidepressants are often the first drugs selected to alleviate neuropathic pain (first-line pharmacological treatment). Although they are very effective in reducing pain in several neuropathic pain disorders, treatment may be compromised (and outweighed) by their side effects. In patients with a history of cardiovascular disorders, glaucoma, and urine retention, pregabalin and gabapentine are emerging as first-line treatment for neuropathic pain. In addition these anti-epileptic drugs have a favourable safety profile with minimal concerns regarding drug interactions and showing no interference with hepatic enzymes. Despite the numerous treatment options available for relieving neuropathic pain, the most appropriate treatment strategy is only able to reduce pain in 70% of these patients. In the remaining patients, combination therapies using two or more analgesics with different mechanisms of action may also offer adequate pain relief. Although combination treatment is clinical practice and may result in greater pain relief, trials regarding different combinations of analgesics are lacking (which combination to use, occurrence of additive or supra-additive effects, sequential or concurrent treatment, adverse-event profiles of these analgesics, alone and in combination) are lacking. Additionally, 10% of patients still experience intractable pain and are refractory to all forms of pharmacotherapy. If medical treatments fail, invasive therapies such as intrathecal drug administration and neurosurgical interventions may be considered.

Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial.

Intravenous morphine is the treatment of choice for severe pain during vaso- occlusive crisis in sickle cell disease (SCD). However, side effects of morphine may hamper effective treatment, and high plasma levels of morphine are associated with severe complications such as acute chest syndrome. Furthermore, adequate dosing remains a problem since no objective measurement of pain severity exists and analgesia should be titrated upon the patient's reported pain. Patient-controlled analgesia (PCA) may therefore be an interesting alternative since patients can titrate the level of analgesia themselves. In this randomized controlled study, the efficacy of intravenous morphine administration with PCA was compared with continuous infusion (CI) of morphine in patients with SCD during vaso-occlusive crisis. Twenty five consecutive episodes of vaso-occlusive crisis in 19 patients with SCD were included in the study. Patients in the PCA-group had a markedly and significant lower mean and cumulative morphine consumption when compared with the patients in the CI-group (0.5 mg/hr versus 2.4 mg/hr (P < 0.001) and 33 mg versus 260 mg (P = 0.018, respectively). The mean daily pain scores were comparable (4.9 versus 5.3). The lower mean and cumulative morphine consumption in the PCA-group led to significant less nausea and constipation during treatment when compared with the CI-group (area under the curve, respectively, 11 versus 18 (P = 0.045) and 30 versus 45 (P = 0.021). Furthermore, a nonsignificant reduction in the duration of hospital admission of 3 days was observed in the PCA-group. PCA results in adequate pain relief at a much lower morphine consumption and should considered to be the first choice in morphine administration to sickle cell patients admitted with vaso-occlusive crisis.

Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine.

BACKGROUND: Ketamine and S(+)-ketamine have been advocated for neuraxial use in the management of postoperative pain and severe intractable pain syndromes unresponsive to opioid escalation. Although clinical experience has accumulated with S(+)-ketamine, safety data on toxicity in the central nervous system after neuraxial administration of S(+)-ketamine are conflicting. In this study, neurologic and toxicologic effects on the spinal cord from repeated daily intrathecal administration of commercially available, preservative-free S(+)-ketamine were evaluated against placebo in a randomized, blinded design. METHODS: Eighteen white New Zealand rabbits were assigned to two groups receiving either 0.5 ml intrathecal S(+)-ketamine, 0.5% solution (12 rabbits), or 0.5 ml saline (6 rabbits) once a day for 7 consecutive days. During general anesthesia, an intrathecal catheter was placed between the fifth and sixth spinous processes (lumbar). Neurologic (according to Tarlov criteria) and histopathologic assessments were performed after 7 days of treatment. RESULTS: Postmortem investigation of the spinal cord and nerve roots revealed histopathologic lesions suggestive of toxic damage in 11 rabbits, from the group of 12 animals receiving S(+)-ketamine. These results were significantly different compared with 5 control animals (no histologic changes observed). There was no significant difference in neurologic status between the two groups after 7 days of intrathecal treatment. CONCLUSIONS: The authors conclude that repeated intrathecal administration of preservative-free S(+)-ketamine in a clinically relevant concentration and dosage has, considering the extent and severity of the lesions, a toxic effect on the central nervous system of rabbits.

Continuous sacral nerve root block in the management of neuropathic cancer pain.

IMPLICATIONS: Neuropathic cancer pain caused by tumor infiltration in the sacral plexus is primarily treated by nonsteroidal antiinflammatory drugs, antidepressants, anticonvulsants, and opioids. In one patient with severe pain despite pharmacotherapy, a catheter for the continuous administration of local anesthetics was inserted along the first sacral root, resulting in markedly improved analgesia.

Measuring perceived activity limitations in lower extremity Complex Regional Pain Syndrome type 1 (CRPS I): test-retest reliability of two questionnaires.

OBJECTIVE: To assess the test-retest reliability of two questionnaires for measuring activity limitations in patients with Complex Regional Pain Syndrome type 1 (CRPS I) of the lower extremity. DESIGN: Patients filled out the Walking Stairs Questionnaire and the Questionnaire Rising and Sitting Down twice during a one-week period. SETTING: Outpatient pain clinic of a university hospital. PATIENTS: Twenty-one outpatients with CRPS I of the lower extremity. RESULTS: The Walking Stairs Questionnaire and the Questionnaire Rising and Sitting Down were reliable in terms of test-retest reliability as expressed by Spearman's r (range 0.79-0.90 and 0.85-0.89 respectively) and the ICC (range 0.78-0.84 and 0.84-0.87 respectively). CONCLUSION: Both questionnaires form a reliable tool for measuring activity limitations of patients with CRPS I of a lower extremity.