Detoxification as a primary treatment modality for chronic pain—Part II

Townsend Letter for Doctors and Patients, Feb-March, 2005 by Gina L. Nick

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)