- Untreatable Pain Resulting from Abdominal Cancer: New Hope from Biophysics?

The onset of pancreatic cancer pain is perceived as an essentially pure visceral pain which occurs via activation of mechanoceptors in response to intense stimuli. As the pathological conditions worsen and the tumor invades other structures, its characteristics develop and it takes on the features of visceral-somatic and visceral-neurogenic pain. The fibres that conduct visceral pain - Adelta fibres, conduction velocity (CV) 2.9-14.9 m/s, and C fibres, CV1, 2]. Frequent failure in responding to drug treatment suggests using neurolesive options, in particular neurolithic celiac plexus blockage (NCPB), as an elective choice in the treatment of pancreatic cancer pain [3]. This option is not always feasible and may present risk factors linked to the mode of execution (paraplegia, monoparesis with loss of vescical and anal function, sexual dysfunctions) [4, 5, 6]. Even when the outcome is successful, the neurolesive technique, in any case, requires the prescription of painkillers, mainly opioids, and the effectiveness of the painkiller wears off in time [7, 8, 9]. This type of intense, devastating pain strongly undermines the patient’s will to survive, often leading to a request for euthanasia. It also has a strong effect on the people caring for the patient and has important implications for health care management policies. These problems have been addressed in an analytical approach in which effective solutions were sought with the help of biophysics and bioengineering. During the basic research design phase leading up to the development of "scrambler therapy", one of the criteria selected as significant was that of non-invasiveness in order to respect the patient's dignity and quality of life as far as possible.

Basic Principles of Scrambler Therapy

The pain system, like the entire tegumentary system, is characterized by a high level of information content which forms its essence. Specific receptors, normally subdivided into two classes (mechanoceptors for mechanical stimuli and multimodal receptors for those that respond indifferently to all painful stimuli), are biological elements that are able to convert a chemical, physical or mechanical event into specific pain information. Many substances have the capacity to dynamically modulate the response to pain by sensitizing or desensitizing the receptors and the conduction/processing pathways during the ascending phase. The complex modifications activated by the nervous system in response to a painful stimulus are thus the focus of a wide variety of organic reactions also designed to re-establish conditions of homeostatic equilibrium which the pain information signals as being disturbed or in danger. In most cases, this equilibrium can be rapidly restored thanks to a series of reactions involving much of the biological system as a whole. In this case, pain information, its purpose achieved, returns to a silent state. However, there are situations in which this has not happened, either due to the impossibility of removing the cause of the biological damage or due to intrinsic damage to the pain system itself (neuropathies) as a result of damage due to compression of the nerve fibres. In such a context, the onset of very extensive, complex reactions may be observed, themselves capable of modifying the original information triggering the pain phenomenon (sensitization-autonomization), thus setting up an iterative process which, in the case of chronic pain, and of neuropathic and visceral pain in particular, tends to render all known therapeutic strategies gradually (or completely) ineffective. The useful fact that emerges from all these scenarios is the central role of control exerted by information over the chemical-structural variations of the system. I mention en passant the fact that by information we mean the measurable and mathematical expressible component of a news item or rather the measurable elimination of the uncertainty of an arbitrary event. In this case, information is represented by the sequence of pulses generated by the activated nociceptor, pulses that "describe" the type of pain, attributing to it specific properties such as, for example, the intensity or the type of sensation experienced. Overall, this represents a good description of a cybernetic process, that is, one of communication (pain information) and regulation (chemical feedback to modify perception and adaptive reactions). It may thus be reasonably assumed that it is possible to control the lower levels of the complexity of the pain system (the chemical reactions regulating the coding of pain information and subsequent feedback) by manipulating the "information" variable alone at higher levels of complexity. An arbitrary system level must, in this case, be such as to be able to make up for the incomplete knowledge characterizing the role of the chemical molecules involved in the pain phenomenon, which may conveniently be represented by means of the "black box technique". This involves using a model in which the input and the output are known but not the internal translation process taking place inside the "box". It must also take place at a stage at which information expression is sufficiently "visible" for it to be investigated analytically and be interpreted univocally. For it to be treated easily enough using comparatively inexpensive technology in order to develop the method, this information content has been defined and investigated at the level of complexity (emerging properties different from the individual variables interacting in this particular state of the system) expressed by the biopotentials generated by the receptors depending on the nociceptive stimulus. A brief parenthesis must be opened at this point. There is a general tendency to accept that the coding of nociceptive stimulus intensity as an equivalent pain sensation is expressed simply by an equivalent variation in the mean receptor discharge frequency, in other words a "frequency modulation". We also know that it is possible to excite a nerve fibre electrically by "synrchonizing" it with the frequency of our generator. Theoretically, therefore, if the generic coding by means of which a receptor transforms the stimulus to which it responds into information, a simple variable frequency generator would be sufficient to successfully simulate and evoke many different types of perception. However, we know that this is not true. In fact, frequency is only one of the aspects which adds information properties to the sequence of pain pulse, just as the same note on a musical instrument can be univocally identified by its frequency. However, we can all easily distinguish the same note played on a piano and on a saxophone or electronic instrument; the information for the same frequency is thus similar but different. We also know that a few musical notes, depending on the sequence linking them together, can form a large number of different sonorities. Those having a wide range of information content are decoded as music, melody, and as various sub-groups characterizing the genre; the others as noise, that is, the sequence of notes adds different significant properties to the "message" composed depending on how it is structured. A similar problem arose in the analytical study of the pain information. After having thus selected the arbitrary level of the system's complexity, a study was made of the biopotentials representing the pain information by means of their variations, expressed this time not only by the mean frequency but by their dynamic structure when placed in a sequence. In practice, the mean frequency was not considered as the mere product of biological tolerance or receptor stress but more realistically as an epiphenomenon of the "information procedure" triggered by the single pulse components generated by the receptor (which then go to make up the mean frequency), together with the sequential relationship among them. The research procedure adopted therefore allowed a comparatively complex system model to be constructed which could be defined in purely conceptual rather than experimental terms, in which the biological variables were translated into cybernetic variables, extrapolating the role and the modality of the pain information regardless of the biochemical aspects and its etiopathogenesis, using systems theory and information theory to rationalize the research procedures. The hypothesis of operating by blocking nervous transmission was immediately rejected although it is actually one of the more commonly adopted solutions. By its very nature, the nervous system reacts to and processes information. Theoretically, the absence of information can only increase the entropy (information disorder) [10] of the channel involved, and very probably will produce adaptive reactions increasing the sensitivity to the painful stimulus. The approach actually adopted to respect the initial theoretical criteria (use of information as the active principle) was to replace the "pain" information with artificial "non-pain" information, in full respect of the information theory, to which the reader is referred to for further information. Essentially, an artificial neuron was developed that behaves as a "pain scramble", that is, as a system capable of interfering with pain signal transmission by "mixing" another signal into the transmission channel (the nerve fibres) for the purpose of masking the original information by modifying its content (from pain to non pain), although still allowing it to be recognized as "self" by the nervous system. The process is outlined in Figure 1.

Note should be taken of the many similarities but also of the important differences as compared to traditional scrambler techniques, used mainly to "protect" confidential information from possible interception during the transmission, with conversion back to the original signal on reception. In our specific case, the ultimate aim is obviously different, and there are additional conditions and aims to be respected in view of the particular type of application involved. In this sense, it is significant that the information produced by the "mixing" is not just any kind of information but has the property of being recognized, as far as possible, as "self" and as non-pain. Otherwise, the system would be totally ineffective. These conditions were obtained by simulating sequences of biopotentials artificially generated by digital synthesis and having the following characteristics.

Compatibility with the Transmitting and Receiving Channel

Construction of a set of wave forms (basic coding) which, when assembled in real time by means of suitable control algorithms, can simulate as exactly as possible the geometric trend specific to endogenous biopotentials.

Compatibility of the Information Content

Dynamic generation using artificial neurons of "packets" (strings) of information recognized as "non pain", the content of which is varied over time by means of suitable algorithms used to recognize the simulated signal as "self" and to reduce the adaptation of the perception as a function of the noise, and the amplitude of which is such that it may be decoded as the dominant stimulus by means of the over-modulation of the endogenous biopotentials. The latter condition has given rise to the theoretical expectation of a favorable readaptation of algogenic sensitivity. It is hypothesized that the learning mechanism of the pain system, now "remodelled" to suit the non-pain scrambler information as a result of the well known adaptive properties that lead to a sensitization to intense and frequent pain stimuli, results in a gradual raising of the subjective pain threshold.

Global Optimization of the Simulation with the Characteristics of the Biological System

Increased compatibility of the simulated signal with the nervous system with the inclusion of the noise figure of the nervous transmission network in the principal information during simulation of the stochastic fluctuation.

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