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11 Articles in Volume 10, Issue #6
Assessing Pain of the Pediatric Patient in the Emergency Setting
Testosterone Replacement in Chronic Pain Patients
Why Some Patients Require High Dose Opioid Therapy
Raising Pain Tolerance Using Guided Imagery
Long-Standing Groin Pain in a Male Athlete
FDA’s Proposed Risk Evaluation and Mitigation Strategy (REMS) for Opioids
Platelet Rich Plasma Prolotherapy as First-line Treatment for Meniscal Pathology
Cluster Headache
Effectiveness of Laser and Non-Coherent Light Therapies
Opinion on Preliminary Guidelines for the Clinical Diagnostic Criteria for Fibromyalgia
Doctors May Now Electronically Prescribe Schedule II Drugs

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.

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

Neurotransmission is the carrying of the signal from neuron to neuron. The PRNS has two directions of flow: from central to peripheral (called efferent transmission) and from peripheral to central (called afferent transmission). Neurons connect with one another by special structures called synapses. In the synapse, a chemical flows from one neuron to the next. In the PRNS, afferent transmission of the pain message is carried towards the brain by glutamate. In order for efferent transmission to suppress the pain message the chemical is gamma-amino-butyric acid (GABA). Along the neuron itself the message travels by way of a method utilizing sodium ions resulting in a form of an electric current. When this current reaches the synapse, stored calcium is released causing microfibers to contract and release the neurotransmitter into the synaptic gap, the minute space between neurons. The transmission of the message across the synaptic gap is completed when the receiving neuron’s receptor combines with the neurotransmitter. This sets off an electric current in the next neuron thus continuing the transmission (see Figure 3).10,12

Figure 2A. Functional MRI (fMRI) showing extensive pain-induced brain activation of the primary somatosensory cortex and anterior cingulate cortex in highly sensitive individuals.16 Figure 2B. Functional MRI (fMRI) showing reduced pain-induced brain activation of the primary somatosensory cortex and anterior cingulate cortex in insensitive individuals. Note that the thalamus displayed generally similar activation in both highly sensitive and insensitive individuals.16 Figure 3. Nerve conduction schematic. Figure 4. Transformation of the pain processing system resulting in a vicious cycle of pain.

The Body’s Failure to Adapt

Depending upon the severity of the unabated pain, there is a period of time (usually three to six months) after which the body’s attempt to adapt fails, and the Pain-Related Nervous System reaches its stage of exhaustion—the third stage of the General Adaptation Syndrome (see Figure 4). It now has a new phenome due, in part, to the activity of the Immediate Early Genes that transformed the normal phenome into a diseased phenome.2,3,8

In 1987, genes were discovered to appear at the termination site of the nociceptors in the dorsal horn of the spinal cord. Some of the changes brought about by these genes and glutamate toxicity are known. For example, the common glutamate receptor used by the normal PRNS is AMPA. This is changed to NDMA. The common RNA polymerase, an enzyme involved in reading the genetic code, is RNA polymerase I. This is changed to RNA polymerase II. Thus, the mode of pain signal transmission, and the mode of genetic performance is changed. In the end, a new phenome is established for pain. The pain signal now follows a grossly-abnormal route traveling in a vicious cycle (i.e., “pain causes pain”; see Figure 4).1-6

How this is brought about is unclear. One theory states that substance P, an inflammatory agent produced by neurons, is the cause. It keeps the inflammation alive. Another theory supports the notion that pain is remembered by the process of long-term potentiation—i.e., the way past events are remembered. A third theory claims that it is a result of glial glutamate transport failure, i.e., toxic glutamate is not removed fast enough by the glial cells.2,7,22-26,28

Chronic Pain Syndrome

Chronic Pain Syndrome (CPS) is the state of the PRNS after chronic pain of any nature has changed it into this new state.

“Chronic pain of any nature” means pain arising from the central nervous system itself, such as thalamic pain, phantom limb pain, diabetic neuropathy, herpes zoster, HIV, etc.; somatic/visceral pain such as chronic pelvic pain, neck pain, low back pain, cancer pain, carpal tunnel and cubital tunnel pain; or the arthritides such as rheumatoid arthritis, lupus arthritis, osteoarthritis, psoriatic arthritis, the enthesopathies, tendinosis, surgical failures, etc.. These can all lead to Chronic Pain Syndrome. The physician who treats this syndrome is not treating the condition that precipitated the syndrome—viz., the physician is not treating low back pain—but is treating the change in the nervous system caused by the persistence of pain (see Figure 5).

Clearly this is not the nervous system of someone experiencing acute pain. Treatment therefore can be expected to be different than simply Aspirin, Tylenol, Vicodin, Norco, Percocet, etc.—or even short acting morphine, methadone, oxycodone, or fentanyl. Experience has shown that for best results, this vicious cycle of pain has to be suppressed throughout the 24 hour day. To do this, long-acting opioids have been the most successful. The extended release forms of morphine, oxycodone, fentanyl, or oxymorphone, can be used. Of these, extended release oxycodone, and extended release fentanyl are preferred due to neuronal handling of receptor recycling. Large doses, often appearing extraordinary to those unfamiliar with Chronic Pain Syndrome, are needed and properly timed for success in achieving adequate pain control. This, no doubt, is due in part to the failure in production of the body’s own modulating substances—viz., endorphins. A host of ancillary medications can be used to accompany these opioids. Short acting opioids, antidepressants, anticonvulsants, antianxiety agents, muscle relaxants, somnolents, and laxatives are commonly used.5,11-14


This article, guided by the prevailing literature, presents the view that chronic pain syndrome is a state of the central nervous system in which the pain stimulus and its interpretation persists indefinitely. The differences in individual anatomical (Figure 2), and interpretive aspects (Figure 1) of pain are presented. The pathophysiology of pain is illustrated in Figure 4 with the changes representative of Hans Selye’s findings on the consequences of chronic stress, namely the “General Adaptation Syndrome” with chronic pain syndrome representing the end stage with pain as the stressor. As a result, homeostasis is severely disturbed in all aspects resulting in abnormal default settings for emotions, immunity, hormone balance, thought, and memory. Treating a person in this end stage is extremely difficult. When using medication, large doses are typically needed.

Figure 5. Comparison of brains in fMRI images (courtesy of Northwestern University) show dramatic differences between chronic pain patients and healthy subjects (activation = red-yellow; deactivation = dark/light blue).29

Last updated on: October 1, 2012
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