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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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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