Catecholamine-induced excitation of nociceptors in sympathetically maintained pain

Sympathetically maintained pain could either be mediated by ephaptic interactions between sympathetic efferent and afferent nociceptive fibers or by catecholamine-induced activation of nociceptive nerve endings. We report here single fiber recordings from C nociceptors in a patient with sympathetically maintained pain, in whom sympathetic blockade had repeatedly eliminated the ongoing pain in both legs. We classified eight C-fibers as mechano-responsive and six as mechano-insensitive nociceptors according to their mechanical responsiveness and activity-dependent slowing of conduction velocity (latency increase of 0.5+/-1.1 vs. 7.1+/-2.0 ms for 20 pulses at 0.125 Hz). Two C-fibers were activated with a delay of several seconds following strong endogenous sympathetic bursts; they were also excited for about 3 min following the injection of norepinephrine (10 microl, 0.05%) into their innervation territory. In these two fibers, a prolonged activation by injection of low pH solution (phosphate buffer, pH 6.0, 10 microl) and sensitization of their heat response following prostaglandin E2 injection were recorded, evidencing their afferent nature. Moreover, their activity-dependent slowing was typical for mechano-insensitive nociceptors. We conclude that sensitized mechano-insensitive nociceptors can be activated by endogenously released catecholamines and thereby may contribute to sympathetically maintained pain. No evidence for ephaptic interaction between sympathetic efferent and nociceptive afferent fibers was found.     

Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain

Tissue injuries, with or without involvement of nerves, may lead to ongoing pain and hyperalgesia to external stimuli. In a subset of patients, the pain is maintained by sympathetic efferent activity (SMP). We investigated if the peripheral administration of the alpha-adrenergic agonist, norepinephrine (NE), in physiologically relevant doses resulted in pain in patients with SMP. To establish the dose of intradermal NE required to induce cutaneous vasoconstriction, NE (1 nM-10 microM, 30 microl) was injected under a laser Doppler probe on the volar forearm of seven normal subjects. A decrease in blood flow was evident at a dose of 10 microM. Twelve patients (five male, seven female) diagnosed to have SMP based on the decrease in pain by a local anesthetic sympathetic blockade (70+/-6%) were enrolled in the study. Pain ratings were obtained continuously for 5 min after intradermal injections of saline and NE (0.1-10 microM) into their hyperalgesic zone and the mirror-image contralateral side. Injections were done during the period of pain relief following a local anesthetic sympathetic blockade. Similar injections were made in eight control subjects. On the affected side of the patients, the two highest concentrations of NE (1 and 10 microM) caused significantly more pain than saline (P<0.05, ANOVA). In contrast, there was no significant pain induced by the NE injections in the unaffected side and in control subjects. Six of nine patients tested reported a marked decrease in pain and hyperalgesia following infusion of phentolamine (1 mg/kg over 10 min). Two of the three patients who did not receive pain relief following phentolamine infusion also did not report pain to the NE injections. We conclude that NE injections produce pain in SMP patients at doses that are at the threshold for producing vasoconstriction. These studies support a role for cutaneous adrenoceptors in the mechanisms of sympathetically maintained pain.     

Spinal recordings suggest that wide-dynamic-range neurons mediate sympathetically maintained pain

In order to determine which classes of spinal neurons are capable of mediating sympathetically maintained pain, recordings were made from single somatosensory neurons in spinal cords of anesthetized cats. Each neuron was functionally identified with mechanical stimuli, and its responses to electrical stimulation of the sympathetic trunk were recorded. Nearly half (45%) of the wide-dynamic-range (WDR) neurons tested were activated by sympathetic stimulation, but none of the high threshold (nociceptor-specific) neurons and only 17% of the low threshold neurons were activated. Sympathetic activation was most common for WDR neurons that had the following: receptive fields proximal to the toes, low thresholds for mechanical activation, and both rapidly and slowly adapting responses to pressure. The predominant WDR response to sympathetic stimulation was long latency (greater than 1 sec) excitation. Sympathetic activation of WDR neurons was abolished by each of the following procedures: subcutaneous injection of local anesthetic, cooling of the receptive field with ice, and intravenous injection of the alpha-adrenergic blocker, phentolamine. The axons of some sympathetically activated WDR were shown to project to higher centers. These results indicate that WDR neurons are the only spinal nociceptive neurons activated by sympathetic efferent activity in this preparation. Therefore, WDR neurons, rather than high threshold neurons, are most likely to mediate the spinal component of sympathetically maintained pain. These results provide supporting evidence for our previous hypothesis that sympathetically maintained pain is mediated by myelinated mechanoreceptors acting on sensitized WDR neurons. Our results also demonstrate that sympathetic activation of WDR neurons is mediated by an alpha-adrenergic mechanism in the skin.     

Historical perspective of causalgia. Management of sympathetically maintained pain

The plethora of terms included in the broad category of sympathetic dystrophies, and causalgia in particular, has made specific disorders, with unique clinical characteristics, very difficult to isolate into discrete clinical entities. Rather, the sympathetic dystrophies currently are regarded as existing along a continuum of varying severity and as having one basic pathophysiological mechanism, with considerable overlap of terms. The purposes of this article are 1) to review the theories of physiological mechanisms of causalgia and other forms of sympathetically maintained pain, 2) to describe their clinical characteristics, and 3) to discuss their physical therapy management.     

Treatment of inflammatory, neuropathic and sympathetically maintained pain in a patient with Sj?gren's syndrome.

We present a case of Sj?gren's syndrome with a painful peripheral neuropathy where pain control required both anti-inflammatory and sympatholytic treatments. This case suggests that the pain in some inflammatory disorders with nerve injury may have a component mediated by an alpha adrenergic receptor.     

Diagnostic and treatment measures in patients with sympathetically maintained pain

The term "sympathetically maintained pain" (SMP) describes a symptom that might accompany a variety of diseases (CRPS, (post-) herpetic and post-injury neuralgia), which might transform into sympathetically independent pain (SIP) after some time. Patients with SMP present a bunch of disorders of the autonomic and sensory system, but the only reliable way to diagnose a pain as SMP is a positive response to an intervention at the sympathetic nervous system. Three ways of influencing the sympathetic system are commonly used: (a) local anesthetic sympathetic blockade (SB), (b) intravenous regional sympathectomy (IVRS) and (c) ganglionic local opioid application (GLOA). A review of current literature shows that SB has certain advantages in diagnostic sensitivity, whereas GLOA might be slightly superior in therapy of some diseases with longstanding pain history. Obviously, the therapeutic benefit of all interventions is complete independent of the accompanying autonomic disorder and of a blockade of efferent fibers. A new heuristic model of the SMP mechanism is presented, including both experimental and clinical data. For reducing the risks of false positive or negative diagnosis of SMP and SIP, a diagnostic algorithm is proposed. This includes optimizing the technique, changes of interventional measures, and adequate monitoring both of analgesia and as well of the extend of efferent sympathetic blockade (e.g. measurement of sympathetic reflexes). The treatment recommendations in patients with SMP vary in dependence of the kind of disease. In SMP, invasive measures play an important, but only limited role within the comprehensive treatment concept. As an example a three-stage, symptom-adapted treatment algorithm is demonstrated for CRPS, including also drug therapy, psychologic and physiotherapeutic approaches.     

Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain.

Patients with reflex sympathetic dystrophy or causalgia characteristically have ongoing pain and pain to light touch (hyperalgesia). Some of these patients obtain relief of their pain following interruption of sympathetic function to the affected area and, therefore, have sympathetically maintained pain (SMP). Evidence suggests that the pain and hyperalgesia in SMP are related to activation of peripheral adrenergic receptors. We wished to determine the contribution of alpha 1- and alpha 2-adrenergic receptors in SMP and thus examined the effects of local application of adrenergic agents in patients with SMP. The alpha 2-adrenergic agonist clonidine, available as a transdermal patch, was delivered topically to the patients' hyperalgesic skin. In four patients with SMP, clonidine eliminated or substantially reduced hyperalgesia to mechanical and cold stimuli. In three of these patients the effects were confined to the skin region beneath the patch, suggesting a peripheral and not central effect. The relief of hyperalgesia was not due to a local anesthetic effect since touch thresholds were unaffected. Topical clonidine did not relieve hyperalgesia of similar severity for two other patients whose hyperalgesia and pain were unaffected by sympathetic ganglion blocks (i.e., diagnosed as having sympathetically independent pain). In two SMP patients, intradermal injection of norepinephrine or phenylephrine (a specific alpha 1-adrenergic agonist) at a site treated with clonidine evoked intense pain and rekindled the pre-clonidine hyperalgesia at that site. It is likely that clonidine locally blocks the release of norepinephrine via activation of alpha 2 receptors on the sympathetic terminals. This study suggests, therefore, that SMP is mediated via alpha 1-adrenergic receptors located in the affected tissue.     

Delayed sympathetically maintained pain caused by electrical burn at the current's entry and exit sites

It is not uncommon for sympathetically maintained pain (SMP) to follow electric burns at the site of current entry. The occurrence of SMP at the exit point has not been reported. This report describes a patient who was exposed transiently to a 220W electrical current. After a delay of 3 months, the typical manifestations of SMP appeared on the right hand (entry point); symptoms appeared on the left foot (exit point) after 11 months. Ultrasonography was helpful in identifying the bony and soft tissue changes that occurred with SMP. Serial sympathetic blocks, oral phenytoin, and an intensive physical rehabilitation program were useful in treating this electrically induced SMP.     

The relation between sympathetically maintained pain,regional vasomotor disturbances and sympathetic nerve activity: a remaining enigma

In simultaneous bilateral nerve recordings, patients with Sympathetically Maintained Pain (SMP) affecting one limb show similar sympathetic traffic in nerves supplying the affected and unaffected limb, also when the painful limb shows a marked regional autonomic (vasomotor) dysfunction. These findings argue against the notion that SMP must be mediated by a reflex change in the pattern of sympathetic discharge. In general, they underline the fact that autonomic effector disturbances may give little information about underlying nerve traffic.     

Spinal cord stimulation in sympathetically maintained complex regional pain syndrome type I with severe disability. A prospective clinical study.

BACKGROUND AND PURPOSE: In this prospective trial we assessed the long-term effect of spinal cord stimulation (SCS) on the improvement of functional status in complex regional pain syndrome type I (CRPS I). METHODS: A prerequisite for eligibility to SCS treatment was the responsiveness of patients to sympathetic nerve block. In 29 patients with chronic sympathetically maintained CRPS I, the efficacy of SCS on deep pain, allodynia and functional disability was determined. Pain intensity was estimated during SCS free intervals of 45 min (inactivation test) every 3 months and compared with that under SCS treatment. RESULTS: On SCS treatment, both deep pain and allodynia could be permanently reduced from 10 to 0-2 on a 10 cm visual analogue scale (VAS) (p<0.01). During the inactivation tests, reoccurrence of pain up to 8 VAS (quartiles 6-8) was measured. Considerable impairments in daily living activities, objectified by the pain disability index, were also restored (p<0.01). After a follow-up period of 35.6+/-21 months, 12 of 16 patients with affected upper limb showed significant increase of the fist grip strength from 0 to 0.35 (quartiles 0.1-0.5) kg compared with 0.9 (quartiles 0.7-1.1) kg on the unaffected side (p<0.01). Eight of ten patients with lower limb disability resumed walking without crutches. Previous pain medication could be significantly reduced (p<0.01). CONCLUSIONS: As a result of permanent pain relief under long-term SCS combined with physiotherapy, the functional status and the quality of life could be significantly improved in sympathetically maintained CRPS I.     

Fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is recognizable syndrome characterized by chronic, diffuse pain, an absence of inflammatory or structural muscloskeletal abnormalities, and a range of symptoms that include fatigue, and sleep and mood disturbances. Physical examination and laboratory testing are unrevealing, except for the presence of pain on palpation of characteristic soft-tissue sites, the tender points. Despite the recognition of FMS by the World Health Organization, it remains a controversial condition and its existence as a distinct entity remains uncertain. However, the concept of FMS is a useful one, allowing many investigations to be avoided and appropriate advice on treatment to be given. FMS may overlap with symptoms of, and the patient further impaired by, anxiety and depression. The term FMS dose not imply causation and merely describes the most common symptoms. Many patients with chronic fatigue syndrome(CFS) fulfill the criteria of FMS and represent one end of a spectrum of presentation. Evidence for triggering viral infection and the lower level of serum acylcarnitine, observed in CFS patients, is lacking in the majority of patients with FMS. These findings are suggestive to be distinctively another disorders between FMS and CFS.     

Sympathetically maintained pain

Reflex sympathetic dystrophy (RSD) is a controversial condition, redefined in 1996 by an ad hoc International Association for the Study of Pain (IASP) task force. One of the strongest critiques against the entire concept of sympathetic-dependent pain is that patients labeled as having RSD harbor in reality a somatoform disorder. Here clinical cases are described to prove that other organic medical conditions may exist other than RSD and still present the clinical picture of pain, sensory, and vasomotor disorders and trophic changes. The analysis of each patient illustrates how the inappropriate diagnosis of RSD may lead to increased worsening of pain intensity, or delay the proper diagnosis, and consequently the appropriate treatment.     

Fibromyalgia syndrome in women

Many more women than men experience the chronically fatiguing condition of fibromyalgia syndrome (FMS), a growing diagnosis in the United States. Estimates are that upwards of 2% to 6% of adults have been diagnosed with FMS, and at high societal costs. In this article, common manifestations are described to guide assessment and various lines of research are explored as a basis for under-standing contributing factors and potential treatments for FMS and other chronic disorders, such as chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), and temporomandibular disorders (TMD), and the effectiveness of current treatment options.     

Fibromyalgia, or whole body pain

Fibromyalgia is a rheumatic syndrome which is being recognized and diagnosed more often all the time. Its symptoms include a general state of pain not localized in the joints, combined with tremendous tiredness and sleep alterations. Although its exact etiology is still unknown, medical professionals speculate on the existence of multiple cause factors. Therefore, an integrated therapeutic treatment having the coordinated participation of medical professionals from different fields of expertise is necessary. Mental health professionals play an important role since it is proven the existence of psychological and socio-psychological factors at the start, during the duration of and in the evolution of this syndrome.