Philip M. Finch

Pain increases during sympathetic arousal in patients with complex regional pain syndrome

Objective: To investigate the effect of sympathetic arousal on pain and vasomotor responses in healthy control subjects and patients with complex regional pain syndrome (CRPS), and to determine whether pain increases in patients with particular symptoms. Methods: In experiments 1 and 2, capsaicin was applied to the forearm of 24 healthy subjects to induce thermal hyperalgesia. Vascular responses were monitored and subjects rated thermal hyperalgesia before and after being startled (experiment 1), and before, during, and after mental arithmetic, breath holding, forehead cooling, the Valsalva maneuver, and a cold pressor test in experiment 2. In a third experiment, sensitivity to heat, cold, and mechanical stimulation was investigated in 61 patients with CRPS. Pain ratings and vascular and electrodermal responses were recorded after patients were startled and during forehead cooling. Results: In experiment 1, thermal hyperalgesia decreased in healthy control subjects after they were startled, and digital blood vessels constricted symmetrically. In experiment 2, thermal hyperalgesia decreased during and after other forms of sympathetic arousal. However, in experiment 3, ratings of clinical pain increased during forehead cooling or after being startled in over 70% of patients with CRPS. Pain increased most consistently during forehead cooling in patients with cold allodynia or punctate allodynia. Digital blood vessels constricted more intensely on the symptomatic than the nonsymptomatic side in patients with CRPS during sympathetic arousal. Conclusions: Normal inhibitory influences on pain during sympathetic arousal are compromised in the majority of patients with CRPS. The augmented vasoconstrictor response in the symptomatic limb during sympathetic arousal is consistent with adrenergic supersensitivity. An adrenergic sensitivity in nociceptive afferents might contribute to pain and hyperalgesia during sympathetic arousal in certain patients with CRPS.

Hypogonadism in patients treated with intrathecal morphine.

OBJECTIVE The objective of this study was to investigate the hypothalamic-pituitary-gonadal response to intrathecal opioids. PATIENTS Thirty patients receiving intrathecal morphine for chronic nonmalignant pain were studied for clinical and biochemical evidence of hypogonadism. Ten men and 10 postmenopausal women with chronic pain of similar duration but who were not receiving any form of opioid therapy acted as control subjects. RESULTS Men and both premenopausal and postmenopausal women had evidence of hypogonadism with low levels of serum testosterone or estrogen coupled with low levels of pituitary gonadotrophins. Control subjects had hormone levels in the expected range for their sex and age. Two men demonstrated recovery after ceasing intrathecal opioid therapy. CONCLUSIONS Hypogonadotrophic hypogonadism is a common complication of intrathecal opioid therapy in both men and women.

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.

Unravelling the pathophysiology of complex regional pain syndrome : focus on sympathetically maintained pain

1 In diseases such as complex regional pain syndrome (CRPS), where neuropathic pain is the primary concern, traditional pain classifications and lesion descriptors are of limited value. To obtain better treatment outcomes for patients, the underlying pathophysiological mechanisms of neuropathic pain need to be elucidated and analysed so that therapeutic targets can be identified and specific treatments developed. 2 In the present review, we examine the current literature on sympathetically maintained pain (SMP), a subset of neuropathic pain, within the context of CRPS. Evidence from both human and animal studies is presented and discussed in terms of its support for the existence of SMP and the mechanistic information it provides. 3 We discuss three current hypotheses that propose both a site and method for sympathetic–sensory coupling: (i) direct coupling between sympathetic and sensory neurons in the dorsal root ganglion; (ii) chemical coupling between sympathetic and nociceptive neuron terminals in skin; and (iii) the development of a‐adrenoceptor‐mediated supersensitivity in nociceptive fibres in skin in association with the release of inflammatory mediators. 4 Finally, we propose a new hypothesis that integrates the mechanisms of chemical coupling and a‐adrenoceptor‐mediated supersensitivity. This hypothesis is based on previously unpublished data from our laboratory showing that a histological substrate suitable for sympathetic–sensory coupling exists in normal subjects. In the diseased state, the nociceptive fibres implicated in this substrate may be activated by both endogenous and exogenous noradrenaline. The mediating a‐adrenoceptors may be expressed on the nociceptive fibres or on closely associated support cells.

Radiofrequency heating of painful annular disruptions: One-year outcomes

Objective: Although several studies have reported on outcomes following heating of annular tears with a thermoresistive catheter (SpineCATH), no data are available on the efficacy of thermal treatment with a flexible radiofrequency electrode (discTRODE). A prospective case-control study was conducted to determine the efficacy of radiofrequency heating of painful annular tears in the lumbar spine. Methods: After at least 6 months of conservative treatment, 46 patients were studied for the presence of single-level painful annular tears with magnetic resonance imaging and provocative discography. Thirty-one patients underwent heating of their annular tears with a flexible radiofrequency electrode placed across the posterior annulus. The remaining 15 patients, who mostly could not obtain funding for the procedure, continued with conservative management and acted as a control group. The Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Medication Quantification Score (MQS) were obtained before and at 3-monthly intervals after treatment. Results: The VAS decreased significantly after the radiofrequency treatment, and this decrease persisted at 12 months of follow-up. The VAS did not change over 12 months in untreated control subjects. The decrease in VAS was significantly greater in the treated patients than the control subjects. The ODI also decreased in treated patients but not in control subjects. The MQS did not change in either group over the 12-month follow-up period. Conclusions: Radiofrequency heating of annular tears can lead to an improvement in the pain of internal disc disruption. The improvement gained by this treatment method is significantly better than that obtained from conservative management.

Plasma neuropeptide Y in the symptomatic limb of patients with causalgic pain

The aim of this experiment was to measure the concentration of neuropeptide Y (NPY), a vasoactive transmitter which coexists with noradrenaline in sympathetic nerve terminals, in venous blood taken from the painful and contralateral limbs of 16 patients with features of reflex sympathetic dystrophy (RSD) or causalgia. In nine patients tapping the skin of the affected limb provoked pain (allodynia). In seven of the nine patients with allodynia the concentration of NPY was lower on the painful side; similar results were obtained in only two of seven patients without widespread allodynia. In addition, the concentration of NPY was generally lower in the painful limb if it was warmer than the contralateral limb. These findings suggest that a reduction in sympathetic activity might accompany allodynia and influence vasomotor disturbances in patients with causalgic pain.

Activation of Cutaneous Immune Responses in Complex Regional Pain Syndrome

UNLABELLED The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are elevated in experimental skin blister fluid from CRPS-affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS, exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS, keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS, there was reduced keratinocyte proliferation, leading to epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS. PERSPECTIVE The results of this study support the hypotheses that CRPS involves activation of the innate immune system, with keratinocyte and mast cell activation and proliferation, inflammatory mediator release, and pain.

Sensory changes in the forehead of patients with complex regional pain syndrome

Abstract The aim of this study was to investigate involvement of central mechanisms in complex regional pain syndrome (CRPS). In particular, we wished to determine whether hyperalgesia extends ipsilaterally from the affected limb to the forehead. The heat‐pain threshold, pressure‐pain threshold, and ratings of cold and sharpness were investigated on each side of the forehead and in the affected and unaffected limbs of 38 patients with features of CRPS. In addition, touch thresholds were investigated in the limbs. The pressure‐pain threshold was lower on the ipsilateral forehead than contralaterally, consistent with the presence of static mechanical hyperalgesia. Although the heat‐pain threshold and ratings of sharpness and cold did not differ between the two sides of the forehead in the group as a whole, the sharpness of pinprick sensations in the affected limb was mirrored by similar sensations in the ipsilateral forehead. Conversely, diminished sensitivity to light touch in the affected limb was associated with diminished sensitivity to sharpness, cold and heat‐pain in the ipsilateral forehead. These findings suggest that central nociceptive processing is disrupted in CRPS, possibly due to disturbances in the thalamus or higher cortical centres.

Innervation of hyperalgesic skin in patients with complex regional pain syndrome

OBJECTIVE To look for anatomical and histochemical signs of interaction between sensory and sympathetic nerves in the hyperalgesic skin of patients with complex regional pain syndrome. SUBJECTS Skin samples were obtained from eight patients whose condition developed after a suspected or confirmed peripheral nerve injury, and from nine patients with features of reflex sympathetic dystrophy (RSD) following a soft-tissue injury. A skin sample was also obtained from 18 control subjects of similar age and sex distribution to patients. DESIGN In patients, skin samples were taken from an area of static mechanical hyperalgesia and from an equivalent site in the contralateral limb. In controls, skin samples were obtained from the dorsum of one hand or foot. HISTOCHEMICAL MARKERS: We used neuron-specific enolase for all classes of nerve fiber; tyrosine hydroxylase for noradrenergic fibers; vasoactive intestinal peptide for sympathetic sudomotor fibers; tyrosine hydroxylase co-existing with neuropeptide Y for sympathetic vasoconstrictor fibers; and calcitonin gene-related peptide with substance P or somatostatin for peptide-containing unmyelinated sensory fibers. RESULTS In patients, the distribution of markers was similar in skin taken from an area of mechanical hyperalgesia and skin taken from an equivalent site contralaterally, and was unrelated to clinical features of RSD. The distribution of markers did not differ between patients and controls. Nerve tangles immunoreactive to neuron-specific enolase, but not to other markers, were detected in samples taken from four patients and two controls. The nerve tangles were present bilaterally in two patients, and only on the affected side in two other patients. The clinical condition was more fully developed in the four patients whose skin samples contained nerve tangles than in most other patients. CONCLUSIONS A major difference in distribution or change in histochemical content of cutaneous autonomic or nociceptor fibers is unlikely to underly static mechanical hyperalgesia following a soft-tissue or peripheral nerve injury. The relevance of cutaneous nerve tangles for the pathophysiology of RSD is uncertain.

Expression of α1-adrenoceptors on peripheral nociceptive neurons

The purpose of this study was to determine whether α(1)-adrenoceptors are expressed on primary nociceptive afferents that innervate healthy skin. Skin and dorsal root ganglia were collected from adult male Wistar rats and assessed using fluorescence immunohistochemistry with antibodies directed against α(1)-adrenoceptors alone or in combination with specific labels including myelin basic protein and neurofilament 200 (markers of myelinated nerve fibres), protein gene product 9.5 (a pan-neuronal marker), tyrosine hydroxylase (sympathetic neurons), isolectin B(4) (IB(4): non-peptidergic sensory neurons), calcitonin gene related peptide (CGRP) and transient receptor potential vanilloid receptor 1 (TRPV1) (peptidergic sensory neurons). Double labelling in dorsal root ganglia confirmed the expression of α(1)-adrenoceptors within sub-populations of CGRP, IB(4) and TRPV1 immunoreactive neurons. Myelinated and unmyelinated sensory nerve fibres in the skin expressed α(1)-adrenoceptors whereas sympathetic nerve fibres did not. The expression of α(1)-adrenoceptors on C- and A-delta nociceptive afferent fibres provides a histochemical substrate for direct excitation of these fibres by adrenergic agonists. This may help to explain the mechanism of sensory-sympathetic coupling that sometimes develops on surviving primary nociceptive afferents in neuropathic pain states.