The literature is full of references concerning the effects of pharmaceuticals upon voltage-dependent gates, which have been found in cell membranes of many Transmitter (hormonal or ligand) voltage gated channels convert extracellular chemical signals into electric signals. This type of gate cannot create a self-amplifying excitation by itself. It can, however, trigger voltage-gated channels to open or close. Ligand voltage gated channels are dependent upon an intact transmembrane potential difference for membrane translocation system function (transport of ions or molecules across the cell membrane) and second messenger formation (internal cellular response) to occur [17,44].The calcium voltage-dependant gates are amplified relative to other ionic channels due to higher transmembrane concentration gradient of calcium. Due to the increased molecular weight and size of Ca2+, this gate is also harder to turn on than K+ or Na+ [4].The sodium voltage-dependant gates are heavily concentrated at Nodes of Ranvier and at neuromuscular junctions. They work in an ‘all or none’ fashion and are responsible for nerve hyperexcitability. Six Na+ ions must move from the extracellular to the intracellular side to turn the gate on [42].The potassium voltage-dependant gates heavily concentrated at the paranodal (fast) and nodal (slow) areas. Slow channels regulate the rate of firing response to a repetitive stimulus and fast channels are required for intensity of response. The Ca2+ activated K+ channel inhibit membrane depolarization when exposed to a continuous stimulus. The potassium voltage-dependent gate is the most responsive channel to an externally applied electrical stimulus [5,17].The voltage-dependent Na+/K+ pump is activated during the ‘supernormal’ period of repolarization. Depending upon the physiological state of the pump, an a.c. can either inhibit or stimulate it. Maximal effects upon the pump with an a.c. occur at 100 Hz with an intensity of 4 x 10-3 V/cm and 6 mA/cm2 [6,7].There are numerous citations that demonstrate how a.c. affects ions and voltage-dependant gates to create both conformational changes in the cell membrane and second messenger formation within the cell [3,6,17,19,45]. When an a.c. is applied across a voltage gated channel, frequency-specific ion concentration changes occur [4,42]. These ion-gated channels have a greater affinity for low frequency currents than middle frequency currents [3,46]. Middle frequency carrier currents can be configured with low frequency modulation so as to maximize the beneficial effects of each (Fig. 7).
The PHD effect refers to the prolonged, hyopexcitable state of a nerve that arises from the application of a relatively short duration electrical current. For example, a 20-min application results in a nerve block that may last for hours. Full recovery may even take days. To obtain the PHD effect, a series of stimuli are timed so that each falls within the refractory range of its predecessor. There is more than one mechanism of action to explain the long duration of the PHD effect. Theories include experimentally proven conformational change at the cell membrane, second messenger formation within the cell, and ephaptic inhibition (a direct inhibition of action potential propagation by the electroceutically exposed segment). Wedensky inhibition does not explain the PHD effect as the block is long lasting and does not abate upon removal of the electroceutical [17,19,47,48]. The C fiber is more sensitive to the PHD effect than the A fiber. Theories explaining this address the larger surface/volume ratio of small fibers vs. large fibers, which make them more susceptible to transmembrane potential effects resulting from extracellular ion concentration changes and known nerve fiber physiology concerning easier fatigue of small nerve fibers vs. large fibers. [49]. Central mechanisms of habituations do not explain the pronounced effect on the C fiber [31,49].The sympathetic nerves are of special interest in the treatment of pain. These fibers are responsible for cold or weather sensitive pain that is described as burning, achy, tingling and numbing in character [50]. When practitioners hear this kind of complaint they should begin to this about a diagnosis of Reflex Sympathetic Dystrophy (RSD), now frequently referred to as acute or chronic complex regional pain syndrome (CRPS I or II) [51].In RSD, there is a decrease in the local blood flow of the injured part. If allowed to persist, cold, sweaty and swollen skin (stage 1) develops. It may progressively worsen until there is loss of range of motion or even loss of muscle mass (stage 2). In more severe cases, the bones may thin as well (stage 3) [52]. In RSD, the sympathetic nerve is felt to be overacting; even when the injury itself is old, it continues to monitor the injury site and generate an abnormally sustained response [53].The abnormal response is not always the same in all of those whom are afflicted. The Angry Backfiring ‘C’ (ABC) Syndrome occurs when the sympathetic never becomes angry, or backfires, in response to an underlying injury. This axon reflex causes the C fiber to emit various vasoactive chemicals such as substance ‘P’, kinens and histamine. These patients are usually warm sensitive and the involved segment is vasodilated [16, 54]. The Triple ‘C’ Syndrome variant occurs when the C fiber fires excessively, causing intense, local vasoconstriction. People with this problem complain of cold hypesthesia (abnormal cold perception), cold hyperalgesia (cold burns) and have regionalized hypothermia [16, 54]. Given the persistent and diverse nature of sympathetic pain syndromes, it is not surprising that the effectiveness of sympathetic blockade can be quite variable. Reeves [55] noted that mixed results with electric sympathetic blockade occur secondary to at least two procedural factors: ‘simulation parameters have not been consistent across prior studies…and previous studies have investigated the effects of TENS on the SNS (sympathetic nervous system) under resting conditions – which may result in the ‘floor effect,’ of ‘physiological levels too flow to demonstrate further reduction.’Finney [56] reported ‘Vasomotor equalization usually begins within 15 min and is associated with a decreased in perceived pain.’ He also states ‘Generally patients in stage I hot phase RSD and those who undergone sympathectomy do not respond as well as stage I or II cold RSD.” Since many of the papers on electric sympathetic block have not utilized skin blood flow studies to determine the clinical condition being treated, it is not surprising that outcomes would be different. If a patient is vasodilated prior to treatment, then sympathetic blockade should not be expected to produce relief [16].The duration of treatment also makes a difference. At least 20 min is the proper treatment time in order to obtain the maximal effect when using electroceuticals [18,57 –60]. Beyond 20 min, the body’s physiologic protection mechanisms begin to respond, attempting to regain normal homeostasis. This response is known as the Hunting Reaction and occurs maximally at 30 min [58, 61].Scudds [62] used infrared thermography to measure skin temperature and studied patients receiving electric sympathetic block for 60-min periods of time. He concluded ‘the first 30 min of the stabilization period demonstrated a significant increase in skin temperature (t = 4.35, P = 0.001).’ A 20 –30 min duration of electroceutical application time is recommended [18, 57, 59, 60,62].Jenkner [63,34] has done extensive work demonstrating the importance of proper electrode size, shape, configuration and placement. If attention is not paid to these requirements, potency will be reduced, increasing the likelihood of mixed results. Whitters [65] demonstrated ‘that increases in spacing correlate with a decrease in rheobase current’ and that ‘Parallel load results demonstrated a large increase in rheobase.’ Rubinstein [66, 67] has published that nerve fibers have different stimulation thresholds along their length, concluding ‘Chronaxie for stimulation near the terminal may be much smaller that at a distance from the terminal and the strength-duration curve may be non-monotonic.’When factors such as electrode size, shape, configuration, placement, electrical parameter selection, duration of application and patient selection are assessed, it becomes clear that inconsistent parameter utilization, electrode montages, and patient selection criteria have made a significant contribution toward outcomes with mixed results. 
