Lone Knudsen

Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine.

ABSTRACT A double‐blind placebo‐controlled crossover trial was used to determine the effects of topical ketamine, an N‐methyl‐d‐aspartate (NMDA) receptor antagonist, on the sensory disturbances in 20 patients with complex regional pain syndrome (CRPS). On two occasions separated by at least one week, sensory tests to light touch, pressure, punctate stimulation, light brushing and thermal stimuli were performed in the symptomatic and contralateral limb and on each side of the forehead before and 30 min after 10% ketamine cream was applied to the symptomatic or healthy limb. Venous blood for the plasma estimations of ketamine and norketamine was obtained 1 h after application of the creams. Ketamine applied to the symptomatic limb inhibited allodynia to light brushing and hyperalgesia to punctate stimulation. Systemic effects of the ketamine are unlikely to account for this as the plasma levels were below detectable limits. As touch thresholds were unchanged, NMDA receptors may contribute to the sensory disturbances in CRPS via actions at cutaneous nociceptors. Allodynia and hyperalgesia were detected in the ipsilateral forehead to a range of stimuli (brushing, pressure, punctate stimulation, cold, heat, and warmth). In several patients, ketamine treatment of the symptomatic limb inhibited allodynia to brushing the ipsilateral forehead, suggesting that the mechanism that mediates allodynia in the symptomatic limb contributed to allodynia at more remote sites. The present study shows promise for the use of topical ketamine as opposed to parenteral and oral forms which often result in undesirable side effects.

Cold-induced limb pain decreases sensitivity to pressure-pain sensations in the ipsilateral forehead

The aim of this study was to investigate the effect of unilateral limb pain on sensitivity to pain on each side of the forehead. In the first experiment, pressure‐pain thresholds and sharpness sensations were assessed on each side of the forehead in 45 healthy volunteers before and after a 10 °C cold pressor of the hand and in 18 controls who were not subjected to the cold pressor. In a second experiment, forehead sensitivity was assessed in 32 healthy volunteers before and after a 2 °C cold pressor. The assessments were repeated without the cold pressor, and before and after six successive 4 °C cold pressor tests. The 10 °C cold pressor did not influence forehead sensitivity, whereas the 2 °C cold pressor and the 4 °C cold pressor tests resulted in bilateral analgesia to sharpness and pressure. The analgesia to pressure was greater in the ipsilateral forehead. Stress‐induced analgesia and diffuse noxious inhibitory controls may have contributed to the analgesia to pressure‐pain and sharpness sensations bilaterally after the most painful cold pressor tests. The locus coeruleus inhibits ipsilateral nociceptive activity in dorsal horn neurons during limb inflammation, and thus may have mediated the ipsilateral component of analgesia. Pain‐evoked changes in forehead sensitivity differed for sharpness and pressure, possibly due to separate thalamic or cortical representations of cutaneous and deep tissue sensibility. These findings suggest that several mechanisms act concurrently to influence pain sensitivity at sites distant from a primary site of painful stimulation.

Central pain modulation and scalp tenderness in frequent episodic tension-type headache.

Objective.— To determine whether the inhibitory effect of acute limb pain on pain to mechanical stimulation of the forehead is compromised in individuals with frequent episodes of tension‐type headache.

Review of neuroimaging studies related to pain modulation

Abstract Background and purpose: A noxious stimulus does not necessarily cause pain. Nociceptive signals arising from a noxious stimulus are subject to modulation via endogenous inhibitory and facilitatory mechanisms as they travel from the periphery to the dorsal horn or brainstem and on to higher brain sites. Research on the neural structures underlying endogenous pain modulation has largely been restricted to animal research due to the invasiveness of such studies (e.g., spinal cord transection, brain lesioning, brain site stimulation). Neuroimaging techniques (e.g., magnetoencephalography (MEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)) provide non-invasive means to study neural structures in humans. The aim is to provide a narrative review of neuroimaging studies related to human pain control mechanisms. Methods: The approach taken is to summarise specific pain modulation mechanisms within the somatosensory (diffuse noxious inhibitory controls, acupuncture, movement), affective (depression, anxiety, catastrophizing, stress) and cognitive (anticipation/placebo, attention/distraction, hypnosis)domains with emphasis on the contribution of neuroimaging studies. Results and conclusions: Findings from imaging studies are complex reflecting activation or deactivation in numerous brain areas. Despite this, neuroimaging techniques have clarified supraspinal sites involved in a number of pain control mechanisms. The periaqueductal grey (PAG) is one area that has consistently been shown to be activated across the majority of pain mechanisms. Activity in the rostral ventromedial medulla known to relay descending modulation from the PAG, has also been observed both during acupuncture analgesia and anxiety-induced hyperalgesia. Other brain areas that appear to be involved in a number of mechanisms are the anterior cingulate cortex, prefrontal cortex, orbitofrontal cortex and nucleus accumbens, but their exact role is less clear. Implications: Neuroimaging studies have provided essential information about the pain modulatory pathways under normal conditions, but much is still to be determined. Understanding the mechanisms of pain control is important for understanding the mechanisms that contribute to failed pain control in chronic pain. Applying fMRI outside the brain, such as in the trigeminal nucleus caudalis of the spinotrigeminal pathway and in the dorsal horn of the spinal cord, and coupling brain activity with activity at these sites may help improve our understanding of the function of brain sites and shed light on functional connectivity in the pain pathway.

The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy

Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.

The specificity and mechanisms of hemilateral sensory disturbances in complex regional pain syndrome

UNLABELLED Hyperalgesia often extends from the affected limb to the ipsilateral forehead in patients with complex regional pain syndrome (CRPS). To investigate whether this is more common in CRPS than other chronic pain conditions, pressure-pain thresholds and sharpness to a firm bristle were assessed on each side of the forehead, at the pain site, and at an equivalent site on the contralateral side in 32 patients with chronic pain other than CRPS (neuropathic or nociceptive limb pain, radicular pain with referral to a lower limb or postherpetic neuralgia), and in 34 patients with CRPS. Ipsilateral forehead hyperalgesia to pressure pain was detected in 59% of CRPS patients compared with only 13% of patients with other forms of chronic pain. Immersion of the CRPS-affected limb in painfully cold water increased forehead sensitivity to pressure, especially ipsilaterally, whereas painful stimulation of the healthy limb reduced forehead sensitivity to pressure pain (albeit less efficiently than in healthy controls). In addition, auditory discomfort and increases in pain in the CRPS-affected limb were greater after acoustic startle to the ear on the affected than unaffected side. These findings indicate that generalized and hemilateral pain control mechanisms are disrupted in CRPS, and that multisensory integrative processes may be compromised. PERSPECTIVE The findings suggest that hemilateral hyperalgesia is specific to CRPS, which could be diagnostically important. Disruptions in pain-control mechanisms were associated with the development of hyperalgesia at sites remote from the CRPS limb. Addressing these mechanisms could potentially deter widespread hyperalgesia in CRPS.

Cutaneous Limb Inflammation Produces Analgesia to Pressure Pain in the Ipsilateral Forehead of Healthy Volunteers

UNLABELLED To investigate the pain-modulatory effects of a local inflammatory stimulus on pain elsewhere in the body, capsaicin was applied topically to the forearm of 14 healthy female volunteers. Pressure-pain thresholds and sensitivity to sharpness were assessed on each side of the forehead twice per day during 48 hours of capsaicin treatment, and in the treated and contralateral forearm before and at the end of treatment. Heat was applied to the treated area to rekindle pain at times of forehead assessment. Hyperalgesia to sharpness, but not pressure pain, developed in the treated area whereas sensations remained stable in the contralateral forearm. Sharpness ratings decreased bilaterally in the forehead after 6 hours of treatment, and ipsilateral analgesia to pressure pain developed in the forehead when the capsaicin site was heated after 48 hours of treatment. These findings suggest that pain modulation involves unilateral regulatory mechanisms in addition to local and generalized pain control. The dissociated changes to sharpness and pressure pain indicate distinct cutaneous and deep central pain pathways. PERSPECTIVE The findings lend support to an increasing body of research which demonstrates that pain modulation involves hemilateral mechanisms in addition to local and generalized controls. Elucidation of mechanisms that modulate ipsilateral pain processing may help to clarify the pathophysiology of complex regional pain syndrome, which is characterized by hemilateral hyperalgesia.

Capillary dysfunction and impaired tissue oxygenation in complex regional pain syndrome: a hypothesis.

http://dx.doi.org/10.1016/j.pain.2014.06.005 0304-3959/ 2014 The Authors. Published by Elsevier B.V. on behalf of International Association for the Study of Pain. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/). ⇑ Corresponding author at: Aarhus University Hospital, Department of Neuroradiology, Center of Functionally Integrative Neuroscience and MINDLab, Building 10G, 5th floor, Nørrebrogade 44, Aarhus C 8000, Denmark. Tel.: +45 7846 4091; fax: +45 7846 1622. E-mail address: leif@cfin.dk (L. Østergaard). Leif Østergaard a,b,⇑, Astrid Juhl Terkelsen , Nanna Brix Finnerup , Lone Knudsen , Kim Ryun Drasbek , Sune Nørhøj Jespersen , Peter Svensson , Jens Christian H. Sørensen , Troels Staehelin Jensen c,d

Cutaneous noradrenaline measured by microdialysis in complex regional pain syndrome during whole-body cooling and heating

Complex regional pain syndrome (CRPS) is characterised by autonomic, sensory, and motor disturbances. The underlying mechanisms of the autonomic changes in CPRS are unknown. However, it has been postulated that sympathetic inhibition in the acute phase with locally reduced levels of noradrenaline is followed by an up-regulation of alpha-adrenoceptors in chronic CRPS leading to denervation supersensitivity to catecholamines. This exploratory study examined the effect of cutaneous sympathetic activation and inhibition on cutaneous noradrenaline release, vascular reactivity, and pain in CRPS patients and in healthy volunteers. Seven patients and nine controls completed whole-body cooling (sympathetic activation) and heating (sympathetic inhibition) induced by a whole-body thermal suit with simultaneous measurement of the skin temperature, skin blood flow, and release of dermal noradrenaline. CRPS pain and the perceived skin temperature were measured every 5 min during thermal exposure, while noradrenaline was determined from cutaneous microdialysate collected every 20 min throughout the study period. Cooling induced peripheral sympathetic activation in patients and controls with significant increases in dermal noradrenaline, vasoconstriction, and reduction in skin temperature. The main findings were that the noradrenaline response did not differ between patients and controls or between the CRPS hand and the contralateral unaffected hand, suggesting that the evoked noradrenaline release from the cutaneous sympathetic postganglionic fibres is preserved in chronic CRPS patients.

Optokinetic stimulation increases limb pain and forehead hyperalgesia in complex regional pain syndrome

Ambiguous visual stimuli increase limb pain in patients with complex regional pain syndrome (CRPS), possibly due to afferent sensory feedback conflicts. Conflicting sensory stimuli can also generate unpleasant sensations in healthy people such as during motion sickness. We wanted to investigate the mechanisms underlying the link between sensory conflicts and pain in CRPS using optokinetic stimulation (OKS) – a method known to induce motion sickness.