This section examines the fundamentals of electrical pain relief methods in order to establish current accepted and recognised parameters of electro-stimulation and treatment as described in the literature. This is necessary because of the confusion, which often surrounds these aspects of electrostimulation, in order that the research studies to be presented later in this thesis are based on sound, and accepted clinical electrical treatments, which in turn are based on recognised and adequately researched electrical parameters.

3.5.1 Pain control by electrical methods

There have been two recent review papers examining both transcutaneous electrical nerve stimulation and electroacupuncture. The first deals with transcutaneous electrical stimulation, which was reintroduced into medical and complementary practice in the early 1970's. Since that time, numerous studies, both controlled and uncontrolled, have suggested its utility for the treatment of pain related to acute musculoskeletal injury, postoperative pain, pain of peripheral vascular origin, pain of myocardial ischaemia and chronic pain of a variety of causes. Pain of labour in delivery was affected equivocally. Pain complicating cancer has not been reliably relieved to date. A small number of controlled studies failed to demonstrate benefit, but the preponderance of evidence suggests that electrical stimulation of the peripheral nervous system is a useful adjunct in the management of many pain states. Most studies indicate that the resultant analgesia of TENS is not opioid-dependent. Pain threshold and perception both appear to be reduced. The physiological mechanism by which pain is affected is not defined in this paper; but local neural blockade, branch block in the dorsal horn and activation of a central inhibitory system have all been postulated (Long 1991).

The second review considered the serious basic research on electroacupuncture, which began in 1976 following the acupuncture endorphin hypothesis. There was an enormous amount of rigorous research into these mechanisms and these studies are comprehensively examined up to 1988 by Pomeranz and Stux (and other contributors), concluding with the observation that 'we now know more about acupuncture analgesia mechanisms than many conventional medical procedures' (Pomeranz and Stux 1989). This review has recently been updated and will be discussed in some detail in the following text (Stux and Pomeranz 1995).

3.5.2 Therapeutic Currents

Research in the 1980's by Prof. Jisheng Han, using a western approach rather than a Traditional Chinese Medicine Model, at Beijing Medical University in China, showed that electroacupuncture at 4pps (pulses per second) releases enkephalins while at 100pps dynorphins were released, he used antibodies to enkephalins injected intrathecally into the spinal cord of rats to block acupuncture analgesia produced by 4pps, with antibodies to dynorphins blocking 100 pps analgesia (Han 1989). Han concluded that low-frequency EAP depends on the release of Beta-endorphin in the brain and Met-enkephalin in the spinal cord, whereas high-frequency EAP analgesia is mediated by dynorphins in the spinal cord. Recent research by Richard Cheng in Toronto Canada has also shown that 4pps work through the endorphin mechanisms, while 200pps stimulation is mediated by the monoamines, serotonin, and norepinephrine (Cheng 1989). Some pulse generators use trains of pulses i.e. bursts instead of continuous pulses, with an internal frequency of say 200 pps and a repetition rate of 1 pps. In this way both endorphins at 1 pps and serotonin at 200 pps can be released. However to achieve De Qi, the dull aching sensation preferred by Traditional Acupuncturists, it is necessary to simulate strongly at 1-4 pps in continuous mode. This strong stimulation appears necessary to release cortisone and endorphins via activation of type III efferents. De Qi is a mild, pleasant, ache, which is easily tolerated by most patients. There is very little danger from this type of electrostimulation as the units are battery operated and use currents well below the levels which can affect the heart. However, patients with on demand pacemakers should not normally be treated and stimulation over the front neck region should be avoided to prevent laryngospasm (Stux and Pomeranz 1995).

3.5.3 Electrical Equipment

There are numerous electrostimulation units available today of variable design and efficacy. A biphasic generator is usually recommended for electroacupuncture and TENS, i.e. a negative pulse followed by a positive pulse or vice versa is generated by the unit, this reduces polarisation of each needle due to electrolysis. The negative pulse cleans the electrode of electrolytes deposited by the preceding positive pulse and if the pulses are perfectly biphasic (symmetrical biphasic pulses), then the net DC current is zero and no polarisation occurs. Polarisation raises the electrode resistance over time, thus reducing the intensity of stimulation, and creates a tendency for the needles to break off in the tissue (Stux and Pomeranz 1995). Since negative pulses cause an action potential on the nerve, it is important that both needles in a pair receive negative pulses, which is only possible in a biphasic stimulator (Stux and Pomeranz 1991). The intensity of stimulation is under the control of an intensity knob, and in order to achieve an optimum effect for acupuncture analgesia, the strongest tolerable intensity is required for De Qi to activate type II and III muscle nerves (Stux and Pomeranz 1995). To achieve De Qi from type III nerves usually requires stimulus intensities 5 to 10 times threshold levels for muscle contraction i.e. 25-50V, 2.5-5ma, at a pulse width of 0.1ms. The pulse width is usually variable between 0.1 and 1.0ms. Another critical parameter is the pulse frequency usually expressed as pps (pulses per second) or as Hertz or Hz. In ancient China the needles were often manipulated with a rhythm of 2-4 pps (Stux and Pomeranz 1995).

3.5.4 Physiological Responses

In ancient times in order to stimulate the nerves the acupuncture needle was manipulated in and out to create 'De Qi', a deep aching sensation, with fullness, tingling, and numbness (Stux and Pomeranz 1991/95). Stimulation of high threshold muscle sensory nerves (type II and III efferents) appears to be the basis of acupuncture analgesia (AA). Neural messages are sent to the brain (or spinal cord) where neurochemicals and hormones are released. However the breakthrough came in 1976, soon after the discovery of endorphins. Two groups, one studying human volunteers (Mayer 1977), the other working on animals (Pomeranz and Chiu 1976) showed that Naloxone (an endorphin antagonist) blocked AA. The acupuncture-endorphin hypothesis, which emerged, proposed that AA is a result of peripheral nerve stimulation, which sends impulses to the brain to release endorphins and causes analgesia. This hypothesis, more than any other, has stimulated research in dozens of laboratories on 4 continents (Pomeranz and Stux 1988). Prof. Bruce Pomeranz laboratory was one of the first to show that acupuncture was mediated by endorphins. He began his work with spinal cord experiments in anaesthetised animals. Recording from single cells involved in nociceptive transmission from spinal cord to brain he showed that electroacupuncture analgesia blocked the message and that this effect was prevented by Naloxone, the endorphin antagonist. In another series of experiments he showed that intrathecal naltrexone only blocked when injected before acupuncture treatment began, but could not block analgesia if given after completion of the acupuncture treatment (Pomeranz and Stux 1988).

Professor Le Bars's (1979/89) group in Paris showed that pain in one part of the body inhibits pain responses in another part. When observed on spinal cord dorsal horn wide dynamic range neurons this effect was called DNIC (diffuse noxious inhibitory control) when observed in rats, or with flexor withdrawal reflexes in humans they called it 'counterirritation'. Whether or not DNIC is a model for acupuncture however is unclear, as unmyelinated 'C' fibres are activated for the conditioning stimulus, whereas acupuncture generally activates myelinated 'A-delta' and Type III muscle afferents. The De Qi sensations produced by acupuncture being a mild ache and not frank pain. Also the time course of DNIC is a matter of controversy; it shows a rapid onset and short after-effect, starting immediately and lasting only several minutes after conditioning stimulus ends. Acupuncture has a much longer induction time and after-effect taking 5-30 minutes to get going, and outlasting the treatment by 20 minutes to several hours (Pomeranz and Stux 1988). The counterirritation experiments conducted in humans had a much more appropriate time course for a model of acupuncture than the DNIC experiments in rats. Moreover, the human experiments were very convincing because of the elegant correlation of flexor reflex suppression (measured by sural evoked reflex EMGs from biceps femoris) and psychophysical measures of sensory analgesia produced by counterirritation. The subjects dipped their arm into hot water (above 45º C) for several minutes to produce counterirritation. This produced analgesia, which had after-effects lasting 10-15 minutes. The effect was blocked by Naloxone (pretreatment), and was absent in paraplegic patients (Pomeranz and Stux 1988). Professor Ulett's (1989) work showed that acupuncture is as effective as morphine or hypnosis in suppressing pain in human volunteers. Since hypnotic susceptibility did not correlate with acupuncture success rate, the two are not the same phenomena (a result confirmed by others using Naloxone antagonists which block acupuncture but not hypnotic analgesia (Pomeranz and Stux 1988). Altogether one can conclude that low-frequency electroacupuncture analgesia depends on the release of beta-endorphins in the brain and met-enkephalins in the spinal cord, whereas high-frequency analgesia is mediated by dynorphins in the spinal cord (Han 1989).

3.5.5 Methods of Administration

The most popular methods of electrical treatment at this time are electroacupuncture and conventional and acupuncture-like transcutaneous electrical nerve stimulation and these modes of application are considered as follows and summarized in Figure IX:

1. Electroacupuncture (EAP): in 1958 when the Chinese were developing methods of acupuncture for surgical anaesthesia, which necessitated long periods of manual manipulation, it was found to be more effective to stimulate the needles electrically by attaching flexible wires, via small crocodile clips, to the needles from a pulse generator. Electroacupuncture was reborn (see 3.2) and later introduced into clinical practice on a more general basis for the treatment of pain and neurological disorders. Usually 4-8 needles can be stimulated at one time via parallel channels on the stimulator. One pair of needles inserted into an acupuncture point, wires and a pulse generator outlet is required to complete one circuit. Pulses of electricity are applied to the needles in order to stimulate nerves via the acupuncture point. In order to achieve an optimum effect for EAP, the strongest tolerable intensity is recommended by Pomeranz (1991) for De Qi.
   
   
2. Acupuncture-like Tens (ALTENS): is a treatment mode given without the use of needles using low-frequency, high intensity treatment currents. Small flexible electrode pads consisting of electroconductive carbon-filled vinyl sheets (as supplied with conventional TENS units) are applied to the skin over an acupuncture point. The electric current is then applied until the nerves are activated transcutaneously. A much higher current/voltage is required than with EAP because of the greater surface area of the electrodes and the greater intact skin resistance. ALTENS is a safer treatment modality eliminating the risks of infection, bruising, organ damage and pneumothorax, needle breakage's, fear of needles, etc. There are few disadvantages to this mode of treatment provided a suitable biphasic unit is used such as the Equinox or VTENS machines. Body or ear punctate treatments are best performed with a suitable point stimulator such as the 'Solitens/Stimplus II' unit but they can be carried out with the above treatment units using the crocodile clip as the electrode.
   
   
3. Conventional TENS: conventional TENS is based on similar units, but these are often monophasic or asymmetrical biphasic as described above, but using a much higher frequency range i.e. 50-200 pps and more and at a low intensity, therapeutically, pain relief is by activation of low-threshold cutaneous afferents (type I and A beta) and is based on the Gate Theory of pain. This form of pain relief starts within a few moments of TENS stimulation and usually disappears within a few seconds of switching the machine off. Hence, TENS must be used for long periods throughout the day to obtain sustained relief. Conventional TENS is mainly segmental in nature and does not appear to involve pituitary mechanisms. In conclusion, ALTENS appears superior to conventional TENS (and many practitioners consider it superior to EAP) because it produces prolonged analgesia, has very few side effects, only requires a 30 minute session once a day or once/twice a week for maximum therapeutic effects. The major differences between conventional TENS and acupuncture-like ALTENS is summarized in the following Figure IX (after Stux and Pomeranz 1995).

3.5.6 Treatment Parameters

Research on animals and human volunteers shows that it takes 20-30 minutes for endorphinergic analgesia to build up, and typically the preparation for surgical 'anaesthesia' takes 30 minutes of stimulation (Stux and Pomeranz 1995). This parameter is reflected in the average clinic treatment time of 25-30 minutes. If one is treating according to traditional Chinese medicine, EAP intensities should be determined by the requirement to sedate or to tonify. When sedating high intensity low frequency stimulation is used to achieve De Qi; when tonifying low intensity stimulation (just above threshold) and a higher frequency are used (Stux and Pomeranz 1995). Generally, pain therapy requires sedation at frequencies below 10 pps, usually less than 3pps, but in some patients who are debilitated by chronic pain, tonification above 10 pps may be indicated or a pulse burst mode stimulation at 1 burst per second, with an internal frequency above 10pps and up to 200 or more. In clinical practice it is also popular to use EAP and ALTENS at alternating frequencies of 2 and 15 or 2 and 100 pps or as a pulse burst mode. In this case, both enkephalins, and/or endorphins, as well as dynorphins are released. Clinical experience indicates that the best analgesic effect of electroacupuncture can be obtained when two frequencies (low and high) shift automatically. It also fits well with the synergism between the analgesic effect of met-enkephalins (released by low-frequency) and dynorphins (released by high-frequency electroacupuncture) (Han 1989).

Following on from and in support of the above are the following study descriptions. The first of which describes a randomised placebo controlled trial of the analgesic effect of electroacupuncture, which was compared to that of placebo electroacupuncture, using low frequency high intensity transcutaneous electrical nerve stimulation, in 14 patients with chronic non-cancer pain. Patients underwent six randomly assigned treatment sessions, each lasting 20 minutes, at least 48 hours apart: two sessions of classical acupuncture, two sessions of placebo electroacupuncture using non-acupuncture points, and two sessions using surface electrodes placed over painful sites. For all sessions, current was set just above pain threshold, at a pulse width of 200ms and a pulse rate of 2Hz. Pain ratings were determined before and immediately after stimulation and at intervals during the subsequent 48 hours. Five of the 14 patients demonstrated significant improvement in pain with all three types of stimulation. There was no significant difference in the degree or duration of analgesia achieved among the three modalities, suggesting that classical electroacupuncture is no more effective than other forms of low frequency high intensity stimulation (Abram 1983). These findings, from nearly fifteen years ago, also support the current trend towards the practice of electro-stimulation using surface electrodes rather than needles and which is now known as acupuncture-like TENS. The thesis author, in his placebo controlled randomised trial described in section 3.6, also used this mode of electro-stimulation.

Secondly, recent studies in anaesthetised rats, show that two successive acupuncture treatments given for 15 minutes (or preferably for 25-30 minutes) 90 minutes apart cause a potentiation of acupuncture analgesia. Moreover, naltrexone blocks the AA only if given prior to the first acupuncture treatment. This suggests that the first endorphin effect modulates the synapses so that the second AA (which need not be endorphinergic) is more powerful. This cumulative AA effect of repeated acupuncture treatments has been known for years anecdotally, but has been recently documented clinically (Price 1984). Hence unlike conventional TENS which must be used continuously because of transient effects, acupuncture and acupuncture like-TENS, need only be given 30 minutes a day because of prolonged after-effects, and the cumulative build-up of potentiation from repeated treatments (Pomeranz 1989). One possible explanation for the prolonged benefit stemming from this protocol could be that acupuncture releases ACTH along with the pituitary endorphins. In a study in awake horses, elevated blood cortisol levels were measured after true acupuncture, but no change observed after sham needling. The latter ruled out the possibility that stress was the mediating factor. Perhaps the cortisol produces anti-inflammatory effects in chronic pain due to arthritis, and thus produces 'cures'. Another possibility is that the cumulative endorphin effects may permanently change the pain circuits (Pomeranz 1989).

3.5.7 Discussion

In addition to the lack of a plausible mechanism to explain acupuncture analgesia, sceptics were concerned about the anecdotal nature of acupuncture and electro-acupuncture claims. Despite the huge size of the anecdotal database (one quarter of the world's population had been using acupuncture for 2500 years for pain and other non-painful applications) sceptics were calling for controlled clinical studies to prove the efficacy of acupuncture (Pomeranz and Stux 1988). A growing body of research published in the last 20 years shows that acupuncture analgesia (AA) is very effective in treating chronic pain, helping from 55% to 85% of patients (Lewith 1982; Richardson and Vincent 1986: Vincent and Richardson 1986), which compares favourably with drugs. Moreover the evidence shows that in placebo control groups only 30% of cases were helped, establishing that AA is more effective than placebo and that AA is a real physical effect. In addition to the clinical studies, which demonstrate efficacy, another way to overcome the deep scepticism towards acupuncture was to establish credible physiological mechanisms of action (Pomeranz and Stux 1988). Some writer's note that there are several studies, (at least seven) which failed to observe Naloxone effects on acupuncture analgesia. This is against 28 papers showing Naloxone blockade of acupuncture analgesia. The reasons for the failed Naloxone experiments are not always clear. However, three of the failed Naloxone experiments were observed with high-frequency, low intensity stimulation, whereas in several animal studies it was found that AA-endorphin mechanism operates best with low frequency (4 pps or less) and high intensity stimulation. This has also been confirmed in man. In one of the failed experiments, low frequency, low intensity was employed with an absence of 'De Qi'. The reasons for the remaining failed Naloxone experiments might be a recently discovered feature of endorphinergic analgesia: Opioid antagonists seem to work best when given before the treatment begins and fail to reverse analgesia that has already been initiated (Pomeranz 1989). So it appears from these observations that Naloxone can prevent but cannot reverse acupuncture analgesia.

In the early days following the discovery of endogenous opioids, people were hoping for a new group of analgesics without the drawbacks of morphine, e.g. without tolerance and dependence. These expectations, however, soon vanished since administration of a large amount of synthetic opioid peptides caused tolerance and dependence in a way similar to morphine. If electroacupuncture (and acupuncture-like TENS) releases endogenous opioids to exert an analgesic effect, one would expect that electroacupuncture analgesia also leads to the development of tolerance, when applied continuously or repeatedly with short intervals (Han 1989). Clinical practice, however, does not support this theory.

It is noted that peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitisation and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. Coderre (1993) examined the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain, and assessed the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system in response to noxious peripheral stimulation. They conclude that clinical and experimental evidence suggests that noxious stimuli sensitise central neural structures involved in pain perception e.g. phantom limb pain. An increased understanding of the central changes induced by peripheral injury or noxious stimulation should lead to new and improved clinical treatment for the relief and prevention of pathological pain (Coderre 1993). I would suggest that electroanalgesia in the form of ALTENS may be this new mode of clinical treatment, especially in view of the beneficial effects of reducing or eliminating long standing pathological pain, and the effects of electrostimulation on central neurotransmitters and their role in pain relief.

So in summary, electro-acupuncture and acupuncture-like TENS uses low frequency high intensity stimulation, below 4pps to prevent muscle spasms, to stimulate the production of enkephalins and dynorphin at a segmental level and beta-endorphin, dynorphin and serotonin at non-segmental levels i.e. brain stem and hypothalamus-pituitary. Conventional TENS uses high frequency low intensity stimulation, usually 50-200pps, as this promotes the optimum presynaptic inhibition through the Gate mechanism (presumably using gamma-aminobutyric acid GABA together with some dynorphin release (Han 1991)) and is therefore mainly segmental in nature, not involving pituitary mechanisms. On the whole, acupuncture-like TENS appears superior to conventional TENS (in theory and in everyday practice too) because it produces prolonged analgesia and thus the stimulator does not have to be worn continuously by the patient. Acupuncture-like TENS treatment, in skilled hands, can relieve both acute and chronic pain and is capable of eliminating pain of many years duration. One 30-minute treatment session a day (or even once or twice a week) is sufficient therapy using acupuncture-like TENS for chronic pain. This is similar to the experience with acupuncture analgesia in which prolonged effects are achieved (Stux and Pomeranz 1995).

This section has drawn heavily on the recent and ongoing work of Professor Bruce Pomeranz from Toronto, one of a small number of prominent neuroscientists deeply involved in finding out how acupuncture and electrostimulation in particular works. He recently presented these findings in London, in October 1996, and one of my colleagues David Mayor attended this seminar and he gives a full account of his lectures in a recent paper (Mayor 1997) which also confirms my assessment of the literature as described above.

Having set the scene in the first four sections of this thesis, the final section of this stage is a piece of clinical research, as a pilot study, based on the findings discussed in this section of the thesis. The study takes the form of a randomised placebo controlled trial of electroanalgesia in palliative medicine, using acupuncture-like transcutaneous electrical nerve stimulation.


3.2 Early development in Electroanalgesia
3.3 John Wesley and eighteenth century health care: A history of medicine study
3.4 Mechanisms of pain
3.5 Mechanisms of electrical pain relief
TENS Electrode Placement Chart
EMS Electrode Placement Chart