Steen Petersen-Felix

Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia

&NA; Patients with chronic pain after whiplash injury and fibromyalgia patients display exaggerated pain after sensory stimulation. Because evident tissue damage is usually lacking, this exaggerated pain perception could be explained by hyperexcitability of the central nervous system. The nociceptive withdrawal reflex (a spinal reflex) may be used to study the excitability state of spinal cord neurons. We tested the hypothesis that patients with chronic whiplash pain and fibromyalgia display facilitated withdrawal reflex and therefore spinal cord hypersensitivity. Three groups were studied: whiplash (n=27), fibromyalgia (n=22) and healthy controls (n=29). Two types of transcutaneous electrical stimulation of the sural nerve were applied: single stimulus and five repeated stimuli at 2 Hz. Electromyography was recorded from the biceps femoris muscle. The main outcome measurement was the minimum current intensity eliciting a spinal reflex (reflex threshold). Reflex thresholds were significantly lower in the whiplash compared with the control group, after both single (P=0.024) and repeated (P=0.035) stimulation. The same was observed for the fibromyalgia group, after both stimulation modalities (P=0.001 and 0.046, respectively). We provide evidence for spinal cord hyperexcitability in patients with chronic pain after whiplash injury and in fibromyalgia patients. This can cause exaggerated pain following low intensity nociceptive or innocuous peripheral stimulation. Spinal hypersensitivity may explain, at least in part, pain in the absence of detectable tissue damage.

Central hypersensitivity in chronic pain after whiplash injury.

ObjectiveThe mechanisms underlying chronic pain after whiplash injury are usually unclear. Injuries may cause sensitization of spinal cord neurons in animals (central hypersensitivity), which results in increased responsiveness to peripheral stimuli. In humans, the responsiveness of the central nervous system to peripheral stimulation may be explored by applying sensory tests to healthy tissues. The hypotheses of this study were: (1) chronic whiplash pain is associated with central hypersensitivity; (2) central hypersensitivity is maintained by nociception arising from the painful or tender muscles in the neck. DesignComparison of patients with healthy controls. SettingPain clinic and laboratory for pain research, university hospital. PatientsFourteen patients with chronic neck pain after whiplash injury (car accident) and 14 healthy volunteers. Outcome MeasuresPain thresholds to: single electrical stimulus (intramuscular), repeated electrical stimulation (intramuscular and transcutaneous), and heat (transcutaneous). Each threshold was measured at neck and lower limb, before and after local anesthesia of the painful and tender muscles of the neck. ResultsThe whiplash group had significantly lower pain thresholds for all tests, except heat, at both neck and lower limb. Local anesthesia of the painful and tender points affected neither intensity of neck pain nor pain thresholds. ConclusionsThe authors found a hypersensitivity to peripheral stimulation in whiplash patients. Hypersensitivity was observed after cutaneous and muscular stimulation, at both neck and lower limb. Because hypersensitivity was observed in healthy tissues, it resulted from alterations in the central processing of sensory stimuli (central hypersensitivity). Central hypersensitivity was not dependent on a nociceptive input arising from the painful and tender muscles.

Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia. I. Motor reactions.

BackgroundPotency of inhaled anesthetics usually is defined by determining the minimal alveolar concentration (MAC) that prevents movement in 50% of patients in response to skin incision. Skin incision, however, is usually only a single event and, thus, determination of potency cannot be repeated in one patient. Traditional MACskin incision cannot be used to predict response to other noxious stimuli. The aim of this study was to investigate the effects of other noxious stimulation patterns and then compare these to MACskin incision measuring the end-tidal isoflurane concentrations with the corresponding arterial concentrations. MethodsIn 26 patients, the end-tidal and corresponding arterial isoflurane concentrations needed to suppress eye opening to verbal command and motor response after trapezius squeeze, 50 Hz electric tetanic stimulation, laryngoscopy, skin incision, and tracheal intubation in 50% of all patients were determined. ResultsThe end-tidal (equivalent arterial) isoflurane concentrations (mean ± SE, adjusted to sea level) expressed in vol% (to allow comparison) increased in the following order (mean ± SE): vocal command 0.37 ± 0.09 (0.36 ± 0.09); trapezius squeeze 0.84 ± 0.07 (0.65 ± 0.07); laryngoscopy 1.00 ± 0.12 (0.78 ± 0.09); tetanic stimulation 1.03 ± 0.09 (0.80 ± 0.06); skin incision 1.16 ± 0.10 (0.97 ± 0.17); and intubation 1.76 ± 0.13 (1.32 ± 0.11). ConclusionsDifferent stimuli require different isoflurane concentrations to suppress motor responses. Tetanic stimulation and, to some extent, trapezius squeeze are reproducible and noninvasive stimulation patterns that can be used as an alternative to skin incision when evaluating potency of an anesthetic agent. In contrast to skin incision, they can be repeated.

Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia. II. Hemodynamic responses.

BackgroundThe hemodynamic effects of isoflurane have been studied extensively. However, most data are obtained from volunteers or patients in the absence of surgical stimulation. The hemodynamic responses to various stimulation patterns of different intensity have not been evaluated. MethodsIn 26 patients, the ability of isoflurane to suppress motor and hemodynamic reactions in response to noxious stimulations of variable degree (trapezius squeeze, tetanic stimulation, laryngoscopy, skin incision, and laryngoscopy plus intubation) was evaluated by measuring arterial blood pressure and heart rate before and after stimulation. ResultsAt concentrations that inhibited motor response to these stimuli in 50% of all patients, systolic blood pressure increased by 9 (trapezius squeeze), 15 (tetanic stimulation), 23 (laryngoscopy), 35 (skin incision) and 49 (intubation) mmHg, and heart rate by 5 (trapezius squeeze), 15 (tetanic stimulation), 17 (laryngoscopy), 36 (skin incision), and 36 (intubation) min-1 compared to the prestimulation values. An analysis using multiple regression showed that blood pressure response was influenced most by the type of stimulation followed by the concomitantly occurring motor reaction, the anesthesia time, and least by the isoflurane concentration per se. A high isoflurane concentration had no influence on the magnitude of blood pressure or heart rate increase to stimulation, but it decreased the prestimulation blood pressure and slightly increased the prestimulation heart rate. Heart rate responses were less consistent than those of blood pressure. ConclusionsIsoflurane used as a sole agent is unable to suppress hemodynamic reactions (blood pressure and heart rate) to painful stimuli. A “normal” blood pressure following stimulation can be achieved only if prestimulation blood pressure is depressed to levels that may be clinically unacceptable. The lack of motor response is not an accurate predictor of the ability of an agent to depress hemodynamic reaction.

The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions

From folk medicine and anecdotal reports it is known that Cannabis may reduce pain. In animal studies it has been shown that delta‐9‐tetrahydrocannabinol (THC) has antinociceptive effects or potentiates the antinociceptive effect of morphine. The aim of this study was to measure the analgesic effect of THC, morphine, and a THC‐morphine combination (THC‐morphine) in humans using experimental pain models. THC (20 mg), morphine (30 mg), THC‐morphine (20 mg THC+30 mg morphine), or placebo were given orally and as single doses. Twelve healthy volunteers were included in the randomized, placebo‐controlled, double‐blinded, crossover study. The experimental pain tests (order randomized) were heat, cold, pressure, single and repeated transcutaneous electrical stimulation. Additionally, reaction time, side‐effects (visual analog scales), and vital functions were monitored. For the pharmacokinetic profiling, blood samples were collected. THC did not significantly reduce pain. In the cold and heat tests it even produced hyperalgesia, which was completely neutralized by THC‐morphine. A slight additive analgesic effect could be observed for THC‐morphine in the electrical stimulation test. No analgesic effect resulted in the pressure and heat test, neither with THC nor THC‐morphine. Psychotropic and somatic side‐effects (sleepiness, euphoria, anxiety, confusion, nausea, dizziness, etc.) were common, but usually mild.

Evidence, mechanisms, and clinical implications of central hypersensitivity in chronic pain after whiplash injury

Objectives:To provide insights into the mechanisms underlying central hypersensitivity, review the evidence on central hypersensitivity in chronic pain after whiplash injury, highlight reflections on the clinical relevance of central hypersensitivity, and offer a perspective of treatment of central hypersensitivity. Methods:A review of animal and human studies focusing on the mechanisms of postinjury central sensitization, an analysis of psychophysical investigations on central hypersensitivity in patients with chronic pain after whiplash injury, and a review of possible treatment modalities. Results:Animal data show that tissue damage produces plasticity changes at different neuronal structures that are responsible for amplification of nociception and exaggerated pain responses. Some of these changes are potentially irreversible. There is consistent psychophysical evidence for hypersensitivity of the central nervous system to sensory stimulation in chronic pain after whiplash injury. Tissue damage, detected or not by the available diagnostic methods, is probably the main determinant of central hypersensitivity. Psychologic distress could contribute to central hypersensitivity via imbalance of supraspinal and descending modulatory mechanisms. Although specific treatment strategies are limited, they are largely unexplored. Implications:Central hypersensitivity may explain exaggerated pain in the presence of minimal nociceptive input arising from minimally damaged tissues. This could account for pain and disability in the absence of objective signs of tissue damage in patients with whiplash. Central hypersensitivity may provide a common neurobiological framework for the integration of peripheral and supraspinal mechanisms in the pathophysiology of chronic pain after whiplash. Therapy studies are needed.

Chronic Phantom Limb Pain: The Effects of Calcitonin, Ketamine, and Their Combination on Pain and Sensory Thresholds

BACKGROUND: Calcitonin was effective in a study of acute phantom limb pain, but it was not studied in the chronic phase. The overall literature on N-methyl-d-aspartate antagonists is equivocal. We tested the hypothesis that calcitonin, ketamine, and their combination are effective in treating chronic phantom limb pain. Our secondary aim was to improve our understanding of the mechanisms of action of the investigated drugs using quantitative sensory testing. METHODS: Twenty patients received, in a randomized, double-blind, crossover manner, 4 IV infusions of: 200 IE calcitonin; ketamine 0.4 mg/kg (only 10 patients); 200 IE of calcitonin combined with ketamine 0.4 mg/kg; placebo, 0.9% saline. Intensity of phantom pain (visual analog scale) was recorded before, during, at the end, and the 48 h after each infusion. Pain thresholds after electrical, thermal, and pressure stimulation were recorded before and during each infusion. RESULTS: Ketamine, but not calcitonin, reduced phantom limb pain. The combination was not superior to ketamine alone. There was no difference in basal pain thresholds between the amputated and contralateral side except for pressure pain. Pain thresholds were unaffected by calcitonin. The analgesic effect of the combination of calcitonin and ketamine was associated with a significant increase in electrical thresholds, but with no change in pressure and heat thresholds. CONCLUSIONS: Our results question the usefulness of calcitonin in chronic phantom limb pain and stress the potential interest of N-methyl-d-aspartate antagonists. Sensory assessments indicated that peripheral mechanisms are unlikely important determinants of phantom limb pain. Ketamine, but not calcitonin, affects central sensitization processes that are probably involved in the pathophysiology of phantom limb pain.

Epidural Epinephrine and Clonidine: Segmental Analgesia and Effects on Different Pain Modalities

Background: It is not known whether epidural epinephrine has an analgesic effect per se. The segmental distribution of clonidine epidural analgesia and its effects on temporal summation and different types of noxious stimuli are unknown. The aim of this study was to clarify these issues. Methods: Fifteen healthy volunteers received epidurally (L2‐L3 or L3‐L4) 20 ml of either epinephrine, 100 micro gram, in saline; clonidine, 8 micro gram/kg, in saline; or saline, 0.9%, alone, on three different days in a randomized, double‐blind, cross‐over fashion. Pain rating after electrical stimulation, pinprick, and cold perception were recorded on the dermatomes S1, L4, L1, T9, T6, T1, and forehead. Pressure pain tolerance threshold was recorded at S1, T6, and ear. Pain thresholds to single and repeated (temporal summation) electrical stimulation of the sural nerve were determined. Results: Epinephrine significantly reduced sensitivity to pinprick at L1‐L4‐S1. Clonidine significantly decreased pain rating after electrical stimulation at L1‐L4 and sensitivity to pinprick and cold at L1‐L4‐S1, increased pressure pain tolerance threshold at S1, and increased thresholds after single and repeated stimulation of the sural nerve. Conclusions: Epidural epinephrine and clonidine produce segmental hypoalgesia. Clonidine bolus should be administered at a spinal level corresponding to the painful area. Clonidine inhibits temporal summation elicited by repeated electrical stimulation and may therefore attenuate spinal cord hyperexcitability.

Sensory assessment of regional analgesia in humans: a review of methods and applications.

SENSORY assessment of regional analgesia is performed routinely for clinical purposes and also plays an important role in anesthesia and pain research. In the past years, new methods were developed and old methods were improved. Technological progress has allowed a more reliable delivery of different stimulation patterns and more advanced recordings of physiologic parameters related to nociceptive processing and modulation. Important developments include methods that explore the activation of different nerve fibers, models that activate specific spinal cord mechanisms (such as temporal summation), and methods that evaluate muscle and visceral pain. As a result of this new knowledge, the application of sensory testing of regional analgesia in humans must be redetermined. New indications of the use of these methods then can be provided. In the current article, we update the knowledge available in the field of sensory assessment of regional analgesia in humans. The aims are as follows: (1) to describe and analyze the methods, (2) to define the applications, (3) to provide evidence-based indications for the use of these methods in anesthesia and pain research, and (4) to define areas in which further research is needed.

Isoflurane Minimum Alveolar Concentration Decreases during Anesthesia and Surgery

BackgroundIt generally is assumed that the potency of inhalational anesthetics remains unchanged during the course of the administration of an anesthetic. Only one study has indicated a decrease of minimum alveolar concentration with time. In this study, an effect of the duration of anesthesia administration and surgery on the potency of isoflurane was investigated by determining MACtetanus (the minimum alveolar concentration that prevents movement in response to electrical tetanic stimulation in 50% of patients) before and after surgery. MethodsTen patients who underwent removal of a herniated intervertebral disc were anesthetized with isoflurane only. Reaction to a standardized electrical stimulation applied to the forearm was observed and was graded as movement or no-movement. The isoflurane concentration was increased in steps of 0.10 vol% if the patient moved and decreased in steps of 0.10 vol% if no reaction was seen, until a “movement/nomovement/movement” or “no-movement/movement/no-movement” pattern, respectively, was achieved. ResultsMACtetanus decreased in all patients from 1.28 ± 0.22 vol% (mean ± SD) before surgery to 1.04 ± 0.22 vol% after surgery (P < 0.01). When the prestimulation arterial blood pressure or the maximal increase in blood pressure caused by stimulation at the individual MACtetanus before surgery were compared to the corresponding values at the individual MACtetanus after surgery, no significant difference could be found. The prestimulation heart rate and the maximal increase in heart rate were significantly lower after surgery, even though the end-tidal isoflurane concentration was 0.24 vol% lower at the individual MACtetanus after surgery. ConclusionThe authors conclude that MACtetanus decreases during the administration of anesthesia and the performance of surgery.