Capsaicin for neuropathic pain: linking traditional medicine and molecular biology

Capsaicin has long been used as a traditional medicine to treat pain and, recently, its mechanism of analgesic action has been discovered. This review article documents the clinical development of capsaicin to demonstrate that pharmacognosy still has a profound influence on modern-day drug development programs. Capsaicin is a highly selective agonist for the transient receptor potential channel vanilloid-receptor type 1 (TRPV1), which is expressed on central and peripheral terminals of nociceptive primary sensory neurons. Knockout studies have revealed the importance of TRPV1 as a molecular pain integrator and target for novel analgesic agents. Topical application of capsaicin at the peripheral terminal of TRPV1-expressing neurons superficially denervates the epidermis in humans in a highly selective manner and results in hypoalgesia. In three recent randomized controlled trials, a patch containing high-concentration capsaicin demonstrated meaningful efficacy and tolerability relative to a low-concentration capsaicin control patch in patients with peripheral neuropathic pain. Data from clinical practice will determine if the high-concentration capsaicin patch is effective in real-world settings. Copyright (C) 2012 S. Karger AG, Base

Challenges of neuropathic pain:focus on diabetic neuropathy

Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in relation to current knowledge of underlying mechanisms

Quick discrimination of A delta and C fiber mediated pain based on three verbal descriptors

Background: A delta and C fibers are the major pain-conducting nerve fibers, activate only partly the same brain areas, and are differently involved in pain syndromes. Whether a stimulus excites predominantly A delta or C fibers is a commonly asked question in basic pain research but a quick test was lacking so far. Methodology/Principal Findings: Of 77 verbal descriptors of pain sensations, "pricking", "dull" and "pressing" distinguished best (95% cases correctly) between A delta fiber mediated (punctate pressure produced by means of von Frey hairs) and C fiber mediated (blunt pressure) pain, applied to healthy volunteers in experiment 1. The sensation was assigned to A delta fibers when "pricking" but neither "dull" nor "pressing" were chosen, and to C fibers when the sum of the selections of "dull" or "pressing" was greater than that of the selection of "pricking". In experiment 2, with an independent cohort, the three-descriptor questionnaire achieved sensitivity and specificity above 0.95 for distinguishing fiber preferential non-mechanical induced pain (laser heat, exciting A delta fibers, and 5-Hz electric stimulation, exciting C fibers). Conclusion: A three-item verbal rating test using the words "pricking", "dull", and "pressing" may provide sufficient information to characterize a pain sensation evoked by a physical stimulus as transmitted via A delta or via C fibers. It meets the criteria of a screening test by being easy to administer, taking little time, being comfortable in handling, and inexpensive while providing high specificity for relevant information

Trigeminal neuralgia: new classification and diagnostic grading for practice and research

Trigeminal neuralgia (TN) is an exemplary condition of neuropathic facial pain. However, formally classifying TN as neuropathic pain based on the grading system of the International Association for the Study of Pain is complicated by the requirement of objective signs confirming an underlying lesion or disease of the somatosensory system. The latest version of the International Classification of Headache Disorders created similar difficulties by abandoning the term symptomatic TN for manifestations caused by major neurologic disease, such as tumors or multiple sclerosis. These diagnostic challenges hinder the triage of TN patients for therapy and clinical trials, and hamper the design of treatment guidelines. In response to these shortcomings, we have developed a classification of TN that aligns with the nosology of other neurologic disorders and neuropathic pain. We propose 3 diagnostic categories. Classical TN requires demonstration of morphologic changes in the trigeminal nerve root from vascular compression. Secondary TN is due to an identifiable underlying neurologic disease. TN of unknown etiology is labeled idiopathic. Diagnostic certainty is graded possible when pain paroxysms occur in the distribution of the trigeminal nerve branches. Triggered paroxysms permit the designation of clinically established TN and probable neuropathic pain. Imaging and neurophysiologic tests that establish the etiology of classical or secondary TN determine definite neuropathic pain

Human brain mechanisms of pain perception and regulation in health and disease

Context The perception of pain due to an acute injury or in clinical pain states undergoes substantial processing at supraspinal levels. Supraspinal, brain mechanisms are increasingly recognized as playing a major role in the representation and modulation of pain experience. These neural mechanisms may then contribute to interindividual variations and disabilities associated with chronic pain conditions. Objective To systematically review the literature regarding how activity in diverse brain regions creates and modulates the experience of acute and chronic pain states, emphasizing the contribution of various imaging techniques to emerging concepts. Data Sources MEDLINE and PRE‐MEDLINE searches were performed to identify all English‐language articles that examine human brain activity during pain, using hemodynamic (PET, fMRI), neuroelectrical (EEG, MEG) and neurochemical methods (MRS, receptor binding and neurotransmitter modulation), from January 1, 1988 to March 1, 2003. Additional studies were identified through bibliographies. Study Selection Studies were selected based on consensus across all four authors. The criteria included well‐designed experimental procedures, as well as landmark studies that have significantly advanced the field. Data Synthesis Sixty‐eight hemodynamic studies of experimental pain in normal subjects, 30 in clinical pain conditions, and 30 using neuroelectrical methods met selection criteria and were used in a meta‐analysis. Another 24 articles were identified where brain neurochemistry of pain was examined. Technical issues that may explain differences between studies across laboratories are expounded. The evidence for and the respective incidences of brain areas constituting the brain network for acute pain are presented. The main components of this network are: primary and secondary somatosensory, insular, anterior cingulate, and prefrontal cortices (S1, S2, IC, ACC, PFC) and thalamus (Th). Evidence for somatotopic organization, based on 10 studies, and psychological modulation, based on 20 studies, is discussed, as well as the temporal sequence of the afferent volley to the cortex, based on neuroelectrical studies. A meta‐analysis highlights important methodological differences in identifying the brain network underlying acute pain perception. It also shows that the brain network for acute pain perception in normal subjects is at least partially distinct from that seen in chronic clinical pain conditions and that chronic pain engages brain regions critical for cognitive/emotional assessments, implying that this component of pain may be a distinctive feature between chronic and acute pain. The neurochemical studies highlight the role of opiate and catecholamine transmitters and receptors in pain states, and in the modulation of pain with environmental and genetic influences. Conclusions The nociceptive system is now recognized as a sensory system in its own right, from primary afferents to multiple brain areas. Pain experience is strongly modulated by interactions of ascending and descending pathways. Understanding these modulatory mechanisms in health and in disease is critical for developing fully effective therapies for the treatment of clinical pain conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90300/1/j.ejpain.2004.11.001.pd

Stress-induced analgesia in patients with chronic musculoskeletal pain and healthy controls

Introduction: Individuals with chronic musculoskeletal pain show impairments in their pain-modulatory capacity. Stress-induced analgesia (SIA) is a paradigm of endogenous pain inhibition mainly tested in animals. It has not been tested in patients with chronic pain despite the important role of stress in pain modulation and the chronicity process. Methods: SIA was tested in 22 patients with chronic musculoskeletal pain and 18 healthy participants matched for age and gender. Pain thresholds, pain tolerance and suprathreshold pain sensitivity were examined before and after a cognitive stressor. Additionally, chronic stress levels, pain catastrophizing and pain characteristics were assessed as potential modulating factors. Results: Patients with chronic musculoskeletal pain compared to healthy controls showed significantly impaired SIA (F(1,37)=5.63, p=.02) for pain thresholds, but not pain tolerance (F(1,37)=0.05, p=.83) and stress-induced hyperalgesia (SIH) to suprathreshold pain ratings (F(1,37)=7.76, p=.008). Patients (r(22)=-0.50, p=.05) but not controls (r(18)=-0.39, p=.13) with high catastrophizing had low SIA as assessed by pain thresholds. In controls suprathreshold pain ratings were significantly positively correlated with catastrophizing (r(18)=0.57, p=.03) and life-time stress exposure (r(18)=0.54, p=.03). In patients neither catastrophizing (r(22)=0.21, p=.34) nor stress exposure (r(22)=0.34, p=.34) were associated with suprathreshold SIH. Discussion: Our data suggest impairments of SIA and SIH in patients with chronic musculoskeletal pain. Catastrophizing was associated with deficient SIA in the patients and higher pain ratings in controls. High life time stress also increased pain ratings in the controls

Pain sensitivities predict prophylactic treatment outcomes of flunarizine in chronic migraine patients: A prospective study

Abstract Background We aimed to assess the differences in quantitative sensory testing between chronic migraine and healthy controls and to explore the association between pain sensitivities and outcomes in chronic migraine following preventive treatment. Methods In this prospective open-label study, preventive-naïve chronic migraine and healthy controls were recruited, and cold, heat, mechanical punctate, and pressure pain thresholds over the dermatomes of first branch of trigeminal nerve and first thoracic nerve were measured by quantitative sensory testing at baseline. Chronic migraines were treated with flunarizine and treatment response was defined as ≥50% reduction in the number of monthly headache days over the 12-week treatment period. Results Eighty-four chronic migraines and fifty age-and-sex-matched healthy controls were included in the analysis. The chronic migraine had higher cold pain thresholds over the dermatomes of the first branch of trigeminal nerve and the first thoracic nerve (p  158 g (p = 0.020) or heat pain threshold over the dermatome of the first branch of the trigeminal nerve > 44.9°C (p = 0.002) were more likely to be responders. Conclusions Chronic migraine were generally more sensitive compared to healthy controls. Preventive treatment with flunarizine should be recommended particularly for chronic migraine who have relatively normal sensitivity to mechanical punctate or heat pain. Trial registration: This study was registered on ClinicalTrials.gov (Identifier: NCT02747940)

Tapentadol in the management of chronic low back pain: a novel approach to a complex condition?

Chronic pain affects approximately 1 in 5 people in Europe, and around half of sufferers receive inadequate pain management. The most common location is the lower back. Pharmacological treatment of this condition is challenging because of the range of causative mechanisms and the difficulty of balancing analgesic efficacy and tolerability. An international panel of clinical pain specialists met in September, 2009, to discuss the treatment of chronic low back pain, and to review preclinical and clinical data relating to the new analgesic, tapentadol. A lack of consensus exists on the best treatment for low back pain. The range of regularly prescribed pharmacological agents extends from nonopioids (paracetamol, NSAIDs, and COX-2 inhibitors) to opioids, antidepressants and anticonvulsants. Pain relief may be compromised, however, by an undetected neuropathic component or intolerable side effects. Treatment is potentially life-long and effective analgesics are urgently needed, with demonstrable long-term safety. Combining separate agents with different mechanisms of action could overcome the limitations of present pharmacological therapy, but clinical evidence for this approach is currently lacking. Tapentadol combines μ-opioid agonism with noradrenaline reuptake inhibition in a single molecule. There is strong evidence of synergistic antinociception between these two mechanisms of action. In preclinical and clinical testing, tapentadol has shown efficacy against both nociceptive and neuropathic pain. Preclinical data indicate that tapentadol’s μ-opioid agonism makes a greater contribution to analgesia in acute pain, while noradrenaline reuptake inhibition makes a greater contribution in chronic neuropathic pain models. Tapentadol also produces fewer adverse events than oxycodone at equianalgesic doses, and thus may have a ‘μ-sparing effect’. Current evidence indicates that tapentadol’s efficacy/tolerability ratio may be better than those of classical opioids. However, further research is needed to establish its role in pain management