Detoxification as a primary treatment modality for chronic pain

The first article in this series dealt with current understanding of chronic pain and disease mechanisms and accepted treatment modalities. This second and last part discusses current research into pain and inflammation, further explores the role of toxins, both endogenous and environmental, in pain generation, and introduces the concept of employing a detoxification program in order to modulate the chronic pain response.

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Future Directions in Pain Pharmacology
The kallikrein-kinin group of peptides comprise yet another system of metabolic mediators.(1) Its active agent, bradykinin, acts upon two receptors (B1 and B2) to modulate pain, inflammation, vasodilation, vascular permeability and natriuresis. B2 is normally present in sensory neural elements, particularly non-myelinated nerve terminals, sensory ganglions and dorsal layers of the spinal cord. Expression of the B1 receptor gene, generally quiescent in normal tissue, is rapidly induced during certain types of tissue damage by transcription factors such as nuclear factor-[kappa]B and cytokines such as tumor necrosis factor-[alpha] and interleukin 1[beta]. Laboratory animal research has demonstrated powerful changes in pain perception with manipulations of this system. Since B1 is expressed primarily in disease states and since it potentiates nociception, B1 receptor antagonists hold promise for a new class of analgesic drugs.

A word of warning: these systems are all intricately interrelated, so all interventions must proceed on the broadest possible level of understanding. For example, hypertensive drugs, notably ACE inhibitors, also interact with the kallikrein-kinin system, causing the common dry cough and occasionally fatal episodes of angioedema.(1)

Other components of the inflammatory cycle also offer opportunities for pharmacologic intervention. Tumor necrosis factor-[alpha] has already been successfully targeted for rheumatoid arthritis and inflammatory bowel disease. Nuclear factor-[kappa]B (NF-[kappa]B) has also generated considerable attention as an initiator of inflammation. NF-[kappa]B is actually a family of transcription factors that mediate not only immune and inflammatory responses but also neoplastic progression and formation of neuronal synapses. Inhibition of this family, easily accomplished by any of multiple agents, reduces production of downstream proinflammatory prostaglandins and leukotrienes. However, because the NF-[kappa]B system is essential to immune function, specific agents are required to target only its pathologic manifestations.

It should also be noted that NF-[kappa]B regulates transcription of the COX-2 gene. This relationship includes a feedback mechanism that has the potential to increase NF-[kappa]B induced inflammation in the presence of COX-2 inhibition.

The Role of Toxins in Inflammation, Immune Function and Pain
Pain, it has become clear, is inescapably associated with the inflammatory process, so that any approach to pain relief must address the complexities of inflammation and its firmly attached counterpart--immunity. Noxious stimuli of all kinds can initiate and perpetuate the entire process, and the diversity of those stimuli is immense. Furthermore, because the variety of responses is limited, toxic stimuli have at least an additive, and frequently a synergistic, effect on the magnitude and duration of the response elicited. On the other hand, many agents have been identified that are as beneficial as their opposites are detrimental. The bulk of the harmful agents appear to be manmade; most of the purely beneficial agents identified to date occur in the natural environment. Pharmaceuticals, as has been demonstrated, are a mixed blessing.

Toxins, as a general rule, stimulate the immune/inflammatory system. Table 1 offers a list of classes and examples of toxic chemicals recognized for their ability to cause immunosuppression.(2)

A principal mechanism for many toxins is the generation of reactive oxygen species (ROS), also known as "free radicals"--unstable oxygen-containing moieties like hydroxyl (O[H.sup.-]), hypochlorite (O[Cl.sup.-]), superoxide (O2-) peroxide (H2O2) and the hydroxyl radical (OH). But ROS also perform essential functions in the cell. They are formed by macrophages and neutrophils to kill ingested bacteria. The synthesis of thyroxine requires H2O2.(3) Therefore, suppression of ROS by superoxide dismutase, catalase and antioxidants must not be too effective. As always, careful, well-informed balance is the rule.

Exogenous toxins also induce autoimmunity, whereby one's own immune system attacks tissues or organs, which results in functional impairment and inflammation and in most cases the expression of chronic pain. Table 2 provides as partial list of autoimmune conditions related to chronic pain that are associated with exposure to exogenous toxins.

Neurotoxicity as it Relates to Pain and Neurobehavioral Symptoms
Neurotoxic chemical, biologic or physical agents cause adverse functional or structural changes to occur in the nervous system. For example, exposure to endogenous and exogenous toxins can prompt the release of proinflammatory cytokines. At least for localized immune challenges brought about by toxins, this proinflammatory cytokine release leads to activation of peripheral nerves that signal the brain. Activation of a centrifugal pathway occurs, resulting in the activation of microglia and astrocytes within the spinal cord dorsal horn. Neurotransmitters released by the centrifugal pathway combined with neuroexitatory substances released by astrocytes and microglia create an exaggerated pain response. This represents one example of the pathophysiology of pain as it relates to exposure to endogenous and exogenous toxins.(6)

Other neurological responses to toxins, and specifically to environmental toxicants are well documented. Neurotoxicity caused by environmental toxicants in this case refers to all external factors, beyond known chemicals that are present in contaminated air, water and soil. These include foods, radiation, pharmaceutical agents, occupational exposures, and lifestyle factors. Some of these toxicants include compounds such as cadmium, dyes, excitatory amino acids, formaldehyde, glycerol, organophosphates, pyrethroids, ricin, toluene, trichloroethylene and more.(7) Table 3 lists neurobehavioral symptoms caused by at least 25 exogenous chemicals. This data was compiled from clinical reports, epidemiological investigations, and experimental studies.(7)

The immense volume of research into the area of toxic exposure and its effects on the body has generated more complexities than it has resolved and has left us with innumerable pieces to an incomplete puzzle. Fortunately, along the way commonalities and relationships have been revealed that recommend relatively simple but highly effective approaches that are, moreover, generally applicable to the entire range of associated conditions.

Detoxification as a Primary Treatment Modality for Chronic Pain
There is extensive evidence from population studies, supported by laboratory and clinical research, to validate a broad general program of detoxification that includes both minimization of toxin exposure and increases in ingestion of naturally occurring protective products. Certainly the employment of a calorie restricted diet, paired with the use of such foods and herbs as broccoli, milk thistle, cayenne, barley grass, juniper berries, beet root, apple pectin, red clover, and other well-researched modulators of the Human Detoxification System offers a simple and cost effective means of treating chronic pain.(9)

It is important that we realize that any effective approach to comprehensive disease prevention must be "holistic." Each intervention makes an immeasurably small contribution to the overall effect, but interventions are at least additive, and frequently synergistic. In addition to calorie restriction and the daily use of select detoxifying foods, herbs and other nutraceutical agents, they must include adequate exercise, adequate sleep, and stress management. The total will be far greater than the sum of the parts.

ROS and NF-[kappa]B
Because NF[kappa]B is both pathogenic and physiologic, artificial attempts to modulate it pharmacologically are fraught with danger. One approach that promises far greater safety is the approach of using the body's own detoxification mechanisms. Reducing toxins reduces ROS. In turn, pathogenic NF[kappa]B activity is selectively diminished, leaving the physiologic function of this essential system intact.

Nutrigenomics
The other approach to selective NFkB modulation lies at the heart of a radical new direction in therapeutics--trigenomics, nutritional alterations specific for each individual's unique genetic profile and added to toxin-reducing environmental modifications. Enough knowledge is already available to begin specific regimens guided by known individual response patterns. As more is learned of each individual genome, more specific recommendations can be added. Eventually, genomically guided pharmacology will be added to the regimen, but nutrigenomics is now in a position to lead the way.

Conclusion
The advance of civilization will inevitably generate an increasing number of artificial elements in our environment. Many of them are toxic. But there are multiple mechanisms both within us and in the natural world about us to minimize their effects. Although there is far more to be learned than we have already discovered, our understanding to date is sufficient to effect dramatic improvements in our health. Given the present state of knowledge, chronic diseases and chronic pain are best approached with a broad brush, a "holistic" combination of generally applicable and safe measures that address the fundamental commonalities of all chronic conditions--deleterious behavior of the immune/inflammatory mechanisms. Within this framework can be added pharmaceutical and other medical ingredients as they prove worthy.

This two-part article has outlined current understanding and future directions in pain and chronic disease research, identified the relationship between chronic disease states and inflammation, noted a growing realization of the role of both exogenous and endogenous toxins in those chronic conditions, and discussed a safe and simple approach that has already proved able to improve overall health. Furthermore, the foundation has been laid for an entirely new approach to treatment--individual regimens based upon the unique genetic identity of each patient. It is now clear that individual responses to nutrients, medications and other interventions will be predictable when distinct variations in metabolic pathways can be elucidated patient by patient.

Table 1: Classes and Examples of Chemicals Causing Immunologic Changes(2)

Class Examples

Polyhalogenated aromatic hydrocarbons TCDD, PBBs, PCDF, PCBs, hexachlorobenzene

Metals Lead, calcium, arsenic, methyl mercury

Aromatic hydrocarbons (solvents) Benezene, toluene

Polycyclic aromatic hydrocarbons DMBA, B[a]P, MCA

Pesticides Trimethyl phosphorothioate, carbofuran, chlordane, malathion

Organotins TBTO

Aromatic amines Benzidene, acetyl aminofluorene

Oxidant gases Nitrogen dioxide, ozone, sulfur, dioxide

Particles Silica, asbestos

Natural products Selected vitamins, antibiotics, vinca alkaloids, estrogen, plant alkaloids, mycotoxins

Drugs of abuse Ethanol, cannabinoids, cocaine, opioids

Therapeutic drugs Diphenylhydantoin, lithium

Others Nitrosamine, BHA

Abbreviations: TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; PBBs, polybrominated biphenyls; PCDF, polychlorinated dibenzofuran; PCBs, polychlorinated biphenyls; DMBA, dimethylbenzanthracene; B[a]P, benzo[a]pyrene; MCA, methylcholanthrene; TBTO, bis(tris-n-butylin) oxide; BHA, butylated hydroxyanisole.
Source: National Research Council (1996).(2)

Table 2: Autoimmune Disease Related to Specific Xenobiotic Exposure with Some Annual Incidence

Disease Substance

Systemic lupus erythematosus Pharmaceuticals, hydrazine, tartrazine, alfalfa sprouts

Autoimmune hemolytic anemia Pharmaceuticals

Myasthenia gravis Penicillamine

Pemphigus Penicillamine, pyrithioxine, [alpha]-mercaptopropionylglycine, captopril

Glomerulonephritis Pharmaceuticals, heavy metals (mercury, cadmium, gold)

Autoimmune thyroid disease Polybrominated biphenyl, polychlorinated biphenyl, lithium, penicillamine, amiodarone

Autoimmune hepatitis A-Methyldopa, oxyphenisatin, halothane

Scleroderma Vinyl chloride, silica dust

Source: Bigazzi (1988)4 and Wyngaarden and Smith (1988).(5)

Table 3: Human and Animal Neurobehavioral Effects Attributed to at Least 25 Chemicals

Effect # Chemicals or Chemical Groups Producing Effect

Motor

Activity changes 32

Ataxia 89

Convulsions 183

Incoordination, unsteadiness, clumsiness 62

Paralysis 75

Pupil changes 31

Reflex abnormalities 54

Tremor, twitching 177

Weakness 179

Sensory

Auditory disorders 37

Equilibrium changes 135

Olfaction disorders 37

Pain 47

Pain disorders 64

Tactile disorders 77

Vision disorders 121

Cognitive

Confusion 34

Memory Problems 33<
Speech impairment 28

Affective or personality

Apathy, languor lassitude, lethargy, listlessness 30

Delirium 26

Depression 40

Excitability 58

Hallucination 25

Irritability 39

Nervousness, tension 29

Restlessness 31

Sleep disturbances 119

General

Anorexia 158

Autonomic dysfunction 26

Cholinesterase inhibition 64

CNS depression 131

Fatigue 87

Narcosis, stupor 125

Peripheral neuropathy 67

Source: Anger (1986)(8)