neuromuscular electrostimulation techniques: historical ...€¦ · 3institute of pharmacology and...

Original©2012 Dustri-Verlag Dr. K. Feistle

ISSN 0301-0430

DOI 10.5414/CNX77S106e-pub: ■■month, ■■day, ■■year

Received ■■■; accepted in revised form ■■■ Correspondence to August Heidland, MD Department of Internal Medicine, University of Würzburg and KfH Kidney Center, Hans-Brandmann-Weg 1, 97080 Würzburg, Germany august.heidland@ t-online

Key wordselectric ray fish – franklinism – galvanism – faradism – transcuta-neous electrical nerve stimulation – percutane-ous electrical nerve stimulation – spinal cord stimulation – high tone external muscle stimulation – electrical myostimulation

Neuromuscular electrostimulation techniques: historical aspects and current possibilities in treatment of pain and muscle waistingAugust Heidland1,2, Gholamreza Fazeli3, André Klassen2, Katarina Sebekova4, Hans Hennemann5, Udo Bahner2 and Biagio Di Iorio6

1Department of Internal Medicine, University of Würzburg, 2KfH-Kidney Center, 3Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany, 4Institute of Molecular Biomedicine, Medical Faculty, Comenius University, Bratislava, Slovakia, 5KfH Kidney Center Coburg, Coburg, Germany, and 6Faculty of Medicine and Surgery, Seconda Universita di Napoli, Italy

Abstract. Application of electricity for pain treatment dates back to thousands of years BC. The Ancient Egyptians and later the Greeks and Romans recognized that electrical fishes are capable of generating electric shocks for relief of pain. In the 18th and 19th centuries these natural producers of electricity were replaced by man-made elec-trical devices. This happened in following phases. The first was the application of stat-ic electrical currents (called Franklinism), which was produced by a friction generator. Christian Kratzenstein was the first to apply it medically, followed shortly by Benjamin Franklin. The second phase was Galvanism. This method applied a direct electrical cur-rent to the skin by chemical means, applied a direct and pulsed electrical current to the skin. In the third phase the electrical current was induced intermittently and in alternate directions (called Faradism). The fourth stage was the use of high frequency currents (called d’Arsonvalisation). The 19th century was the “golden age” of electrotherapy. It was used for countless dental, neurological, psychiatric and gynecological disturbances. However, at beginning of the 20th century electrotherapy fell from grace. It was dis-missed as lacking a scientific basis and be-ing used also by quacks and charlatans for unserious aims. Furthermore, the develop-ment of effective analgesic drugs decreased the interest in electricity. In the second half of the 20th century electrotherapy underwent a revival. Based on animal experiments and clinical investigations, its neurophysiologi-cal mechanisms were elucidated in more details. The pain relieving action of electric-ity was explained in particular by two main mechanisms: first, segmental inhibition of pain signals to the brain in the dorsal horn of the spinal cord and second, activation of the descending inhibitory pathway with en-

hanced release of endogenous opioids and other neurochemical compounds (serotonin, noradrenaline, gamma aminobutyric acid (GABA), acetylcholine and adenosine).

The modern electrotherapy of neuro-musculo-skeletal pain is based in particular on the following types: transcutaneous elec-trical nerve stimulation (TENS), percutane-ous electrical nerve stimulation (PENS or electro-acupuncture) and spinal cord stimu-lation (SCS). In mild to moderate pain, TENS and PENS are effective methods, whereas SCS is very useful for therapy of refractory neuropathic or ischemic pain. In 2005, high tone external muscle stimulation (HTEMS) was introduced. In diabetic peripheral neu-ropathy, its analgesic action was more pro-nounced than TENS application. HTEMS appeared also to have value in the therapy of symptomatic peripheral neuropathy in end-stage renal disease (ESRD). Besides its pain-relieving effect, electrical stimulation is of major importance for prevention or treat-ment of muscle dysfunction and sarcopenia. In controlled clinical studies electrical myo-stimulation (EMS) has been shown to be effective against the sarcopenia of patients with chronic congestive heart disease, dia-betes, chronic obstructive pulmonary disease and ESRD.

Introduction

Pain is a constant companion from birth to death in our everyday life [1]. Its prevalence in patients with end-stage re-nal disease (ESRD) is much higher than in the general population. In the majority of these individuals management of pain is inadequate [2, 3]. This is in particular due

Clinical Nephrology, Vol. 78 – No. Suppl. 1/2012 (S12-S23)

Neuromuscular electrostimulation techniques: historical aspects and effects S13

to enhanced adverse side effects of many analgesic agents (owing to their altered pharmacokinetics and pharmacodynam-ics in renal failure) and saturation of the patients due to daily tablet overload. Con-sequently, non-pharmacological strategies such as electrotherapy could be a useful al-ternative. It is the goal of this paper to con-vey a better understanding of the potential clinical applications of electrotherapy in its different forms. Their non-invasive kinds are fortunately without relevant side effects – a good reason for its broader application.

Historical aspects of electro-therapy

Application of electricity for pain relief dates back to antiquity. It is assumed that as early as 9000 BC magnetite and amber (“animated minerals”) were used by Ancient Egyptians for treatment of headaches and arthritis [4]. Also some hints assumes that in the time of Pharaohs the Egyptians were even able to produce electricity from a direct current battery (Ureus battery) [5].

A very effective approach was the con-tact with electrical fishes. There are hints that the Ancient Egyptians employed the Nile catfish for treatment of severe painful conditions. Their power has been shown in tomb paintings as early as 2750 BC [6]. In a

similar manner Hippocrates (420 BC) used the numbing action of the electrical ray fish (black torpedo fish). The Roman physician Scribonius Largus (AD 47) (Figure 1) was the first who, in the Compositiones Medicae, prescribed the direct contact with the ray fish for pain relief in patients with gout, arthritis or headaches [6]. The torpedo fish generates discharges from as little as 8 volts up to 220 volts, depending on the species. The average current is ~50 volts.

In the 18th – 19th centuries, pain treat-ment by natural electricity was replaced by man-made electricity with invention of elec-trical devices. According to Turrell [8] the following four phases of electrotherapy have to be mentioned: the first phase was the ap-plication of static or atmospheric electricity, called Franklinism. It was characterized by high voltage and low milliampere currents, which were derived from a frictional machine which induced sudden shocks and sparks. The method dates back to the German engineer Otto von Guericke who developed frictional electricity by an electrostatic sulphur sphere in 1672 [9]. Later, the storage of the electri-cal charge (Figure 2) was made possible by invention of the Leiden jar (the forerunner of the electrical capacitor). The first medical use of static electricity in Europe was performed in 1744 by the German physician Christian Kratzenstein. A few years later (1752), the American scientist and politician, Benjamin Franklin, invented the “Magic Square”, a simple form of a condenser capable of giv-ing strong shocks for treatment of various illnesses [10]. Another approach was the use of a large-sized static-induction machine, the “improved Holtz”, which worked with high power under any weather conditions. In con-trast the old-fashioned friction machines did not work in stormy weather or when the atmo-sphere was damp or humid [11].

The second phase was Galvanic cur-rent (around 1800s), which allowed the di-rect contact of dynamic electricity over the nerves without shocks and sparks. Introduc-tion of “contact electricity” was preceded by the discovery of Galvani (1780) showing that the severed legs of a dead frog kicked out-ward when stimulated by electrical currents. Galvani’s assumption of “animal electric-ity” was criticized by Alessandro Volta. He could demonstrate that the electricity leading

Figure 1. Artist’s impression of use of the elec-trical torpedo fish in the treatment of gout (a) and headache (b). Reproduced with permission from Perdikis 1977, South Africa Journal of Surgery [7].

Heidland, Fazeli, Klassen et al. S14

to contraction of the frog muscle was not of animal source but of electrochemical origin [10]. Subsequently in 1800, Volta showed that when two dissimilar metals and brine-soaked cloth are placed in a circuit, an electric current could be produced. This discovery resulted in the invention of the voltaic pile – the first form of a battery. Galvanism was used for manage-ment of numerous illnesses including depres-sion by placing the voltaic pile on the parietal region of the head (Figure 2) [9].

In 1825, the French physician Jean-Bap-tiste Sarlandière demonstrated that the effect of Galvanism could be enhanced by use of acupuncture needles leading to the first devel-opment of electro-acupuncture. He resumed: “... in my opinion electro-acupuncture is the most proper method of treating rheumatism, nervous afflictions and attacks of gout …” [9]. It should be mentioned that before Sar-landière, the French physician and composer, Hector Berlioz, suggested the combination of classic Chinese method of acupuncture with electrotherapy. He mentioned that “apparently the application of Galvanic shock produced by the voltaic pile heightens the medical ef-fect of acupuncture” [9].

Application of Galvanic current was not without side effects. Its prolonged use led to necrotic changes in the tissues. This damaging action was later employed for destruction of superficial tumors including prostate cancer.

The third phase was the introduction of Faradism. The British scientist, Michael Faraday, in 1832 employed the voltaic pile

and discovered that the flow of electricity could be induced intermittently (interrupted) and in alternate directions. Stimulations were performed with a short pulse duration (< 1 millisecond), thereby preventing any risk of tissue damage. The most important promot-er of Faradism in the mid 19th century was the French physician, Guillaume Duchenne, (“father of electrotherapy”), who used this technique in particular for muscle stimula-tion. In 1849 he stated “Faradism is the best form of muscular electricity and can be prac-ticed frequently and for a long time… The results are of highest importance” [8].

The fourth phase was the discovery of high frequency currents by the French phy-sician, Jacques Arsène d`Arsonval, in 1888 who observed that frequencies beyond 5.000 Hz decreased the excitation of muscles [8].

Throughout the 19th century the analgesic effects of electricity were widely popular and enjoyed their “golden age”. Electrotherapy was used for countless dental, neurological, psychiatric and gynecological disturbances. It was even used by quacks and charlatans for enhancing health and beauty with the slo-gan “vibrate your body and make it well”. With regard to these unserious applications, electricity fell into disregard more and more.

Figure 2. Otto von Guericke’s demonstration of the first electrical machine using friction [9].

Figure 3. Illustration of the voltaic pile, the first battery consisting of copper and zinc, separated by electrolyte solution to increase the conductivity (Adolphe Ganot in Elementary Treatise on Physics: Experimental and Applied 1893).


Another cause of the declined interest was the advance of potent analgesic drugs.

Modern development of neuro-muscular stimulation

In the second half of the 20th century, the scientific bases of electrotherapy was increasingly elucidated, offering the chance for a rational treatment of various painful conditions. The new techniques included transcutaneous electrical nerve stimula-tion (TENS), percutaneous electrical nerve stimulation (PENS) and spinal cord stimu-lation (SCS). In 2005 the so-called high tone external muscle stimulation (HTEMS) was introduced to combat pain. The electri-cal devices differ in regard to the amplitude (intensity), frequency, duration and pattern of the electrical currents (Figure 4).

Transcutaneous electrical nerve stimulation

TENS is currently the most frequent form of non-pharmacological pain management. It is based on the observation by Wall and Sweat in 1967 [12] that an electrical stimula-tion with 100 Hz applied on the skin surface resulted in a dramatic relief of pain. TENS consists of a battery-powered portable elec-tric unit with electrodes applied to the skin,

delivering electrical impulses to the underly-ing nerve fibers. Different kinds of frequency modes are: high frequency (HF-TENS > 50 Hz), low frequency (LF-TENS < 10 Hz) and variable frequency (VF-TENS) [13]. The intensity is usually adjustable. After ap-plication of HF-TENS intensity is generally low (low pulse amplitude), associated with a non-painful feeling of tingling. On the other hand, application of LF-TENS is associated with a high intensity (high pulse amplitude) resulting in strong, but mostly comfortable muscle twitching. Pain relief after TENS may be rapid, but initially the effects are not long-lasting.

PENS (acupuncture-like TENS) com-bines the effect of both LF- TENS (usually 2 pps and high intensity) and acupuncture-like needle probes leading to a transcutane-ous hyperstimulation [15]. Administration is performed over muscles, acupuncture and trigger points. In general about ten 32 gauge needle probes are used [16].

Spinal cord stimulation (SCS) is an inva-sive method. The electrode is implanted in the epidural space and exerts pulsed electri-cal signals directly to the spinal cord. The electrical pulse generator is placed in the lower abdominal area. In 1967, the dorsal horn of the spinal cord was stimulated for the first time by Shealy and Mortinor [17]. In the following years, its marked effects led to the development of implanted electrodes with a modern radiofrequency receiver. SCS is indi-

Figure 4. Output characteristics (settings) of a standard TENS device. The user can control the amplitude (intensity), duration (width), frequency (rate) and pattern (mode) of the pulsed electrical currents.” With permission from Tashani and Johnson (2009) [14].


cated to control severe chronic pain, which is unresponsive to other kinds of therapy.

Potential mechanisms involved in the analgesic action of electrical stimulation

In 1965 Melzack and Wall [18] developed the Gate Control Theory of Pain. The authors suggested that “the substantia gelatinosa in the dorsal horn acts as a gate control system, which modulates the synaptic transmission of nerve impulses from peripheral fibers to the central cells.” According to this hypothesis the small nociceptive A-δ and C fibers hold the hypothetical gate in a relative opened po-sition, while stimulation of the large mecha-noreceptive A-β fibers (which are stimulated by touch, pressure or vibration) close the gate and inhibit the pain transmission to the brain. Because small nociceptive fibers are charac-terized by a higher threshold of action than the large mechanoreceptive fibers, the selec-tive stimulation of the latter ones can prevent or reduce pain transmission (Figure 5). The concept of Melzack and Wall led to the appli-cation of gentle electrical stimulation to elec-trode taped to the skin, the later called TENS [19]. In line with the concept of the gate con-

trol mechanisms, TENS application in cats reduced the activity of dorsal horn cells which was evoked spontaneously or noxiously [20].

Besides the segmental inhibition of pain in the dorsal horn, Melzack and Wall also sug-gested that an activation of descending pain inhibitory mechanisms is implicated in the analgesic action of electricity. The role of this pathway was underlined by two observations: first, the analgesic action of HF-TENS was partly reduced by cutting of the spinal cord (spinalization), which removes the descend-ing inhibitory components [21] and second, the analgesic effect of TENS outlasts the time of stimulation by several hours, implicating the involvement of extra-segmental factors [13].

The descending pathway originates in the midbrain and starts in the periaqueduc-tal grey (PAG), which sends projections to the rostral ventral medulla (RVM), fol-lowed by projections to the spinal dorsal horn [22, 23]. TENS-induced activation of PAG and RVM is involved in the reduction of hyperalgesia in arthritic rats [22]. Of particular importance is the enhanced re-lease of endogenous opioids and serotonin, which act through the PAG-RVM pathway [24]. In the spinal fluid of arthritic rats LF-TENS enhanced the levels of µ-opioids, while HF-TENS increased the δ-opioids concentrations. Pre-treatment of these rats with the µ-opioid receptor antagonist, nal-oxone, blocked the effect of LF-TENS, while the δ-opioid receptor antagonist, naltrindole, prevented the action of HF-TENS [25]. Furthermore in humans, HF- and LF-TENS application is associated with enhanced levels of β-endorphin, both in spinal fluid and blood plasma [26, 27].

Serotonin exerts its analgesic action su-praspinally and spinally, depending on the activated receptor type and the used dose [28]. Correspondingly, in brain homog-enates its concentration was elevated. The effect of HF-TENS is enhanced by applica-tion of serotonin and reduced by its deple-tion. Norepinephrine is antinociceptive in the PAG-RVM pathway and in the spinal dorsal horn by activating α2-adrenoceptors [29]. In the analgesic action of electricity, adenosine is implicated via activation of pu-rinergic (adenosine) receptors at peripheral and spinal sites [30].

Figure 5. The hypothetical gate of the pain mech-anism. Activation of small nociceptive fibers holds the gate open, while activation of large mechano-receptive fibers closes the gate and inhibits pain transmission to the brain.


An important factor in TENS-induced analgesia is the neuroinhibitory transmitter GABA as shown in arthritic rats. HF-TENS enhanced the release of GABA in the deep dorsal horn of the spinal cord and both HF- and LF-TENS reduced the hyperalgesia by activation of spinal GABA-A receptors [31].

Moreover, SCS produces in the dorsal horn an augmented release of acetylcholine, indicating an activation of the cholinergic system in the analgesic effect [32].

In arthritic rats HF-TENS, but not LF-TENS, lowered the levels of some excitatory amino acids such as glutamate and aspartate in the dorsal horn [33].

TENS also reduces the production of sub-stance P in this region [34]. Several lines of evidence suggest that the motor-cortex excit-ability can be modulated by peripheral nerve stimulation with LF- and HF-TENS [35].

Daily administration of TENS is followed by an analgesic tolerance at the spinal opioid receptor as early as on the 4th day [36]. Re-cent data suggest that this tolerance can be delayed or prevented by simultaneous acti-vation of µ-opioid and δ-opioid receptors. Therefore, either a mixed frequency (HF- and LF-TENS at the same session) or an al-ternating frequency (HF- and LF-TENS) ap-plied separately on alternating days) should be used [37].

Circulatory effects of electrotherapy

According to laser Doppler investiga-tions, TENS application in healthy vol-unteers stimulates the peripheral micro-circulation [38], potentially contributing to the analgesic action of TENS. In diabetic neuropathy, a relationship between capil-lary abnormalities and severity of neu-ropathy has been observed [39]. In these patients TENS-induced vasodilation is as-sociated with the enhanced microcircula-tion and increased endoneural blood flow [40]. Electrotherapy, in particular in the form of SCS, enhances the blood flow in ischemic peripheral vascular and coro-nary heart disease [41]. The vasodilation may be induced by release of vasoactive substances such as calcitonin gene-related peptide and possibly nitric oxide (NO) [42,

43, 44]. In certain conditions an inhibition of sympathetic afferent activity may con-tribute to vasodilation [45].

Clinical trials of various types of electrotherapy

Transcutaneous electrical nerve stimulation

The effectiveness of TENS was shown in many clinical studies. However, in numerous investigations evidence of TENS was incon-clusive due to short-comings of the random-ized clinical trials (RCTs), among others due to poor classification of the patient groups and lack of standardization of the therapy etc. Moreover, the possibility of tolerance to TENS has to be considered in the case of negative results. In diabetic polyneuropathy three RCTs were performed with positive results. In the first placebo-controlled RCT of 31 patients with type II diabetes, TENS improved the painful distal polyneuropathy significantly [46]. The same authors likewise demonstrated that TENS in combination with amitriptyline appears to be “a useful ad-junctive modality” [47]. In a third RCT of a German research group, the effect of TENS was significant [48].

Analgesic effects of TENS have also been reported in pain caused by knee osteo-arthritis [49], which was not confirmed in a recent RCT [50]. In the treatment of lower back pain beneficial effects of TENs have been reported [51]. However, according to Cochrane database the treatment with TENS for lower back pain seems not to be effective [52]. TENS was shown to be beneficial for pain caused by renal colic in the emergency care unit [53]. These data correspond to an experimental visceral model of renal pain in cats, induced by occlusion of the ureter or renal artery [54]. Moreover, after various surgical procedures the analgesic effects of TENS seem to be significant [55].

Intermittent use of TENS is recommend-ed for patients with acquired polycystic kid-ney disease (APKD), who frequently suffer from chronic dull acting pain due to enlarge-ment of the cysts [56]. In cancer-related pain the data about effectiveness of TENS are still insufficient (Cochrane review) [57].


Interestingly, TENS was reported to be beneficial in severe angina pectoris [58]. In another study LF-TENS lowered the blood pressure [59]. It was even successfully ap-plied in a small group of patients with ther-apy-resistant hypertension, as documented by 24-h blood pressure measurements [60]. This effect appears to be partly due to in-hibition of the central sympathetic activity. Recently, the blood pressure lowering ac-tions of TENS could not be confirmed [61].

Percutaneous electrical nerve stimulation

In a sham-controlled cross-over study, PENS lowered pain from diabetic peripheral neuropathy and improved the physical activ-ity of the patients. Also mental components of the SF-36 showed improvements com-pared to sham [62]. In another sham-con-trolled crossover study in patients with lower back pain PENS was more effective than TENS [16]. It is also reported that PENS is effective in post-herpetic neuropathy, severe sciatica and lower back pain (among others due to bone metastasis).

Spinal cord stimulation

The efficacy of SCS in neuropathic pain of diabetic patients has been demonstrated in a prospective randomized controlled multicenter trial with a 24-month follow-up [63]. It is well established in the treatment of failed back surgery syndrome (FBSS) and the complex regional pain syndrome (CRPS) [64, 65]. In an earlier study in patients with multiple sclerosis, SCS improved the spas-ticity [66].

SCS was very successful in patients with severe intractable angina pectoris (unsuitable for coronary artery bypass grafting – CABG or percutaneous laser revascularization). Re-sults showed improvements in chest pain, less ST segment depression, augmented myocardial blood flow and enhanced exer-cise capacity [67]. Notably, SCS was as ef-fective as CABG surgery [68]. Its beneficial long-term actions on angina pectoris were recently confirmed [69].

Also in patients with ischemic periph-eral artery disease (unsuitable for vascular reconstruction) SCS was successfully ap-plied [70]. It markedly alleviated pain and delayed or even prevented amputations [71]. In dialysis patients with critical lower limb ischemia (Leriche-Fountain Stage 3 or 4), SCS dramatically improved pain and quality of life [72]. The benefits persisted for up to 6 – 12 months and are also attributed to an improved microvascular blood flow of the legs [73].

However, SCS does not come without complications: The device fails in 3 – 4% of the cases, and 3 – 5% of the patients develop infections [74]. Most frequently, the exter-nal electrode is either dislocated or broken (11 – 36%).

In recent animal models of Parkinson’s disease, SCS restored the locomotion [75]. Conceivably, it could be helpful also in pa-tients suffering from severe Parkinson’s dis-ease, who are currently treated with the more invasive electrical deep brain stimulation.

High tone external muscle stimulation

HTEMS is a new device for pain treat-ment. With this method a continuous scan of the carrier frequency, varying in short inter-vals between 4,096 and 32,786 Hz, is applied. The amplitude and frequency are modulated simultaneously. In a short-term comparative study (3 consecutive days for 30 min) be-tween TENS and HTEMS in painful diabetic polyneuropathy, HTEMS was nearly three times more effective than TENS in reliev-ing pain symptoms and discomfort [76]. The analgesic action was recently confirmed and extended [77]. In a prospective uncontrolled study (twice weekly 60 min sessions, for 4 weeks) in 92 Type 2 diabetic patients with peripheral neuropathy, a marked improve-ment of pain and of sleeping disturbances was observed in 73% of the patients.

Our group investigated in a pilot study the effect of HTEMS in dialysis patients with symptomatic peripheral polyneuropathy (25 patients with diabetic and 15 with uremic peripheral polyneuropathy) [78]. Electrodes were placed on the femoral muscles. The pa-tients were treated intradialytically for up to


60 min, three times a week. After a period of 1 – 3 months, more than 70% of the patients reported a significant improvement of neu-ropathic symptoms and sleep disturbances (Figure 6) [78]. In a subgroup of 12 dialysis patients with diabetic polyneuropathy, the effect was followed for 12 months [79]. In these individuals the beneficial action of HTEMS remained significant as compared to baseline with exception of sleeping disor-ders.

It is well known that placebos are very effective in the treatment of pain. However, their effects diminish with repeated admin-istration. Therefore, the persistence of the analgesic action of HTEMS over a period of one year is a strong indicator of the impact of this kind of therapy. Meanwhile, the effi-cacy of HTEMS in dialysis patients with pe-ripheral neuropathy has been confirmed and extended [80].

According to recent studies of our group, HTEMS treatment of painful neuropathy in dialysis patients is associated with an im-provement of some components of Short Form of the SF-36 questionnaire [81].

Electrical muscle stimulation for prevention and treatment of muscle wasting

In 1988 Gibson at al. [82] postulated that in rheumatic arthritis the motor fibers should be stimulated electrically in order

to prevent muscle atrophy and to restore muscle function. In a subsequent study, TENS was associated with increased mus-cle function as evaluated by a Hand-Grip test [83]. In the last decade further devel-opments led to functional electrical stimu-lation (FES), in particular in patients with spinal cord damage.

An important indication for electrother-apy is sarcopenia which is defined as loss of muscle mass and weakness. Sarcopenia is a frequent complication in ESRD, chron-ic heart failure, diabetes mellitus, obesity, cancer and old age. It is a critical factor in normal daily activity and associated with a high risk for falls and fractures with en-hanced morbidity and mortality. Myopathy typically affects the proximal muscles of the thighs, while peripheral neuropathy causes muscle loss of the lower legs [84]. The most important causes of sarcopenia in ESRD are uremic toxins, deficiency of vitamin D and of carnitine, secondary hy-perparathyroidism, poor nutritional state, vascular ischemia, metabolic acidosis, muscle unloading due to physical inactiv-ity and immobilization, and enhanced in-sulin resistance [85].

In the therapy of sarcopenia, besides correction of the altered biochemical pa-rameters, physical exercise is of funda-mental importance [86], in particular with regard to an improved insulin resistance [87]. However, training is often difficult to realize due to severe co-morbid conditions. In these individuals electrical myostimula-tion (EMS) might be an alternative, as it mimics various effects of active exercise. EMS (20 Hz) increases muscle oxidative capacity [88] and enhances glucose dispos-al [89]. In paraplegic patients, EMS of the paralyzed muscles (3 days per week for 8 weeks) enhanced expression of the GLUT-1 and GLUT-4 transporters, oxidative ca-pacity, and insulin sensitivity [90].

In the past several years EMS has proven quite effective in the treatment of sarcope-nia of patients with chronic heart failure. In a randomized clinical trial TENS (low fre-quency) of the upper legs for 10 weeks (2 times for 2 h per day) enhanced the peak exercise capacity and oxygen consumption considerably, while the corresponding val-ues in the Sham TENS group remained un-

Figure 6. Effects of HTEMS on five neuropathic symptoms and on sleeping disorder in mainte-nance hemodialysis patients. **p < 0.005. Repro-duced from Klassen et al. [78].


changed [91]. Similar results were obtained in another randomized study of home-based EMS of the legs and conventional bicycle exercise training in chronic heart failure [92]. Also in patients with chronic obstruc-tive pulmonary disease application of EMS improved muscle function significantly [93].

Recently, in a randomized trial in ESRD patients, the effect of intradialytic EMS (fre-quency of 10 Hz) of leg extensors was in-vestigated and compared to both intradialytic active exercise training (on a bicycle ergom-eter) and to an untreated control group of dialysis patients [94]. After 20 weeks EMS exerted pronounced effects on functional muscle capacity and mental components of quality of life. In many aspects, EMS was comparable to the group performing active exercise [94]. Interestingly, intradialytic EMS was associated with an enhanced re-moval rate of urea and inorganic phosphate. The effect was comparable to the group per-forming intradialytic active exercise.

Up to now the effects of intradialytic HTEMS on muscle function have not been investigated. However, some patients re-ported spontaneously about an improved strength of the legs and an easier stair-climbing after long-term HTEMS. More-over, there are data that HTEMS improves the insulin resistance which is an important risk factor of muscle wasting. In a study in obese diabetic individuals, daily application of HTEMS (1 h) for 6 weeks ameliorated the elevated HbA1c levels and lowered the body weight [95], suggesting an improved insulin resistance.

Currently, there are only few contra-in-dications for electrotherapy. These include active bacterial infection, presence of a pace-maker or cardiac defibrillator, pregnancy, re-cent fractures, acute thrombosis and epilepsy.

Summarizing, in the last decades electro-neuro-muscular stimulation improved the therapy of various kinds of pain and sarcope-nia and was associated with the reduction of needed medications. In the case of HTEMS despite the current lack of RTCs, the avail-able clinical data support its benefits. In particular in ESRD patients its application during dialysis has the advantage that the patients do not need any extra time for this treatment.

Conflict of interest

A.H. received lecture honoraria from gbo. The other authors declare no conflict of interest.

References[1] Murken AH. Pain as man’s constant companion

from birth to death. Verlag Murken Altrogge, 2005.

[2] Davison SN. Pain in hemodialysis patients: preva-lence, cause, severity, and management. Am J Kidney Dis. 2003; 42: 1239-1247.

[3] Bailie GR, Mason NA, Bragg-Gresham JL, Gil-lespie BW, Young EW. Analgesic prescription pat-terns among hemodialysis patients in the DOPPS: potential for underprescription. Kidney Int. 2004; 65: 2419-2425.

[4] Schechter DC. Origins of electrotherapy. I. N Y State J Med. 1971; 71: 997-1008.

[5] Ose R. Elektrizität im alten Ägypten? In Erich von Däniken: Jäger verlorenen Wissens, Kopp Verlag; Rottenburg. 2003. p. 69-78

[6] Rossi U. The history of electrical stimulation of the nervous system for the control of pain. Electri-cal stimulation and the relief of pain. Edited by Simpson BA, Elsevier BV 2003. p. 6 - 16

[7] Perdikis P. Transcutaneous nerve stimulation in the treatment of protracted ileus. S Afr J Surg. 1977; 15: 81-86.

[8] Turrell WJ. The landmarks of electrotherapy. Arch Phys Med Rehabil. 1969; 50: 157-160.

[9] Stillings D. A survey of the history of electrical stimulation for pain to 1900. Med Instrum. 1975; 9: 255-259.

[10] Macdonald AJR. A brief review of the history of electrotherapy and its union with acupuncture. Acupunct Med. 1999; 11: 66-75.

[11] Garratt AC. Franklinism or atmospheric electric-ity as remedy. Boston Med Surg J. 1883; 108: 123-125.

[12] Wall PD, Sweet WH. Temporary abolition of pain in man. Science. 1967; 155: 108-109.

[13] Sluka KA, Walsh D. Transcutaneous electrical nerve stimulation: basic science mechanisms and clinical effectiveness. J Pain. 2003; 4: 109-121.

[14] Tashani O, Johnson MJ. Transcutaneous electri-cal nerve stimulation (TENS) a possible aid for pain relief in developing countries? Libyan J Med. 2009; 4: 62-65.

[15] Johnson M. The analgesic effects and clinical use of Acupuncture – like TENS (AL – TENS). Phys Ther Rev. 1998; 3: 73-93.

[16] Ghoname EA, Craig WF, White PF, Ahmed HE, Hamza MA, Henderson BN, Gajraj NM, Huber PJ, Gatchel RJ. Percutaneous electrical nerve stimulation for low back pain: a randomized crossover study. JAMA. 1999; 281: 818-823.

[17] Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by stimulation of the dorsal col-umns: preliminary clinical report. Anesth Analg. 1967; 46: 489-491.

[18] Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965; 150: 971-979.


[19] Gildenberg PL. History of Electrical neuromodu-lation of chronic pain. Pain Medicine. 2006; 7: S7-S13.

[20] Garrison DW, Foreman RD. Decreased activity of spontaneous and noxiously evoked dorsal horn cells during transcutaneous electrical nerve stimu-lation (TENS). Pain. 1994; 58: 309-315.

[21] Woolf CJ, Mitchell D, Barrett GD. Antinocicep-tive effect of peripheral segmental electrical stim-ulation in the rat. Pain. 1980; 8: 237-252.

[22] DeSantana JM, Walsh DM, Vance C, Rakel BA, Sluka KA. Effectiveness of transcutaneous electri-cal nerve stimulation for treatment of hyperalgesia and pain. Curr Rheumatol Rep. 2008; 10: 492-499.

[23] DeSantana JM, Da Silva LF, De Resende MA, Sluka KA. Transcutaneous electrical nerve stimu-lation at both high and low frequencies activates ventrolateral periaqueductal grey to decrease me-chanical hyperalgesia in arthritic rats. Neurosci-ence. 2009; 163: 1233-1241.

[24] Sabino GS, Santos CM, Francischi JN, de Re-sende MA. Release of endogenous opioids follow-ing transcutaneous electric nerve stimulation in an experimental model of acute inflammatory pain. J Pain. 2008; 9: 157-163.

[25] Kalra A, Urban MO, Sluka KA. Blockade of opi-oid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS). J Pharmacol Exp Ther. 2001; 298: 257-263.

[26] Salar G, Job I, Mingrino S, Bosio A, Trabucchi M. Effect of transcutaneous electrotherapy on CSF beta-endorphin content in patients without pain problems. Pain. 1981; 10: 169-172.

[27] Hughes GS Jr, Lichstein PR, Whitlock D, Harker C. Response of plasma beta-endorphins to trans-cutaneous electrical nerve stimulation in healthy subjects. Phys Ther. 1984; 64: 1062-1066.

[28] Schmauss C, Hammond DL, Ochi JW, Yaksh TL. Pharmacological antagonism of the antinocicep-tive effects of serotonin in the rat spinal cord. Eur J Pharmacol. 1983; 90: 349-357.

[29] Yaksh TL. Pharmacology of spinal adrenergic sys-tems which modulate spinal nociceptive processing. Pharmacol Biochem Behav. 1985; 22: 845-858.

[30] Sawynok J. Adenosine receptor activation and no-ciception. Eur J Pharmacol. 1998; 347: 1-11.

[31] Maeda Y, Lisi TL, Vance CG, Sluka KA. Release of GABA and activation of GABA(A) in the spi-nal cord mediates the effects of TENS in rats. Brain Res. 2007; 1136: 43-50.

[32] Schechtmann G, Song Z, Ultenius C, Meyerson BA, Linderoth B. Cholinergic mechanisms in-volved in the pain relieving effect of spinal cord stimulation in a model of neuropathy. Pain. 2008; 139: 136-145.

[33] Sluka KA, Vance CG, Lisi TL. High-frequency, but not low-frequency, transcutaneous electrical nerve stimulation reduces aspartate and glutamate release in the spinal cord dorsal horn. J Neuro-chem. 2005; 95: 1794-1801.

[34] Rokugo T, Takeuchi T, Ito H. A histochemical study of substance P in the rat spinal cord: effect of transcutaneous electrical nerve stimulation. J Nihon Med Sch. 2002; 69: 428-433.

[35] Tinazzi M, Zarattini S, Valeriani M, Romito S, Fa-rina S, Moretto G, Smania N, Fiaschi A, Abbruzz-ese G. Long-lasting modulation of human motor

cortex following prolonged transcutaneous elec-trical nerve stimulation (TENS) of forearm mus-cles: evidence of reciprocal inhibition and facili-tation. Exp Brain Res. 2005; 161: 457-464.

[36] Chandran P, Sluka KA. Development of opioid tolerance with repeated transcutaneous electrical nerve stimulation administration. Pain. 2003; 102: 195-201.

[37] DeSantana JM, Santana-Filho VJ, Sluka KA. Modulation between high- and low-frequency transcutaneous electric nerve stimulation delays the development of analgesic tolerance in arthritic rats. Arch Phys Med Rehabil. 2008; 89: 754-760.

[38] Wikström SO, Svedman P, Svensson H, Tanweer AS; Sven Olof Wikström, Paul Svedman, H. Effect of transcutaneous nerve stimulation on microcir-culation in intact skin and blister wounds in healthy volunteers. Scand J Plast Reconstr Surg Hand Surg. 1999; 33: 195-201.

[39] Malik RA, Newrick PG, Sharma AK, Jennings A, Ah-See AK, Mayhew TM, Jakubowski J, Boulton AJ, Ward JD. Microangiopathy in human diabetic neuropathy: relationship between capillary abnor-malities and the severity of neuropathy. Diabeto-logia. 1989; 32: 92-102.

[40] Kaada B. Vasodilation induced by transcutaneous nerve stimulation in peripheral ischemia (Rayn-aud’s phenomenon and diabetic polyneuropathy). Eur Heart J. 1982; 3: 303-314.

[41] Kaada B, Vik-mo H, Rosland G, Woie L, Opstad PK. Transcutaneous nerve stimulation in patients with coronary arterial disease: haemodynamic and biochemical effects. Eur Heart J. 1990; 11: 447-453.

[42] Croom JE, Foreman RD, Chandler MJ, Koss MC, Barron KW. Role of nitric oxide in cutaneous blood flow increases in the rat hindpaw during dorsal column stimulation. Neurosurgery. 1997; 40: 565-570.

[43] Göksel HM, Karadag O, Turaçlar U, Taş F, Ozto-prak I. Nitric oxide synthase inhibition attenuates vasoactive response to spinal cord stimulation in an experimental cerebral vasospasm model. Acta Neurochir (Wien). 2001; 143: 383-390.

[44] Tanaka S, Barron KW, Chandler MJ, Linderoth B, Foreman RD. Role of primary afferents in spinal cord stimulation-induced vasodilation: character-ization of fiber types. Brain Res. 2003; 959: 191-198.

[45] Foreman RD, Linderoth B, Ardell JL, Barron KW, Chandler MJ, Hull SS Jr, TerHorst GJ, DeJongste MJ, Armour JA. Modulation of intrinsic cardiac neurons by spinal cord stimulation: implications for its therapeutic use in angina pectoris. Cardio-vasc Res. 2000; 47: 367-375.

[46] Kumar D, Marshall HJ. Diabetic peripheral neu-ropathy: amelioration of pain with transcutaneous electrostimulation. Diabetes Care. 1997; 20: 1702-1705.

[47] Kumar D, Alvaro MS, Julka IS, Marshall HJ. Dia-betic peripheral neuropathy. Effectiveness of elec-trotherapy and amitriptyline for symptomatic re-lief. Diabetes Care. 1998; 21: 1322-1325.

[48] Forst T, Nguyen M, Forst S, Disselhoff B, Pohl-mann T, Pfützner A. Impact of low frequency transcutaneous electrical nerve stimulation on symptomatic diabetic neuropathy using the new


Salutaris device. Diabetes Nutr Metab. 2004; 17: 163-168.

[49] Osiri M, Welch V, Brosseau L, Shea B, McGowan J, Tugwell P, Wells G. Transcutaneous electrical nerve stimulation for knee osteoarthritis. Co-chrane Database Syst Rev. 2000; CD002823

[50] Vance CG, Rakel BA, Blodgett NP, Desantana JM, Amendola A, Zimmerman MB, Walsh DM, Sluka KA. Effects of transcutaneous electrical nerve stimulation on pain, pain sensitivity, and func-tion in people with knee osteoarthritis: a ran-domized controlled trial. Phys Ther. 2012; 92: 898-910.

[51] Melzack R, Vetere P, Finch L. Transcutaneous electrical nerve stimulation for low back pain. A comparison of TENS and massage for pain and range of motion. Phys Ther. 1983; 63: 489-493.

[52] Milne S, Welch V, Brosseau L, Saginur M, Shea B, Tugwell P, Wells G. Transcutaneous electrical nerve stimulation (TENS) for chronic low back pain. Cochrane Database Syst Rev. 2001; CD003008.

[53] Mora B, Giorni E, Dobrovits M, Barker R, Lang T, Gore C, Kober A. Transcutaneous electrical nerve stimulation: an effective treatment for pain caused by renal colic in emergency care. J Urol. 2006; 175: 1737-1741.

[54] Nam TS, Baik EJ, Shin YU, Jeong Y, Paik KS. Mechanism of transmission and modulation of renal pain in cats; effects of transcutaneous elec-trical nerve stimulation on renal pain. Yonsei Med J. 1995; 36: 187-201.

[55] Bjordal JM, Johnson MI, Ljunggreen AE. Trans-cutaneous electrical nerve stimulation (TENS) can reduce postoperative analgesic consumption. A meta-analysis with assessment of optimal treat-ment parameters for postoperative pain. Eur J Pain. 2003; 7: 181-188.

[56] Bajwa ZH, Gupta S, Warfield CA, Steinman TI. Pain management in polycystic kidney disease. Kidney Int. 2001; 60: 1631-1644.

[57] Robb K, Oxberry SG, Bennett MI, Johnson MI, Simpson KH, Searle RD. A cochrane systematic review of transcutaneous electrical nerve stimula-tion for cancer pain. J Pain Symptom Manage. 2009; 37: 746-753.

[58] Mannheimer C, Carlsson CA, Ericson K, Vedin A, Wilhelmsson C. Transcutaneous electrical nerve stimulation in severe angina pectoris. Eur Heart J. 1982; 3: 297-302.

[59] Kaada B, Flatheim E, Woie L. Low-frequency transcutaneous nerve stimulation in mild/moderate hypertension. Clin Physiol. 1991; 11: 161-168.

[60] Jacobsson F, Himmelmann A, Bergbrant A, Svensson A, Mannheimer C. The effect of transcu-taneous electric nerve stimulation in patients with therapy-resistant hypertension. J Hum Hypertens. 2000; 14: 795-798.

[61] Silverdal J, Mourtzinis G, Stener-Victorin E, Mannheimer C, Manhem K. Antihypertensive ef-fect of low-frequency transcutaneous electrical nerve stimulation (TENS) in comparison with drug treatment. Blood Press. 2012; epub ahead of print.

[62] Hamza MA, White PF, Craig WF, Ghoname ES, Ahmed HE, Proctor TJ, Noe CE, Vakharia AS, Gajraj N. Percutaneous electrical nerve stimula-tion: a novel analgesic therapy for diabetic neuro-pathic pain. Diabetes Care. 2000; 23: 365-370.

[63] Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisen-berg E, Milbouw G, Buchser E, Fortini G, Rich-ardson J, North RB. The effects of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective random-ized controlled multicenter trial of the effective-ness of spinal cord stimulation. Neurosurgery. 2008; 63: 762-770.

[64] Kunnumpurath S, Srinivasagopalan R, Vadivelu N. Spinal cord stimulation: principles of past, present and future practice: a review. J Clin Monit Comput. 2009; 23: 333-339.

[65] Prager JP. What does the mechanism of spinal cord stimulation tell us about complex regional pain syndrome? Pain Med. 2010; 11: 1278-1283.

[66] Cook AW. Electrical stimulation in multiple scle-rosis. Hosp Pract. 1976; 11: 51-58.

[67] Mannheimer C, Augustinsson LE, Carlsson CA, Manhem K, Wilhelmsson C. Epidural spinal elec-trical stimulation in severe angina pectoris. Br Heart J. 1988; 59: 56-61.

[68] Mannheimer C, Eliasson T, Augustinsson LE, Blomstrand C, Emanuelsson H, Larsson S, Norr-sell H, Hjalmarsson A. Electrical stimulation ver-sus coronary artery bypass surgery in severe an-gina pectoris: the ESBY study. Circulation. 1998; 97: 1157-1163.

[69] Eckert S, Horstkotte D. Management of angina pectoris: the role of spinal cord stimulation. Am J Cardiovasc Drugs. 2009; 9: 17-28.

[70] Klomp HM, Spincemaille GH, Steyerberg EW, Habbema JD, van Urk H; ESES Study Group. Spinal-cord stimulation in critical limb ischaemia: a randomised trial. Lancet. 1999; 353: 1040-1044.

[71] Oakley JC, Prager JP. Spinal cord stimulation: mechanisms of action, Spine (Phila Pa 1976). 2002; 27: 2574-2583.

[72] Brümmer U, Condini V, Cappelli P, Di Liberato L, Scesi M, Bonomini M, Costantini A. Spinal cord stimulation in hemodialysis patients with critical lower-limb ischemia. Am J Kidney Dis. 2006; 47: 842-847.

[73] Jacobs MJ, Jörning PJ, Joshi SR, Kitslaar PJ, Slaaf DW, Reneman RS. Epidural spinal cord elec-trical stimulation improves microvascular blood flow in severe limb ischemia. Ann Surg. 1988; 207: 179-183.

[74] Torrens JK, Stanley PJ, Ragunathan PL, Bush DJ. Risk of infection with electrical spinal-cord stim-ulation. Lancet. 1997; 349: 729.

[75] Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA. Spinal cord stimulation restores lo-comotion in animal models of Parkinson’s dis-ease. Science. 2009; 323: 1578-1582.

[76] Reichstein L, Labrenz S, Ziegler D, Martin S. Ef-fective treatment of symptomatic diabetic poly-neuropathy by high-frequency external muscle stimulation. Diabetologia. 2005; 48: 824-828.

[77] Humpert PM, Morcos M, Oikonomou D, Schaefer K, Hamann A, Bierhaus A, Schilling T, Nawroth PP. External electric muscle stimulation improves burning sensations and sleeping disturbances in patients with type 2 diabetes and symptomatic neuropathy. Pain Med. 2009; 10: 413-419.

[78] Klassen A, Di Iorio B, Guastaferro P, Bahner U, Heidland A, De Santo N. High-tone external mus-cle stimulation in end-stage renal disease: effects


on symptomatic diabetic and uremic peripheral neuropathy. J Ren Nutr. 2008; 18: 46-51.

[79] Klassen A, Di Iorio B, Guastaferro P, et al. Short- and long-term results of high-tone external mus-cle stimulation in symptomatic diabetic and ure-mic peripheral polyneuropathy in end-stage renal disease. Third international congress on neuro-pathic pain, Athens, Greece, 2010, Abstract p. 40

[80] Strempska B, Bilinska M, Weyde et al. The effect of High-tone electrical muscle stimulation on the symptoms and electrophysiological parameters of the uremic peripheral neuropathy. Clin Nephrol. 2012; 78 (suppl 1): S24-S27.

[81] Klassen A, Racasan S, Blaser C et al. High tone external muscle stimulation: effects on quality of life in patients with peripheral neuropathy. Clin Nephrol. 2012; 78 (suppl 1): S28-S33.

[82] Gibson JN, Smith K, Rennie MJ. Prevention of disuse muscle atrophy by means of electrical stimulation: maintenance of protein synthesis. Lancet. 1988; 2: 767-770.

[83] Oldham JA, Stanley JK. Rehabilitation of atro-phied muscle in the rheumatoid arthritic hand: a comparison of two methods of electrical stimula-tion. J Hand Surg [Br]. 1989; 14: 294-297.

[84] Ritz E, Schoemig M, Massry SG. Uremic myopa-thy, in Textbook of Nephrology, edited by Massry and Glassock, Fourth edition, 2001, 1426-1429

[85] Hung AM, Ikizler TA. Factors determining insulin resistance in chronic hemodialysis patients. Con-trib Nephrol. 2011; 171: 127-134.

[86] Koh KP, Fassett RG, Sharman JE, Coombes JS, Williams AD. Effect of intradialytic versus home-based aerobic exercise training on physical func-tion and vascular parameters in hemodialysis pa-tients: a randomized pilot study. Am J Kidney Dis. 2010; 55: 88-99.

[87] Houmard JA, Tanner CJ, Slentz CA, Duscha BD, McCartney JS, Kraus WE. Effect of the volume and intensity of exercise training on insulin sensi-tivity. J Appl Physiol. 2004; 96: 101-106.

[88] Martin TP, Stein RB, Hoeppner PH, Reid DC. In-fluence of electrical stimulation on the morpho-logical and metabolic properties of paralyzed muscle. J Appl Physiol. 1992; 72: 1401-1406.

[89] Hamada T, Hayashi T, Kimura T, Nakao K, Mori-tani T. Electrical stimulation of human lower ex-tremities enhances energy consumption, carbohy-drate oxidation, and whole body glucose uptake. J Appl Physiol. 2004; 96: 911-916.

[90] Chilibeck PD, Bell G, Jeon J, Weiss CB, Murdoch G, MacLean I, Ryan E, Burnham R. Functional electrical stimulation exercise increases GLUT-1 and GLUT-4 in paralyzed skeletal muscle. Me-tabolism. 1999; 48: 1409-1413.

[91] Nuhr MJ, Pette D, Berger R, Quittan M, Crevenna R, Huelsman M, Wiesinger GF, Moser P, Fialka-Moser V, Pacher R. Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure. Eur Heart J. 2004; 25: 136-143.

[92] Harris S, LeMaitre JP, Mackenzie G, Fox KA, Denvir MA. A randomised study of home-based electrical stimulation of the legs and conventional bicycle exercise training for patients with chronic heart failure. Eur Heart J. 2003; 24: 871-878.

[93] Bourjeily-Habr G, Rochester CL, Palermo F, Sny-der P, Mohsenin V. Randomised controlled trial of

transcutaneous electrical muscle stimulation of the lower extremities in patients with chronic ob-structive pulmonary disease. Thorax. 2002; 57: 1045-1049.

[94] Dobsak P, Homolka P, Svojanovsky J, Reichertova A, Soucek M, Novakova M, Dusek L, Vasku J, Eicher JC, Siegelova J. Intra-dialytic electrostim-ulation of leg extensors may improve exercise tolerance and quality of life in hemodialyzed pa-tients. Artif Organs. 2012; 36: 71-78.

[95] Rose B, Lankisch M, Herder C, Röhrig K, Kempf K, Labrenz S, Hänsler J, Koenig W, Heinemann L, Martin S. Beneficial effects of external muscle stimulation on glycaemic control in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes. 2008; 116: 577-581.

neuromuscular electrostimulation techniques: historical ...€¦ · 3institute of pharmacology and...

Documents