Cathrine Baastrup

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.

Spinal Cord Injury Pain: Mechanisms and Management

Patients with spinal cord injury (SCI) may experience several types of chronic pain, including peripheral and central neuropathic pain, pain secondary to overuse, painful muscle spasms, and visceral pain. An accurate classification of the patient’s pain is important for choosing the optimal treatment strategy. In particular, neuropathic pain appears to be persistent despite various treatment attempts. In recent years, we have gained increasing knowledge of SCI pain mechanisms from experimental models and clinical studies. Nevertheless, treatment remains difficult and inadequate. In line with the recommendations for peripheral neuropathic pain, evidence from randomized controlled treatment trials suggests that tricyclic antidepressants and pregabalin are first-line treatments. This review highlights the diagnosis and classification of SCI pain and recent improvements in the understanding of underlying mechanisms, and provides an update on treatment of SCI pain.

Spinal-, brainstem- and cerebrally mediated responses at- and below-level of a spinal cord contusion in rats: Evaluation of pain-like behavior

&NA; Pain is a frequent consequence of spinal cord injury (SCI) which may profoundly impair the patients’ quality of life. Valid experimental models and methods are therefore desirable in the search for better treatments. Usually, experimental pain assays depend on stimulus‐evoked withdrawal responses; however, this spinal‐mediated reflex response may be particularly problematic when evaluating below‐level SCI pain due to the development of hyperactive reflex circuitries. In this study, we applied and compared assays measuring cold (acetone), static (von Frey filaments), and dynamic mechanical (soft brush) hypersensitivity at different levels of the neuroaxis at and below the level of injury in a rat model of SCI. We induced an experimental SCI (MASCIS 25 mm weight‐drop) and evaluated the development of spinal reflexes (withdrawal), spinal–brainstem–spinal reflexes (licking, guarding, struggling, vocalizing, jumping, and biting) and cerebral‐dependent behavior (place escape/avoidance paradigm (PEAP)). We demonstrated increased brainstem reflexes and cerebrally mediated aversive reactions to stimuli applied at the level of SCI, suggesting development of at‐level evoked pain behavior. Furthermore, stimulation below‐level increased innate reflex responses without increasing brainstem reflexes or aversive behavior in the PEAP, suggesting development of the spasticity syndrome rather than pain‐like behavior. While spinal reflex measures are acceptable for studying changes in the spinal reflex pathways and spinal cord, they are not suited as nociceptive behavioral measures. Measuring brainstem organized responses eliminates the bias associated with the spastic syndrome, but pain requires cortical involvement. Methods depending on cortical structures, as the PEAP, are therefore optimal endpoints in animal models of central pain.

Pregabalin attenuates place escape/avoidance behavior in a rat model of spinal cord injury.

Spinal cord injury (SCI) pain in humans is difficult to treat, and the lack of valid methods to measure behavior comparable to the complex human pain experience preclinically represents an important obstacle to finding better treatments for this type of central pain. The place escape/avoidance paradigm (PEAP) relies on the active choice of an animal between its natural preference for a dark environment or pain relief, and it has been suggested to measure the affective-motivational component of pain. We have modified the method to a T10 spinal cord contusion model (SCC) of at-level central neuropathic pain in Sprague-Dawley rats. In order to demonstrate sensitivity to change in escape/avoidance behavior and thus the applicability of the PEAP method to predict drug efficacy, we investigated the effect of pregabalin (30 mg/kg) treatment in a randomized design. SCC animals displayed increased escape/avoidance behavior postinjury, indicating at-level mechanical hypersensitivity. Second, we found no correlation between state anxiety levels in SCC animals (elevated plus maze) and PEAP behavior, suggesting that the PEAP measurement is not biased by differences in anxiety levels. Third, we demonstrated a decrease in escape/avoidance behavior in response to treatment with the analgesic drug pregabalin. Thus, the PEAP may be applicable as a surrogate correlate of human pain. In conclusion, the primary finding in this study was a sensitivity to change in escape/avoidance behavior induced by pharmacological modulation with analgesics, supporting the use of the PEAP as a central outcome measure in preclinical SCI pain research.

Neuropathic pain following spinal cord injury pain: mechanisms and treatment

Abstract Patients suffering from a spinal cord injury (SCI) face functional loss and physical dependence, and historically most SCI research has focused on locomotor recovery and bladder and bowel dysfunction. We now realize that chronic pain may have a major impact on the quality of life in patients with SCI. The purpose of this paper is to review the current knowledge of mechanisms and treatment of neuropathic pain following SCI and to highlight some of the obstacles for improved pain treatment. Several preclinical models mimic human spinal cord injury reasonably well, but the interpretation of pain assessment and its translation into human SCI pain is not always straightforward and may be biased by other consequences of a spinal injury such as spasms and anxiety. Both preclinical and human studies suggest that a SCI causes major structural and biochemical changes in widespread areas of the central nervous system. The causal relationship between these changes and at- and below-level SCI pain needs to be further addressed. Neuropathic SCI pain is difficult to treat but evidence supports a treatment algorithm similar to what is proposed for peripheral neuropathic pain. As for any chronic pain condition, a biopsychosocial framework is necessary to understand the various aspects of pain interference and associated comorbidities such as anxiety and depression and to improve treatment.

A preclinical model of hyperalgesia following spinal stenosis/compression

Identification of mechanisms for pain/hyperalgesia following spinal cord injury requires long‐term evaluation of individual subjects because of the variability in effect over time for humans.

Experimental design and reporting standards for improving the internal validity of pre-clinical studies in the field of pain: Consensus of the IMI-Europain consortium

Abstract Background and aims Pain is a subjective experience, and as such, pre-clinical models of human pain are highly simplified representations of clinical features. These models are nevertheless critical for the delivery of novel analgesics for human pain, providing pharmacodynamic measurements of activity and, where possible, on-target confirmation of that activity. It has, however, been suggested that at least 50% of all pre-clinical data, independent of discipline, cannot be replicated. Additionally, the paucity of “negative” data in the public domain indicates a publication bias, and significantly impacts the interpretation of failed attempts to replicate published findings. Evidence suggests that systematic biases in experimental design and conduct and insufficiencies in reporting play significant roles in poor reproducibility across pre-clinical studies. It then follows that recommendations on how to improve these factors are warranted. Methods Members of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance is focused on two aspects: experimental design and conduct, and study reporting. Results Minimum requirements for experimental design and conduct were agreed upon across the dimensions of animal characteristics, sample size calculations, inclusion and exclusion criteria, random allocation to groups, allocation concealment, and blinded assessment of outcome. Building upon the Animals in Research: Reportingin vivo Experiments (ARRIVE) guidelines, reporting standards were developed for pre-clinical studies of pain. These include specific recommendations for reporting on ethical issues, experimental design and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome of analgesic drug studies are considered. Flow diagrams are standard requirements in all clinical trials, and flow diagrams for preclinical trials, which describe number of animals included/excluded, and reasons for exclusion are proposed. Creation of a trial registry for pre-clinical studies focused on drug development in order to estimate possible publication bias is discussed. Conclusions More systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity and the sources of experimental biases, as well as increasing the transparency in reporting, are likely to improve preclinical research broadly by ensuring relevant progress is made in advancing the knowledge of chronic pain pathophysiology and identifying novel analgesics. Implications We are now disseminating these Europain processes for discussion in the wider pain research community. Any benefit from these guidelines will be dependent on acceptance and disciplined implementation across pre-clinical laboratories, funding agencies and journal editors, but it is anticipated that these guidelines will be a first step towards improving scientific rigor across the field of pre-clinical pain research.

Coexisting mechanical hypersensitivity and anxiety in a rat model of spinal cord injury and the effect of pregabalin, morphine, and midazolam treatment

Abstract Background and purpose Spinal cord injury (SCI) has detrimental consequences that include chronic neuropathic pain, which is seen in 40-50% of patients, and symptoms of anxiety and depression, which affect 13-45% of SCI patients. The coexistence of pain, anxiety, and depression is known from other neuropathic pain conditions, but the relationship between these symptoms is not clear and has not been investigated in a preclinical model of SCI so far. The aim of this study was to investigate anxiety-like behavior and at-level mechanical hypersensitivity following experimental spinal cord contusion (SCC) in female Sprague-Dawley rats, and the effects of analgesic and anxiolytic drugs. Methods Mechanical sensitivity and elevated plus maze (EPM) behavior were measured pre- and postinjury in SCC and sham animals. Pregabalin 30 mg/kg, morphine 3 mg/kg, midazolam 0.5 mg/kg, and 0.9% NaCl were evaluated in a randomly allocated, blinded balanced design. Results SCC animals developed persistent at-level mechanical hypersensitivity and decreased open arm activity in the EPM, which indicates an anxiety-like state. Pregabalin, a dual-acting analgesic and anxiolytic drug reduced both hypersensitivity and anxiety-like behavior, while the analgesic drug morphine only reduced hypersensitivity. The anxiolytic drug midazolam in the dose used had no effect on either parameter. Conclusions SCC animals developed long lasting coexisting at-level mechanical hypersensitivity and anxiety-like behavior, but there was no evidence to support a causal relationship between pain and anxiety following SCI. Implications The findings that at-level mechanical hypersensitivity and anxiety-like behavior develops concomitantly in the spinal cord contusion models and that both symptoms is persistent provide basis for further investigation of the mechanisms and connection behind these two clinically relevant symptoms after injury to the central nervous system.

Does conditioned pain modulation predict the magnitude of placebo effects in patients with neuropathic pain

Conditioned pain modulation (CPM) is a validated measure of the function of endogenous pain inhibitory pathways. Placebo effects reflect top‐down inhibitory modulation of pain. CPM and placebo effects are both influenced by expectations, albeit to varying degrees, and are related to neurotransmitter systems such as the endogenous opioid system, and it can be speculated that CPM responses are positively associated with the magnitude of placebo effects. Yet, no studies have tested this.

Dopaminergic tone does not influence pain levels during placebo interventions in patients with chronic neuropathic pain

Abstract Placebo effects have been reported in patients with chronic neuropathic pain. Expected pain levels and positive emotions are involved in the observed pain relief, but the underlying neurobiology is largely unknown. Patients with neuropathic pain are highly motivated for pain relief, and as motivational factors such as expectations of reward, as well as pain processing in itself, are related to the dopaminergic system, it can be speculated that dopamine release contributes to placebo effects in neuropathic pain. Nineteen patients with neuropathic pain after thoracic surgery were tested during a placebo intervention consisting of open and hidden applications of the pain-relieving agent lidocaine (2 mL) and no treatment. The dopamine antagonist haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) were administered to test the involvement of dopamine. Expected pain levels, desire for pain relief, and ongoing and evoked pain were assessed on mechanical visual analog scales (0-10). Significant placebo effects on ongoing (P ⩽ 0.003) and evoked (P ⩽ 0.002) pain were observed. Expectancy and desire accounted for up to 41.2% and 71.5% of the variance in ongoing and evoked pain, respectively, after the open application of lidocaine. We found no evidence for an effect of haloperidol and levodopa/carbidopa on neuropathic pain levels (P = 0.071-0.963). Dopamine seemed to influence the levels of expectancy and desire, yet there was no evidence for indirect or interaction effects on the placebo effect. This is the first study to suggest that dopamine does not contribute to placebo effects in chronic neuropathic pain.