Sickle Cell Disease is an inherited disease caused by abnormal hemoglobin. When the red blood cells of these patients encounter areas of the body with decreased amounts of oxygen, the cells deform. These red blood cells may break open or block small blood vessels. As the red blood cells are destroyed, the patient's hemoglobin is reduced and the patient's ability to supply adequate oxygen throughout their body is diminished. This creates even more areas of decreased oxygen and the vicious cycle continues. STS treatments have been found to increase the available oxygen in the skin. This allows nonhealing skin ulcerations to heal. Sickle Cell Disease patients receiving STS treatments report that they have markedly less pain and, therefore, have a decreased need for strong pain medications (including narcotics).

Clinical experience has shown that STS treatments are effective in decreasing the morbidity of Sickle Cell Disease. Multiple digital skin temperature, skin temperature gradients, and photoplethysmography have shown that STS treatments increase peripheral perfusion. In addition, it has been shown that plasma VIP levels are increased and that heart rate variability decreases, with STS treatments.

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. (9)

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. Recent heart rate variability studies and other autonomic nervous system studies have shown that there is a significant abnormal autonomic nervous system dysfunction, in sickle cell anemia patients. In our office, chronic pain patients have been tested on numerous occasions for heart rate variability. With the exception of those patients who are on heavy doses of narcotics, the chronic pain patients were found to have autonomic dysfunction on the basis of heart rate variability. With the first STS treatment, the heart rate variability and, therefore, the autonomic dysfunction decreased.

The current working hypothesis 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 and to support the efficacy of STS treatments in reducing the morbidity of Sickle Cell Disease.

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. (1)

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. (14)(15)(16)

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. (12)

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. (13)

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. (25)(5)

It has been noted that low frequency TENS stimulation of nerves causes significant increases in the levels of CGRP. (17)(26)

Gherardini concluded that CGRP, but not lidocaine, significantly increased blood flow after mechanically induced vasospasm. He also found that CGRP was effective in promoting recovery of the microcirculation after mechanically induced ischemia in neurovascular island flaps in rats. (6)(7)

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. (2)

There was a significant increase in intracellular cAMP with low-frequency (10 Hz) currents. (28)(18)

It was found that VIP caused increased intracellular cAMP. (23)

Recent heart rate variability studies, along with other autonomic nervous system, studies showed that there is a significant abnormal autonomic nervous system dysfunction, in sickle cell anemia patients. It was found that none of the control patients but 58% of the sickle cell patients had significant autonomic nervous system dysfunction. (24)

Michaels et al found that, in children with sickle cell disease, substance P blood levels were increased, when compared to controls at baseline and again during pain crisis. In each case, serum levels during pain crisis were higher than they were when the sickle cell patient was well. He concluded that these results imply that substance P plays a prominent role in the pain and inflammation of SCD and may be a measurable laboratory marker of vaso-occlusive crisis. Substance P is a known stimulator of tumor necrosis factor-alpha (TNF-alpha) release and a promoter of interleukin-8 (IL-8), which are increased in sickle cell disease. These cytokines enhance adhesion of leukocytes to endothelium and may play a role in vaso-occlusive events. (22)

Cheung et al studied the conjunctival microcirculation of 18 homozygous sickle cell disease (SCD) patients during steady-state, painful crisis, and postcrisis conditions. They found that at steady-state (baseline), all SCD patients exhibited some of the following morphometric abnormalities: abnormal vessel diameter, comma signs, blood sludging, boxcar blood flow phenomenon, distended vessels, damaged vessels, hemosiderin deposits, vessel tortuosity, and microaneurysms. There was a decrease in vascularity (diminished presence of conjunctival vessels) in SCD patients compared with non-SCD controls, giving the bulbar conjunctiva a "blanched" avascular appearance in most but not all SCD patients during steady-state. Averaged steady-state red cell velocity in SCD patients was slower than in non-SCD controls. During painful crisis, a further decrease in vascularity (caused by flow stoppage in small vessels) and a 36.7% +/- 5.2% decrease in large vessel (mostly venular) diameter resulted. In addition, the conjunctival red cell velocities either slowed significantly (6.6% +/- 13.1%; P <.01) or were reduced to a trickle (unmeasurable) during crisis. The microvascular changes observed during crisis were transient and reverted to steady-state baseline after resolution of crisis. (3)

Lipowsky et al demonstrated that homozygous sickle cell disease patient's capillary red cell (rbc) flux exhibited greater intermittence compared with normal subjects, which increased with painful crisis. Crisis subjects exhibited a significantly depressed postocclusive reactive hyperemia, with the ratio of peak red cell velocity to resting values reduced by 15% due to a loss of vasodilatory reserve, whereas crisis-free subjects exhibited a normal response. A 55% increase in the time to attain peak velocities of rbcs was attributed to resistance increases, possibly resulting from red cell and leukocyte-to-endothelium adhesion during the induced ischemia. (19)

Van Meurs et al found that sickle cell patients had a decreased vasoconstriction of the superior and inferior temporal veins and arteries, compared to normal controls, after breathing pure oxygen. They felt that their findings indicated a factor not yet well known in the pathophysiology of sickle cell disease: an abnormality of local microvascular control. (30)

Wun found that the averaged steady-state red cell velocity in SCD patients was slower than in non-SCD controls. During painful crisis, a further decrease in vascularity (caused by flow stoppage in small vessels) and a 36.7% +/- 5.2% decrease in large vessel (mostly venular) diameter resulted. In addition, the conjunctival red cell velocities either slowed significantly (6.6% +/- 13.1%; P <.01) or were reduced to a trickle (unmeasurable) during crisis. (32)

Lipowski found that in the resting state, Sickle Cell Disease capillary red cell (rbc) flux exhibited greater intermittence compared with normal subjects, which increased with painful crisis. . Crisis subjects exhibited a significantly depressed postocclusive reactive hyperemia with the ratio of peak red cell velocity to resting values reduced by 15% due to a loss of vasodilatory reserve, whereas crisis-free subjects exhibited a normal response. A 55% increase in the time to attain peak rbc velocity was attributed to resistance increases, possibly resulting from red cell and leukocyte-to-endothelium adhesion during the induced ischemia. (19)

Wun stated that acute and chronic vascular occlusion underlies much of the morbidity and mortality in sickle disease. Am abnormal polymerization of deoxygenated hemoglobin S (HbS) resulting in stiff, non-deformable erythrocytes is central to sickle cell pathogenesis. However, a complex interplay of many factors determines the balance between adequate blood flow and vessel obstruction. Serum markers of inflammation have provided evidence for a state of chronic inflammation in sickle cell disease (SCD). Inflammation promotes endothelial adherence to sickle erythrocytes. Studies demonstrating a beneficial effect of steroid therapy for painful episodes and acute chest syndrome provide indirect evidence for the role of inflammation in this disease. Leukocytosis, in the absence of infection, is common in SCD patients and predicts for stroke, acute chest syndrome, and overall mortality. Neutrophils and monocytes are activated, in these patients. Activated leukocytes further promote vascular inflammation and vessel damage. A reduction in leukocytes, and thus inflammation, may partially explain the beneficial effects of hydroxyurea in this disease. These data provide a strong rationale for clinical studies of therapy directed at inflammation and/or leukocytes in sickle cell disease. (32)

Graido-Gonzalez et al showed that as a potent long-acting mediator of vasoconstriction and inflammation, endothelin-1 may play a key role in the cycle of ischemia and inflammation that initiates and sustains pain of crisis. (8)

Luporini et al found that plasma concentrations of IGF-I (total, free, and free/total fraction) and IGFBP-3 were significantly reduced in all patients with sickle cell anemia compared with the healthy children. The positive relationship between hematocrit and fetal hemoglobin percentages with total IGF-I, free/total IGF-I, and IGFBP-3 in patients with sickle cell anemia could show that the delayed growth of these patients may be linked to intrinsic factors of the disease, which also determine the low circulating concentrations of the various elements of the GH/IGF-I axis. (20)

Guo et al evaluated the possible relationship between insulin-like growth factor-1 (IGF-1) and diabetic neuropathy (DNP). They found that the neuropathic group had significantly lower levels for IGF-1 (86.43 ng/ml +/- 45.18 ng/ml) compared to normal controls (119.68 ng/ml +/- 89.42 ng/ml) (P < 0.05), and to diabetic patients without neuropathy (113.75 ng/ml +/- 66.58 ng/ml) (P < 0.05). No significant difference was found between diabetic non-neuropathic group and normal control subjects (P < 0.05). In diabetic subjects there was a positive correlation (gamma = 0.27, P < 0.05) between IGF-1 and beat to variation in heart rate. There were negative correlation between IGF-1 and postprandial blood glucose (gamma = -0.3, P < 0.05), and aspartic acid translocase (gamma = -0.27, P < 0.05). They concluded that in diabetic patients with peripheral neuropathy there are abnormalities of IGF-1 that may contribute to the pathogeneses of diabetic neuropathy. (10)

Thrailkill also found that type 1 diabetes mellitus patients have reduced circulating levels of insulin-like growth factor-I (IGF-I) and IGFBP-3, and elevated levels of IGFBP-1. (29)

Chiarelli et al found that the structural changes characterising diabetic microangiopathy are altered by insulin-like growth factor I (IGF-I). (4)

Jannsen and Lamberts found that there is a decrease in serum IGF-I levels as well as an increase in IGFBP-l levels in adult diabetic type 1 and type 2 subjects. This is especially observed in diabetic type 1 subjects with manifest microvascular complications. He proposed that increased serum IGF-I levels in diabetic patients as an adjunct to insulin might prevent the development of diabetic microvascular complications. (11)

A study by Servoss et al showed that VIP functions as a regulator of IGF-I gene expression in the embryo. Treatment with VIP resulted in a 2-fold increase in embryonic IGF-I mRNA. (27)

McCarthy et al showed that cyclic AMP induces insulin-like growth factor synthesis. (21)

Calcitonin gene-related peptide (CGRP)-immunoreactive sensory nerve terminals infiltrate all tissues including bone, in which CGRP may play a local regulatory role. To initiate studies on the role of this neuropeptide in bone, osteoblasts were isolated from fetal rat calvariae, treated with CGRP, and analyzed for cAMP and insulin-like growth factor I (IGF-I) production. CGRP alpha and -beta induced a cAMP accumulation in osteoblastic cells, suggesting that they express functional receptors for CGRP. CGRP induced an increase in both IGF-I transcripts and immunoreactive polypeptide. (31)

1 Brain SD, Tippins JR, Morris HR, MacIntyre I, Williams TJ "Potent Vasodilator activity of calcitonin gene-related peptide in human skin" J Invest Dermatol. 1986 Oct;87(4):533-6

2 Brain SD, Williams TJ. "Substance P regulates the vasodilator activity of calcitonin gene-related peptide." Nature Vol 335 Sept. 1988 3-5.

3 Cheung AT, Chen PC, Larkin EC, Duong PL, Ramanujam S, Tablin F, Wun T. "Microvascular abnormalities in sickle cell disease: a computer-assisted intravital microscopy study." Blood 2002 Jun 1;99(11):3999-4005.

4 Chiarelli F, Santilli F, Mohn A. "Role of growth factors in the development of diabetic complications." Horm Res 2000;53(2):53-67.

5 Fahrenkrug J, Emson PC. "Vasoactive intestinal polypeptide: functional aspects" Br Med Bull. 1982 Sep;38(3):265-70. Review.

6 Gherardini G, Jernbeck J, Samuelson U, Heden P. "Effects of calcitonin gene-related peptide and lidocaine on mechanically-induced vasospasm in a rat island flap." J Reconstr Microsurg. 1995 May;11(3):179-83.

7 Gherardini G, Lundeberg T, Matarasso A, Michaels B, Gazelius B, Brodda-Jansen G, Samuelson U. "Calcitonin gene-related peptide increases microcirculation after mechanically induced ischemia." Ann Plast Surg. 1995 Aug;35(2):178-83.

8 Graido-Gonzalez E, Doherty JC, Bergreen EW, Organ G, Telfer M, McMillen MA. "Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis". Blood 1998 Oct 1; 92(7): 2551-5.

9 Guido E. "Effects of Sympathetic Therapy on Chronic Pain in Peripheral Neuropathy Subjects". American Journal of Pain Management 2002 Jan; 12(1):31-34.

10 Guo H, Yang Y, Geng Z, Zhu L, Yuan S, Zhao Y, Gao Y, Fu H. "The change of insulin-like growth factor-1 in diabetic patients with neuropathy." Chin Med J (Engl) 1999 Jan;112(1):76-9.

11 Janssen JA, Lamberts SW. "Circulating IGF-I and its protective role in the pathogenesis of diabetic angiopathy." Clin Endocrinol (Oxf) 2000 Jan;52(1):1-9.

12 Kaada B. "Promoted healing of chronic ulceration by transcutaneous nerve stimulation (TNS)." Vasa. 1983;12(3):262-9.

13 Kaada, B "Successful treatment of esophageal dysmotility and Raynaud's phenomenon in systemic sclerosis and achalasia by transcutaneous nerve stimulation. Increase in plasma VIP concentration." Scand J Gastroenterol. 1987 Nov;22(9):1137-46.

14 Kaada B "Systemic sclerosis: successful treatment of ulcerations, pain, Raynaud's phenomenon, calcinosis, and dysphagia by transcutaneous nerve stimulation. A case report." Acupunct Electrother Res. 1984;9(1):31-44.

15 Kaada B "Vasodilation induced by transcutaneous nerve stimulation in peripheral ischemia (Raynaud's phenomenon and diabetic polyneuropathy)". Eur Heart J. 1982 Aug;3(4):303-14.

16 Kaada B, Lygren I "Lower plasma levels of some gastrointestinal peptides in Raynaud's disease. Influence of transcutaneous nerve stimulation." Gen Pharmacol.1985;16(2):153-6.

17 Kashiba H, Ueda Y "Acupuncture to the skin induces release of substance P and calcitonin gene-related peptide from peripheral terminals of primary sensory neurons in the rat". Am J Chin Med. 1991; 19(3-4):189-97.

18 Knedlitshek G, Noszvai-Nagy M, Meyer-Waarden H, Schimmelpfeng J, Weibezahn KF, Dertinger H. "Cyclic AMP response in cells exposed to electric fields of different frequencies and intensities." Radiat Environ Biophys. 1994;33(2):141-7.

19 Lipowsky HH, Sheikh NU, Katz DM. "Intravital microscopy of capillary hemodynamics in sickle cell disease." J Clin Invest 1987 Jul;80(1):117-27.

20 Luporini SM, Bendit I, Manhani R, Bracco OL, Manzella L, Giannella-Neto D. "Growth hormone and insulin-like growth factor I axis and growth of children with different sickle cell anemia haplotypes." J Pediatr Hematol Oncol 2001 Aug-Sep; 23(6):357-63.

21 McCarthy TL, Centrella M, Canalis E. "Cyclic AMP induces insulin-like growth factor I synthesis in osteoblast-enriched cultures." J Biol Chem 1990 Sep 15;265(26):15353-6.

22 Michaels LA, Ohene-Frempong K, Zhao H, Douglas SD. "Serum levels of substance P are elevated in patients with sickle cell disease and increase further during vaso-occlusive crisis." Blood 1998 Nov 1;92(9):3148-51.

23 O'Dorisio MS, Wood CL, Wenger GD, Vassalo LM. "Cyclic AMP-dependent protein kinase in Molt 4b lymphoblasts: identification by photoaffinity labeling and activation in intact cells by vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI)." J Immunol. 1985 Jun;134(6):4078-86.

24 Romero Mestre JC, Hernandez A, Agramonte O, Hernandez P. "Cardiovascular autonomic dysfunction in sickle cell anemia: a possible risk factor for sudden death?" Clin Auton Res 1997 Jun;7(3):121-5.

25 Said SI. "Vasoactive intestinal polypeptide (VIP): Current Status." Peptides. 1984 Mar-Apr;5(2):143-50. Review. "Vasoactive intestinal polypeptide: functional aspects." Br Med Bull. 1982 Sep;38(3):265-70. Review.

26 Saurstein K, Klede M. Hilleges M, Schmelz M. "Electrically evoked neuropeptide release and neurogenic inflammation differ between rat and human skin". J Physiol. 2000 Dec 15;529 Pt3:803-10.

27 Servoss SJ, Lee SJ, Gibney G, Gozes I, Brenneman DE, Hill JM. "IGF-I as a mediator of VIP/activity-dependent neurotrophic factor-stimulated embryonic growth." Endocrinology 2001 Aug;142(8):3348-53.

28 Sontag W, Dertinger H. "Response of cytosolic calcium, cyclic AMP, and cyclic GMP in dimethylsulfoxide-differentiated HL-60 cells to modulated low frequency electric currents." Bioelectromagnetics. 1998;19(8):452-8.

29 Thrailkill KM. "Insulin-like growth factor-I in diabetes mellitus: its physiology, metabolic effects, and potential clinical utility." Diabetes Technol Ther 2000 Spring;2(1):69-80.

30 van Meurs JC, Schwoerer J, Schwartz B, Mulder PG, Meiselmann HJ, Johnson CS. "Retinal vessel autoregulation in sickle cell patients." Graefes Arch Clin Exp Ophthalmol 1992;230(5):442-5.

31 Vignery A, McCarthy TL. "The neuropeptide calcitonin gene-related peptide stimulates insulin-like growth factor I production by primary fetal rat osteoblasts." Bone 1996 Apr;18(4):331-5.

32 Wun T. "The Role of Inflammation and Leukocytes in the Pathogenesis of Sickle Cell Disease; Haemoglobinopathy." Hematol 2001;5(5):403-412.

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Coastal Bend
Chronic Pain Center

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