Why Some Patients Require High Dose Opioid Therapy

Chronic pain syndrome represents the end stage of maladaption of having pain as the stressor and, as a result, homeostasis is severely disturbed in all aspects—with abnormal default settings for emotions, immunity, hormone balance, thought, and memory.
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Years ago, I observed that some chronic pain patients required very high opioid dosage to control their pain and live a meaningful life. Other patients with similar injuries required only low dosages of opioids, or even none at all. To explain this phenomenon, I have reviewed as much relevant literature as I could find. I’ve come to some conclusions as to why some chronic pain patients require ultra high opioid dosages—even in the absence of CYP450 chromosome metabolic abnormalities—and I present my findings in this editorial. Fundamentally, unabated chronic pain produces an altered nervous system and, once this occurs, it is described as a ‘chronic pain syndrome.’ I believe that opioid treatment of this syndrome is actually more directed to the altered nervous system than to the peripheral nerve injury that initiated the alteration.

Pain Causes an Altered Nervous System

This article is a synopsis of the prevailing literature giving an oversight of chronic pain. The literature indicates that unabated chronic pain eventually results in a genetically-altered pain-related nervous system (PRNS).1-3 This alteration is characterized by a vicious cycle of pain.4-6 Immediate Early Genes (IEG), described in a subsequent section, play a role in this restructuring.1-3,7,8 In this restructuring process, the homeostatic activity of the hypothalamus is perturbed, affecting the production and activity of pro-opiomelanocortin, a prohormone which connects the PRNS with the immune system, the endocrine system, and the energy system, resulting in impairment of these systems.4,9 The PRNS includes central nervous system (CNS) components involved with memory (hippocampus), emotion (amygdala), cognitive function (frontal cortex), and proprioception (sensory cortex), all of which become perturbed.10 Degeneration of the pain modulating pathways leads to the need for uncommonly large doses of medication.11-14

Description of Pain

Pain is a phenomenon resulting from the interaction of two major components of the central nervous system. One is the sensory component (SC); the other is the interpretive component (IC). Together, I call this combination the “pain-related nervous system” (PRNS). Each component has afferent neurons traveling centrally and efferent neurons traveling peripherally.10,15 The sensory component brings messages to the interpretive component to be interpreted. We like to call the interpretation the feeling of pain. Many factors go into each of these two components.

Figure 1. Comparative Pain Scale for different individuals; a stimulus that produces level 10 pain for person E, may produce only a level 3 pain for person A.

The sensory component includes both the peripheral and central nervous systems. It is composed of pathways emanating from the somatic and visceral components of the body traveling from the periphery to the cerebral cortex, and from the cerebral cortex to the periphery. The somatic source for the pain message includes bone, muscle, skin, connective tissue, etc. The visceral source includes the internal organs, blood vessels, and nervous tissues. The sensory component can be activated anywhere along its path—viz., from the tip of a toe to the top of the brain.

The interpretive component involves memory, thought, emotion, beliefs, likes, and dislikes. Thus we have a wide range of interpretations of sensory input. Some people enjoy pain, some people hate pain. If the message is interpreted as pain, and disliked, then the interpretive component tries to stop the message. Failure to stop the message results in continual pain. Most people can tolerate some degree of pain. But to what degree? How do we measure the degree of pain?

Usually a scale of 0 to 10 (where “0” indicates no pain and “10” indicates severe pain) is used clinically to measure the degree of pain, but this measure can vary from person to person (see Figures 1 and 2). Each individual has a different scale and it may vary with time and place.

Initiation of the Altered Nervous System

A common painful experience begins with a somatic injury, say a ruptured lumbar disc. There is an immediate response and a delayed response to such a stressful event. The immediate response, the so-called “Alarm Stage,” was de-scribed by Nobel Laureate Hans Selye in the 1950s as the first component of what became known as the General Adaptation Syndrome (GAS) with, in this case, pain as the stressor. The immediate response is instigated by nociceptors, neurons of the sensory component of pain. They are activated at the site of injury by physical and chemical changes, and carry the message to the spinal cord where a reflex response is initiated. The reflex action of neurons in the spinal cord includes neurons of the sympathetic system resulting in the direct stimulation of the adrenal medulla to release epinephrine and, indirectly, through the hypothalamic-pituitary-axis (HPA) to release pro-opio-melanocortin (POMC). This ultimately causes the release of cortisol from the adrenal cortex and beta-endorphin (the body’s own “morphine”) from the pituitary to help the body withstand the initial impact of pain. The body goes into what Walter Cannon, in the 1920s, called the “flight or fight” mode, and later called the “Alarm Stage” by Hans Selye. Hippocrates probably had a similar name for it.4,9,17-19

After the initial alarm, the body passes shortly (i.e., within seconds to days) into the Adaptation Stage, the second of the three stages of the General Adaptation Syndrome. This is a much longer stage. In the case of pain as the stressor, the transition begins within minutes of the injury and may last three to six months if the pain is unabated. One of the early events is the initiation of genetic changes brought about by the Immediate Early Genes—c-fos, c-jun, c-zif, etc.—which appear throughout the sensory component of the pain related nervous system and begin to modify it. Pro-opiomelanocortin, which is released from the pituitary and is also present in peripheral tissues, is fractioned into its components influencing stress (ACTH), pain (beta-endorphin), energy (alpha-MSH), and the immune system (ACTH, alpha-MSH).1-4,17,20

Genetic Reprogramming by Immediate Early Genes

A word about genetics and the Immediate Early Genes. Human conception combines 23 chromosomes from each parent, the total comprising about 20,000 genes in the adult. This is the “genome.” Not all genes in the genome are active. Those that are active comprise the “phenome.” The PRNS has its set of active genes which maintain it, the PRNS phenome. Within the set of inactive genes there is a set that can be activated when called upon. These are called the Immediate Early Genes. In this case—at the beckoning of glutamate—the neurotransmitter involved in carrying the pain message across synaptic junctions on its way to the interpretive component of the PRNS—are called into duty to change the pain phenome. When glutamate appears in excess, as it does with persistent painful stimulation, it becomes toxic and initiates the attempt to adapt by initiating the Adaptation Stage.2,3,8,17,21

First published on: July 1, 2010