Raynaud's Disease Treatments, Raynauds Disease Causes, Symptom of Raynaud's Disease, Raynauds Phenomenon Treatment

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RAYNAUD'S PHENOMENON/DISEASE

Patient Summary:

Raynaud's Phenomenon/Disease is a disorder, which is caused by decreased blood flow through the vessels in the fingers and toes.
This disease process is more common in colder climates and in women.
It may occur following emotional stress or weather changes.
When there is decreased circulation in the fingers and toes, a burning, stinging pain is felt.
In our clinic, we have had excellent results utilizing STS treatments to treat the acute symptoms, as well as, preventing future episodes.
STS treatments are designed to create various neuropeptides (normally occurring nerve chemicals, within the body), which prevent the underlying disease processes.
By doing this, the cause of the disease is being treated rather than just covering up the symptoms of the disease.
Medical literature is quoted below showing that this has a broad base of support.

Physician Summary:

Clinical trials detailed in the referenced medical literature have shown beneficial effects of the vasodilatory action of VIP (Vasoactive Intestinal Polypeptide) and CGRP (Calcitonin Gene-related Peptide) in Raynaud's disease.
Studies have shown that digital cutaneous neurons show a decreased release of the calcitonin gene-related peptide in Raynaud's Phenomenon/Disease.
Emotional or psychological stress increases the production of norepinephrine.
Norepinephrine increases vasoconstriction and areas of hypoxia.
Hypoxia creates substance P.
Substance P causes the destruction of CGRP by causing the release of a proteolytic enzyme from mast cells.
STS treatments are designed to create VIP (Vasoactive Intestinal Polypeptide) and CGRP (Calcitonin Gene-related Peptide).
STS treatments are designed to decrease norepinephrine and substance P.
Among other things, STS treatments are designed to create VIP and CGRP.
VIP inhibits the production of pro-inflammatory agents (cytokines, chemokines, and nitric oxide), and stimulates the production of the anti-inflammatory cytokine IL-10.
Clinical experience has shown that STS treatments are an effective treatment of the underlying etiology of Raynaud's Phenomenon/Disease rather than just masking the symptoms of the disease.

MEDICAL JOURNAL BACKGROUND INFORMATION

In a recent study performed by Ernesto Guido, M.D. it was found that treatment utilizing the Dynatronic STS system successfully decreased the objective signs and subjective symptoms of peripheral neuropathy patients. During that study, daily skin temperatures were obtained from the palmar surface of the thumbs and the plantar surface of the bilateral hallux. It was found in that study that there was a partial or complete normalization of the actual skin temperature and the skin temperature gradient, left to right. (13)

In reviewing that study's results, it could be hypothesized that improved micro- circulation to the nerves resulted in the improvement in the peripheral neuropathy patients. If this is true, then it could be hypothesized that the improvement in the patients' skin temperatures was due to an improved skin microcirculation probably caused by the creation of various neuropeptides by the treatment. It has been shown with laboratory testing that STS treatments have significantly increased the plasma level of VIP. In addition, heart rate variability (HRV) has been shown to be a reliable indicator of autonomic nervous system function. Therefore, if the STS treatments are improving autonomic nervous system functioning, there should be a corresponding normalizing of the HRV. In our clinic, HRV studies are performed before and after the first STS treatment. With the exception of those patients on significant amounts of narcotics, almost always there is a normalizing of the HRV. This data will result in an upcoming publication

The current working hypothesis is that the STS treatments are effective due to a combination of the following aspects of the treatments: low frequency electrical current passing through long sections of nerves; electrode pad placement; production of cyclic adenosine monophosphate; the choice of the peripheral nerves being stimulated so that there is a cross-over effect in the Central Nervous System; leakage of action potentials from the nerves being stimulated into nerves entering the sympathetic ganglia; the quadrilateral location of stimulation; creation of action potentials through sympathetic nerve fibers, in the peripheral nerves being stimulated; creation of action potentials in peripheral nerves being stimulated; activation of the sodium pump, in the nerves being stimulated; production of ACTH; production of dynorphins, enkephalins or beta-endorphins; creation of action potentials in sympathetic fibers within the peripheral nerves being stimulated, which enter the sympathetic ganglia directly; analgesia causing a reduction in the production of substance P; and/or the production of circulation altering neuropeptides such as vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP).

There is considerable peer review medical journal literature to support these hypotheses.

Brain found that a subcutaneous injection of VIP induces a local erythema persisting for 3 hours. In contrast, CGRP induced an intense local erythema, slow in onset but very persistent, up to 10-12 hours duration at high doses. In addition, Brain found that in some patients with Raynaud's phenomenon or diabetic polyneuropathy, electrical transcutaneous nerve stimulation induces vasodilation and relief from ischemic pain. It has been suggested that the release of an endogenous vasodilator is partly responsible for the beneficial effects. Transcutaneous nerve stimulation has been associated with a rise in plasma VIP in these patients and normal individuals, although further studies have suggested that this endogenous vasodilator is not VIP but is probably CGRP. In the periphery, immunoreactive CGRP was found in thin beaded nerve fibers that were associated with the smooth muscle of blood vessels and was found to work on arterioles. (2)

Kaada found that distant, low frequency TNS (2 Hz) improved microcirculation in ischemic limbs of patients with Raynaud's phenomenon and diabetic neuropathy and to accelerate healing of chronic skin ulcerations. He also found that skin temperature increased 1.8 to 2.8 degrees centigrade and persisted for several hours after treatment. Plasma VIP was increased 60% following stimulation.

Kaada felt that the improved microcirculation of the skin was most likely caused by a sympatho-inhibition effectuated through a central serotoninergic link, since the response was blocked by the serotonin blocker cyproheptadine. In addition, the vasodilation was proportional to the increase in plasma VIP.

He stated that the mechanism of the relief of pain from wounds and ulcers was probably due to the vasodilation and endorphins, as well as, the release of ACTH and adrenocortical hormones caused by the electrical stimulation. Naloxone did not alter the vasodilatory effect or pain relief. He felt that this was due to an increase in VIP, which evidently affects the arterio-venous anastomoses. (19)(20)(21).

Kaada felt that the improved microcirculation resulting from the electrical stimulation was probably due to:

1. Sympatho-inhibition. It has been shown that this reflex inhibition is relayed over the depressor area of the medulla oblongata. Experiments have shown that the vasodilatory response can be antagonized by the administration of a central serotonin blocker, suggesting the involvement of a central serotonergic link.

2. Release of a vasodilatory substance, which was probably vasoactive intestinal polypeptide.

3. ACTH-release. In addition to improved microcirculation, tissue repair may possibly also be accelerated by an endogenous ACTH-release; which has been shown to occur in response to low-frequency peripheral stimulation. (17)

VIP is not a blood-borne hormone. An increase in plasma VIP in the systemic circulation represents an overflow from synapses, caused either by an increased release or by a reduced degradation of the neuromodulator. An unexpected finding in these studies was that the resting values of plasma VIP were significantly (about 30%) lower in Raynaud and sclerodermic patients than in normal subjects. It has previously been suggested that one explanation could be that this lower plasma VIP concentration represents a defect in the VIP system in these patients and that it is a pathogenetic factor in the disease. (18) Said stated that VIP stimulates the release of multiple chemicals, including serotonin. It has been shown that VIP enhances the binding of serotonin to its receptors in rat hippocampus. VIP binding sites have been identified in the hypothalamus, cerebral cortex, and pineal. Intracerebroventricular administration of VIP has a hypnogenic effect in rats and cats rendered partially insomniac. VIP stimulates cyclic AMP production, which in turn increases the production of melatonin. VIP is a dominant factor in increasing the availability of glucose from glycogen, promotes glucose utilization, and inhibits platelet aggregation. (30)(9)

It has been noted that low frequency TENS stimulation of nerves causes significant increases in the levels of CGRP. (22)(31)

Gherardini concluded that CGRP, but not lidocaine, significantly increased blood flow after mechanically induced vasospasm. (10) Gherardini also found that CGRP was effective in promoting recovery of the microcirculation after mechanically induced ischemia in neurovascular island flaps in rats. (11)

It was found that CGRP retains biological activity for long periods in cutaneous tissue fluid. However, even extremely small amounts of substance P converts the long-lasting vasodilation induced by CGRP into a transient response. It was found that substance P causes a release of proteolytic enzymes from mast cells, which cause the destruction of CGRP. (3)

There is a significant increase in intracellular cAMP with low-frequency (10 Hz) currents. (34)(25)

It was found that VIP caused increased intracellular cAMP. (28)

O'Reilly et al showed that, by using computed thermography continuous temperature recordings which were made before and after cold challenge of the fingers of control subjects and patients with primary Raynaud's phenomenon, basal skin temperature measurements (Tpre) were significantly lower in patients with primary Raynaud's phenomenon than in the controls. Temperatures immediately after cold challenge (T0) were significantly lower in patients with primary Raynaud's phenomenon and Raynaud's phenomenon associated with systemic sclerosis than in controls. The lag phase before the start of temperature recovery (Tlag) was significantly greater in patients with primary Raynaud's phenomenon than in control subjects. The maximum recovery index (R%) was significantly less in patients with primary Raynaud's phenomenon than in controls. The maximum rate of change of temperature during the rapid phase of rewarming (Gmax) was significantly greater in controls than in patients with primary Raynaud's phenomenon. (29)

Von Bierbrauer et al study showed that cold provocation in primary Raynaud's syndrome causes an increase in endothelin liberation and that this plays a role in the pathogenesis of the vasospasms. Apparently not only local but also reflex mechanisms contribute to this. (37)

Interestingly, Graido-Gonzalez, et al showed that as a potent long-acting mediator of vasoconstriction and inflammation, endothelin-1 plays a key role in the cycle of ischemia and inflammation that initiates and sustains pain of crisis, of Sickle Cell Disease. (12)

Knapik-Kordecka et al stated that endothelin is an endogenous vasoconstrictor and plays an important role in pathogenesis of Raynaud's phenomenon. Plasma endothelin-1 (ET-1) and von Willebrand factor (vWF) concentrations following cold exposure in 52 patients with Raynaud's phenomenon were measured. Statistically significant increase of ET-1 and vWF was found in the study group in compared to healthy volunteers. There was positive correlation between ET-1 and vWF in those cases. The data suggest that ET-changes indicate a vasospastic effect on vascular injury. Treatment with endothelin-receptor antagonist may prevent structural changes in vessel well. (24)

The effect of total-body cold exposure on plasma concentrations of von Willebrand factor (vWF), endothelin-1 (ET) and thrombomodulin (TM), which are considered to be generated from the endothelium; was studied in systemic lupus erythematosus (SLE) patients with and without Raynaud's phenomenon. The plasma levels of vWF, ET and TM in SLE patients, irrespective of the presence of Raynaud's phenomenon, were significantly higher than in normal controls even before the cold provocation test. After the cold provocation test, plasma levels of vWF and ET were significantly higher in SLE patients with Raynaud's phenomenon than in those without and in normal controls. No significant increase in TM was observed in either the SLE patients or the controls. (26)

Doggrell stated that CGRP is a potent vasodilator that has been shown to have a role in the creation of focal angiopathies. CGRP is also a positive inotrope and increases heart rate. Clinical trials have shown beneficial effects of the vasodilatory action of CGRP in hypertension, angina, heart failure, Raynaud's disease and venous stasis ulcers. However, the clinical potential of CGRP is limited as it has to be given by infusion and is quickly broken down. Oral long acting CGRP-mimetics may have potential in disorders in which CGRP has been shown to be beneficial. (8)

Turton et al state that the literature on Raynaud's phenomenon (RP) describes a complex and confusing picture of abnormalities that has suggested a multifactorial etiology. Current research suggests that the underlying disorder is related to a local fault at the level of the digital microcirculation. It is likely that many of the biological changes described in RP are secondary manifestations of this primary abnormality. The strong familial relationship of RP suggests a genetic link although this has not yet been characterized. An overactivity of the sympathetic nervous system appears less likely as a candidate for the primary abnormality but dysfunction at the level of the nerve, and vessel wall may be more important. Digital cutaneous neurones show a deficient release of the calcitonin gene-related peptide in PR. This may represent a primary fault that is confounded by other factors, which are influenced by cold or emotional triggers. Vasoconstricting substances such as catecholamines, endothelin-1 and 5-hydroxytryptamine, which may all be released in response to cold exposure, could cause digital artery closure and the associated symptoms of RP. In some cases, this would trigger a cascade of neutrophil and platelet activation, which through the release of inflammatory mediators, contribute to the endothelial damage seen with more severe RP. It is hypothesised that disturbance to the intricate functioning of the endothelium, and secondary compensation at local or systemic level, may appear over time. (36)

Bunker et al stated that the pathophysiology of Raynaud's phenomenon is not well defined, but that active cutaneous microvascular vasoconstriction and emptying must occur to account for the pallor and are reasons for studying the microvasculature. It has been proposed that there may be a defect in a local histamine vasodilator mechanism. To study the histaminergic and peptidergic axes in Raynaud's phenomenon, they measured the cutaneous microvascular responses of patients with Raynaud's phenomenon to digital intradermal injections of saline, histamine, the histamine-releasing agent, compound 48/80, substance P, and calcitonin gene-related peptide. They compared these results with those obtained in normal subjects. Intradermal cutaneous microvascular blood flow responses were quantified by planimetry and laser Doppler flowmetry. The results showed: a) that in primary Raynaud's phenomenon there is no evidence of local deficiency in histamine release or insensitivity to histamine in the cutaneous microvasculature; and b) that patients with Raynaud's phenomenon react normally to the neuropeptides calcitonin gene-related peptide and substance P, providing a rationale for treating Raynaud's phenomenon with vasoactive peptides. (4)

Bunker et al stated that it has been argued that the digital cutaneous microvasculature is the site the anomaly, which causes Raynaud's phenomenon (RP). Both endothelin-1 (ET-1), a potent vasoconstrictor peptide present in the digital cutaneous microvasculature, and calcitonin gene-related peptide (CGRP), a powerful vasodilator present in digital cutaneous perivascular nerves, have been implicated in the pathogenesis of RP. Circulating ET-1 levels are raised, and there is a diminution of CGRP-containing perivascular nerves in finger skin in RP. Their study investigated the sensitivity of the digital cutaneous microvasculature to intradermal ET-1 and CGRP. Differences were found in RP compared with normal digital skin, supporting the idea that the digital cutaneous microvasculature is actively involved in the pathogenesis of RP. In RP, the erythematous response to ET-1 was diminished at both 20 and 5 degrees C (a low temperature at which RP classically occurs) providing pharmacological support for the morphological evidence that in RP there is a deficiency of CGRP-containing nerves in the distal digital skin. (5)

Bunker et al studied skin biopsy samples from the fingers of nine patients with primary Raynaud's phenomenon, nine with the disorder associated with systemic sclerosis, and eleven healthy controls were examined by immunocytochemistry. There were no differences between the groups in the distribution of PGP 9.5 (a pan-neuronal marker) immunoreactivity, but there was a significant reduction in the number of calcitonin gene-related peptide (CGRP) immunoreactive neurons in the skin of patients with primary Raynaud's phenomenon and those with systemic sclerosis. These findings implicate dysfunction of the CGRP neurovascular axis in the pathophysiology of Raynaud's phenomenon. (7)

Mourad et al stated that the discovery of the increase in the vasoconstrictive peptide endothelin-1 and the quantitative deficit in the potent vasodilating calcitonin gene-related peptide may lead to a better understanding of vasospasm mechanisms and open the field for new therapeutical approaches to Raynaud's phenomenon. (27)

Bunker et al stated that there is evidence that CGRP in digital cutaneous perivascular nerves is deficient in Raynaud's phenomenon. Ten patients with severe Raynaud's phenomenon secondary to connective tissue disease were randomly assigned to groups receiving intravenous CGRP (0.6 micrograms/min for 3 h per day on 5 days) or saline. Hand and digital blood flow and skin temperature were measured by thermocouple and laser doppler flowmetry. Blood flow was significantly (p < 0.05) increased by CGRP in both hands (median blood flow after infusion as percentage of baseline reading 179 [range 100-355]%) and fingers (149 [100-161]%); saline had no effect (hands 102 [84-123]%, fingers 96 [81-113]%). Hand temperature was increased more by CGRP than by saline (2.8 [1.5-4.0] vs 1.0 [-1.0 to 2.5] degrees C, p < 0.05). All ulcers healed in four of five CGRP-treated patients but in no saline-treated patients. Thus intravenous CGRP effectively dilates the compromised digital cutaneous vasculature in severe Raynaud's phenomenon. (6)

Shawket et al studied the effects of intravenous infusion of three vasodilators on skin blood flow in eight patients with Raynaud's phenomenon and eight controls, matched for age and sex, by means of the non-invasive technique of laser doppler flowmetry (LDF). The responses to calcitonin-gene-related peptide (CGRP) were compared with those to the endothelium-dependent vasodilator adenosine triphosphate (ATP) and the endothelium-independent vasodilator prostacyclin (epoprostenol; PGI2). In the patients with Raynaud's phenomenon, CGRP induced flushing of the face and hands accompanied by a rise in skin blood flow, whereas in the controls CGRP caused flushing and increased blood flow only in the face. PGI2 caused similar rises in skin blood flow in the hands and face in both groups. ATP did not cause any significant changes in skin blood flow in the face or hands in the patients, but in the controls it increased skin blood flow in the face. Since the suprasensitivity to CGRP of skin blood flow in the hands of patients with Raynaud's phenomenon is not common to other vasodilators, it may reflect a deficiency of endogenous CGRP release in this disorder. (33)

Shawket et al investigated whether long infusion of CGRP can relieve symptoms of patients with Raynaud's disease using prostacyclin as a control. The thermographic results showed significant improvement in hand rewarming 3 days after CGRP but not after PGI2. (32)

Terenghi, et al showed that in Raynaud's phenomenon patients there was a decrease of calcitonin gene-related peptide (CGRP) immunoreactive nerves in the epidermis and around capillaries in the dermal papillae (P = 0.005). In the skin of RP patients, these changes were readily demonstrated by image analysis, although they were not always apparent on visual screening. (35)

Bunker et al showed that there was a significant reduction in the number of calcitonin gene-related peptide (CGRP) immunoreactive neurons in the skin of patients with primary Raynaud's phenomenon and those with systemic sclerosis. These findings implicate dysfunction of the CGRP neurovascular axis in the pathophysiology of Raynaud's phenomenon. (7)

Jernbeck et al studied the effect of intravenous and intra-arterially administered calcitonin gene-related peptide (CGRP) on the human forearm blood flow and on the cutaneous blood flow. These were investigated by means of venous occlusion plethysmography and laser-Doppler flowmetry, respectively. Infusion of CGRP (11-216 pmol min-1) into the brachial artery resulted in a dose-dependent increase in forearm blood flow and cutaneous blood flow, which persisted for up to 90 min after the infusion was stopped. Repeated infusions resulted in an identical response. Systemic intravenous infusion of CGRP (104-520 pmol min-1) resulted in a dose-dependent flush in the face, neck, upper trunk and upper arms, and an increase in the forearm blood flow. The cutaneous blood flow was dramatically increased on the forehead, whereas on the hand only a slight increase was noted. By intravenous infusions a significant drop in blood pressure and increase in heart rate were seen at 520 pmol min-1. Thus, it is possible to give CGRP in doses that increase the blood flow in muscle and skin without resulting in a fall in systemic arterial blood pressure and tachycardia, suggesting that CGRP may be used as a tool for the treatment of various conditions in man with compromised blood flow. (16)

Brain et al studied the cutaneous responses of the forearm to local cold exposure and intradermal injection of CGRP and other vasoactive mediators were compared in primary Raynaud's sufferers and normal volunteers. Cooling (5-6 degrees C for 2 min) of a 1 cm2 area of the forearm caused a localised reactive hyperaemia response in normal volunteers, measured using the last Doppler blood flow meter. The peak response in Raynaud's patients was significantly smaller than that of normal volunteers. The cutaneous responses of Raynaud's patients and normal volunteers to intradermal injections of CGRP, histamine and PGE2 were not significantly different. The results suggest that Raynaud's sufferers do not exhibit a diminished response to CGRP in the cutaneous microvasculature and can respond normally to histamine with an axon reflex mediated flare. (1)

Jansen et al studied the effect on blood flow caused by electro-acupuncture (EA), injection of substance P (SP), and calcitonin gene-related peptide (CGRP) in musculocutaneous flaps in the rat, using laser Doppler flowmetry. The circulatory border was estimated before and after treatment. It was shown that treatment with EA increased the blood flow moving the circulatory border distally 66% after a treatment. Injection of NaCl into the dorsal central vein of the flap resulted in no increase in blood flow whereas SP 10(-9) M and CGRP 10(-9) M increased the blood flow so that the circulatory border moved distally 31% and 49%, respectively. It is suggested that the effect of EA on blood flow is similar to the effect achieved by injecting CGRP and SP. (15)

Kjartansson et al showed the effect of transcutaneous electrical nerve stimulation (TENS) and injection of calcitonin gene-related peptide (CGRP) on blood flow in a musculocutaneous flap of the rat, using laser Doppler flowmetry. The circulatory border was estimated before and after treatment. It was shown that repeated treatments with TENS gradually increased the blood flow, moving the circulatory border distally more than 100% after three treatments. Injection of NaCl into the dorsal central vein of the flap resulted in no increase in blood flow, whereas CGRP 10(-10) M increased the blood flow, so that the circulatory border moved distally 70% and 60%, respectively. (23)

Jager et al showed that 60-min infusions of 80 pmol.kg-1.h-1 human calcitonin gene-related peptide caused an increased skin blood flow, assessed by a laser Doppler unit, up to 682% of the basal level. They found that CGRP increased regional blood flow to the brain and the skin at the expense of the gastrointestinal tract. (14)

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