Torsten Gordh

Complex regional pain syndromes: Guidelines for therapy

This report aims to present an orderly approach to the treatment of Chronic Regional Pain Syndrome (CRPS) types I and II through an algorithm. The central theme is functional restoration: a coordinated but progressive approach that introduces each of the treatment modalities needed to achieve both remission and rehabilitation. Reaching objective and measurable rehabilitation goals is an essential element. Specific exercise therapy to reestablish function after musculoskeletal injury is central to this functional restoration. Its application to CRPS is more contingent on varying rates of progress that characterize the restoration of function in patients with CRPS. Also, the various modalities that may be used, including analgesia by pharmacologic means or regional anesthesia or the use of neuromodulation, behavioral management, and the qualitatively different approaches that are unique to the management of children with CRPS, are provided only to facilitate functional improvement in a stepwise but methodical manner. Patients with CRPS need an individual approach that requires extreme flexibility. This distinguishes the management of these conditions from other well-described medical conditions having a known pathophysiology. In particular, the special biopsychosocial factors that are critical to achieving a successful outcome are emphasized. This algorithm is a departure from the contemporary heterogeneous approach to treatment of patients with CRPS. The underlying principles are motivation, mobilization, and desensitization facilitated by the relief of pain and the use of pharmacologic and interventional procedures to treat specific signs and symptoms. Self-management techniques are emphasized, and functional rehabilitation is the key to the success of this algorithm.

Neonatal Exposure to a Combination of N -Methyl-d-aspartate and γ-Aminobutyric Acid Type A Receptor Anesthetic Agents Potentiates Apoptotic Neurodegeneration and Persistent Behavioral Deficits

Background:During the brain growth spurt, the brain develops and modifies rapidly. In rodents this period is neonatal, spanning the first weeks of life, whereas in humans it begins during the third trimester and continues 2 yr. This study examined whether different anesthetic agents, alone and in combination, administered to neonate mice, can trigger apoptosis and whether behavioral deficits occur later in adulthood. Methods:Ten-day-old mice were injected subcutaneously with ketamine (25 mg/kg), thiopental (5 mg/kg or 25 mg/kg), propofol (10 mg/kg or 60 mg/kg), a combination of ketamine (25 mg/kg) and thiopental (5 mg/kg), a combination of ketamine (25 mg/kg) and propofol (10 mg/kg), or control (saline). Fluoro-Jade staining revealed neurodegeneration 24 h after treatment. The behavioral tests—spontaneous behavior, radial arm maze, and elevated plus maze (before and after anxiolytic)—were conducted on mice aged 55–70 days. Results:Coadministration of ketamine plus propofol or ketamine plus thiopental or a high dose of propofol alone significantly triggered apoptosis. Mice exposed to a combination of anesthetic agents or ketamine alone displayed disrupted spontaneous activity and learning. The anxiolytic action of diazepam was less effective when given to adult mice that were neonatally exposed to propofol. Conclusion:This study shows that both a &ggr;-aminobutyric acid type A agonist (thiopental or propofol) and an N-methyl-d-aspartate antagonist (ketamine) during a critical stage of brain development potentiated neonatal brain cell death and resulted in functional deficits in adulthood. The use of thiopental, propofol, and ketamine individually elicited no or only minor changes.

Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration.

The early postnatal brain development, when many potentially sensitive processes occur, has been shown to be vulnerable to different pharmacological and environmental compounds. In the present investigation, four groups of neonatal NMRI male mice were administered the glutamate NMDA receptor antagonist ketamine (50 mg/kg, s.c.), or the GABA(A) receptor agonist diazepam (5 mg/kg, s.c.), or co-administered ketamine (50 mg/kg, s.c.) and diazepam (5 mg/kg, s.c.), or vehicle (0.9% saline, s.c.) on day 10 after birth. On day 11, mice from each treatment group were sacrificed and brains were taken for analysis of neuronal cell degeneration, using Fluoro-Jade staining technique. Ketamine, but not diazepam, induced a severe degeneration of cells in the parietal cortex. The opposite was observed for diazepam in the laterodorsal thalamus. The most pronounced cell degeneration was seen in parietal cortex of mice exposed to both ketamine and diazepam. At 2 months of age each treatment group was tested for motor activity and learning performance. Ketamine and ketamine + diazepam treated mice displayed severe deficits of habituation to the test chamber in the spontaneous motor activity test, marked deficits of acquisition learning and retention memory in the radial arm maze-learning task and less shift learning in the circular swim maze-learning task. This study indicates that the observed functional deficits can be related to cell degeneration induced during a critical stage of neonatal brain development. The potentiated apoptosis induced by ketamine and diazepam may have implications for the selection of drugs used in neonatal paediatric anaesthesia.

Peripheral neuropathic pain—a multidimensional burden for patients

The present study was undertaken to assess the health‐related quality of life (HRQoL) and burden of illness due to pain and its treatment for patients with peripheral neuropathic pain (PNP). It is the first step in finding reliable instruments/targets to evaluate treatment outcome in this patient population. Study population consisted of 126 patients suffering from neuropathic pain due to a peripheral nerve or root lesion, recruited from two multidisciplinary pain clinics. HRQoL was examined using Short Form 36 (SF‐36) Health Survey and Nottingham Health Profile (NHP). Pain intensity in four categories (at rest and evoked by movement, touch and cold) was rated on a visual analogue scale (VAS). Degree of discomfort from pain and 25 symptoms related to pain and side‐effects was also assessed. Reduction in workload due to pain was recorded, as was the pain relief from previous and current treatments and the reasons for discontinuing previous treatments.

Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography.

Abstract Regional cerebral blood flow was measured with positron emission tomography (PET) in six healthy volunteers at rest and during experimentally induced, sustained cutaneous pain on the dorsum of the right hand or on the dorsum of the right foot. Pain was inflicted by intracutaneous injection of capsaicin, providing a mainly C-fibre nociceptive stimulus. Statistical analysis showed significant activations along the central sulcus (SI) area when comparing pain in the hand to pain in the foot. Separate comparison of both pain states to a baseline revealed different locations along the central sulcus for hand pain and foot pain. The encountered differences are consistent with what is previously known about the somatotopics of non-painful stimuli. When comparing painful stimuli to baseline, the contralateral anterior cingulate gyrus, the ipsilateral anterior insular cortex and the ipsilateral prefrontal cortex were implicated. The results are consistent with an involvement of SI in the spatial discrimination of acute cutaneous pain.

Guided internet-delivered acceptance and commitment therapy for chronic pain patients: A randomized controlled trial

Acceptance and commitment therapy (ACT) interventions for persons with chronic pain have recently received empirical support. ACT focuses on reducing the disabling influences of pain through targeting ineffective control strategies and teaches people to stay in contact with unpleasant emotions, sensations, and thoughts. The aim of the present study was to investigate the effect of a guided internet-delivered ACT intervention for persons with chronic pain. A total of 76 patients with chronic pain were included in the study and randomized to either treatment for 7 weeks or to a control group that participated in a moderated online discussion forum. Intent-to-treat analyses showed significant increases regarding activity engagement and pain willingness. Measurements were provided with the primary outcome variable Chronic Pain Acceptance Questionnaire which was in favour of the treatment group. Reductions were found on other measures of pain-related distress, anxiety and depressive symptoms. A six month follow-up showed maintenance of improvements. We conclude that an acceptance based internet-delivered treatment can be effective for persons with chronic pain.

The incidence of chronic post-sternotomy pain after cardiac surgery : a prospective study

Background: Post‐sternotomy pain is sometimes a sequela of cardiac surgery. The incidence, characteristics and clinical course of post‐sternotomy pain are not well known. The aim of our study was to determine the incidence of chronic post‐sternotomy pain in patients undergoing sternotomy for cardiac surgery in general and according to the specific surgical procedure.

Histopathology after repeated intrathecal injections of preservative-free ketamine in the rabbit: a light and electron microscopic examination.

Epidural and spinal administration of ketamine has been used in humans. Single-dose studies have shown that preservative-free ketamine lacks neurotoxic effects, but there are no studies after repeated administrations. The aim of this study was to examine the effects of daily administration of preservative-free ketamine. Fourteen New Zealand albino rabbits were assigned to two groups receiving either intrathecal preservative-free ketamine 5 mg, 0.5 mL 1% solution (eight rabbits) or saline 0.5 mL (six rabbits) once a day for 14 consecutive days. The rabbits had a total subcutaneous implanted intrathecal catheter, which was introduced during general anesthesia. On Day 15 the rabbits were anesthetized and in vivo fixated by transcardial perfusion with Tyrodes solution followed by a mixture of 2% glutaraldehyde and 1% formaldehyde in a 0.1 mol/L phosphate buffer. A segment 5 cm on each side of the catheter tip was removed and kept in a cold solution of the fixative. Light microscopic, electron microscopic, and morphometric examinations showed no differences between the spinal cords from the rabbits injected with ketamine versus saline. Intrathecal ketamine produced motor impairment for a period of 15 min. We conclude that repeated intrathecal administration of preservative-free ketamine confirms the lack of neurotoxicity from single-dose studies.

Gabapentin in traumatic nerve injury pain: A randomized, double-blind, placebo-controlled, cross-over, multi-center study

&NA; A double‐blind, randomized, placebo‐controlled cross‐over multi‐center study was conducted to evaluate the efficacy and safety of gabapentin in the treatment of neuropathic pain caused by traumatic or postsurgical peripheral nerve injury, using doses up to 2400 mg/day. The study comprised a run‐in period of two weeks, two treatment periods of five weeks separated by a three weeks’ washout period. The primary efficacy variable was the change in the mean pain intensity score from baseline to the last week of treatment. Other variables included pain relief, health related quality of life (SF‐36), interference of sleep by pain, Clinician and Patient Global Impression of Change, and adverse effects. Nine centers randomized a total of 120 patients, 22 of whom withdrew. There was no statistically significant difference between the treatments for the primary outcome efficacy variable. However, gabapentin provided significantly better pain relief (p = 0.015) compared with placebo. More patients had at least a 30% pain reduction with gabapentin compared with placebo (p = 0.040) and pain interfered significantly less with sleep during gabapentin treatment compared with placebo (p = 0.0016). Both the Patient (p = 0.023) and Clinician (p = 0.037) Global Impression of Change indicated a better response with gabapentin compared with placebo. Gabapentin was well tolerated. The most common adverse effects were dizziness and tiredness.

Spinal nerve lesion alters blood–spinal cord barrier function and activates astrocytes in the rat

Abstract Alterations in the spinal cord microenvironment in a neuropathic pain model in rats comprising right L‐4 spinal nerve lesion were examined following 1, 2, 4 and 10 weeks using albumin and glial fibrillary acidic protein (GFAP) immunoreactivity. Rats subjected to nerve lesion showed pronounced activation of GFAP indicating astrocyte activation, and exhibited marked leakage of albumin, suggesting defects of the blood–spinal cord barrier (BSCB) function in the corresponding spinal cord segment. The intensities of these changes were most prominent in the gray matter of the lesioned side compared to the contralateral cord in both the dorsal and ventral horns. The most marked changes in albumin and GFAP immunoreaction were seen after 2 weeks and persisted with mild intensities even after 10 weeks. Distortion of nerve cells, loss of neurons and general sponginess were evident in the gray matter of the spinal cord corresponding to the lesion side. These nerve cell and glial cell changes was mainly evident in the areas showing leakage of endogenous albumin in the spinal cord. These novel observations indicate that chronic nerve lesion has the capacity to induce a selective increase in local BSCB permeability that could be instrumental in nerve cell and glial cell activation. These findings may be relevant to our current understanding on the pathophysiology of neuropathic pain.