Law of Pain: The Prior Theories – We are proposing a unifying theory or law of pain, which states: The origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters.
Abstract
We are proposing a unifying theory or law of pain, which states: The origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. We are proposing a re-classification and treatment of pain syndromes based upon their inflammatory profile. Treatment of pain syndromes should be based on these principles:
- Determination of the inflammatory profile of the pain syndrome
- Inhibition or suppression of production of the appropriate inflammatory mediators e.g. with inflammatory mediator blockers or surgical intervention where appropriate
- Inhibition or suppression of neuronal afferent and efferent (motor) transmission e.g. with anti-seizure drugs or local anesthetic blocks
- Modulation of neuronal transmission e.g. with opioid medication
At the L.A. Pain Clinic, we have successfully treated a variety of pain syndromes by utilizing these principles. This theory of the biochemical origin of pain is compatible with, inclusive of, and unifies existing theories and knowledge of the mechanism of pain including the gate control theory, and theories of pre-emptive analgesia, windup and central sensitization.
Keywords: inflammation, cytokine, interleukin 1 beta, tumor necrosis factor alpha, sympathetic nerve block, sympathectomy, lumbar block, stellate ganglion, non-steroidal anti-inflammatory drugs (NSAIDs), Steroid, Etanercept, Anakinra, Oxcarbazepine, Ketamine, arthritis, migraine, Complex Regional Pain Syndrome (CRPS), Reflex Sympathetic Dystrophy (RSD), back pain, neck pain, herniated disks, migraine, Fibromyalgia, Interstitial cystitis, Neuropathic pain, Post-stroke pain
Description of the Prior Theories
The prior theories do not contain any unifying Law of Pain. Each disease entity e.g. fibromyalgia, Complex Regional Pain Syndrome/Reflex Sympathetic Dystrophy (RSD/CRPS), carpal tunnel syndrome, rheumatoid arthritis and ankylosing spondylitis is considered distinct from the other entities and is classified in terms of symptomatology, structural pathology, genetic markers, presence of autoantibodies e.t.c. The prior theories assign a different mechanism to nociceptive and neuropathic pain, a different mechanism to acute and chronic pain, and a different mechanism to peripheral and central pain. The prior theories result in a treatment of pain syndromes that focuses mainly on structural pathology. Where present, treatment of inflammation in these disease entities has hitherto addressed one biochemical mediator of inflammation at a time (mostly focused on prostaglandin), instead of addressing the inflammatory soup of biochemical mediators that are present in all pain syndromes.
Four centuries ago Descartes described pain in terms of an alarm bell ringing in a bell tower. In 1898, in his landmark work, The Integrative Action of the Nervous System[1], the British physiologist, Sir Charles Scott Sherrington, proposed the key concept of nociception: pain as the evolved response to a potentially harmful, “noxious” stimulus.. Livingston wrote in his Pain Mechanisms [2]: “I believe that the concept of ‘specificity’ in the narrow sense in which it is sometimes used has led away from a true perspective. Pain is a sensory experience that is subjective and inpidual; it frequently exceeds its protective function and becomes destructive. The impulses, which subserve it, are not pain, but merely a part of its underlying and alterable physical mechanisms. The specificity of function of neuron units cannot be safely transposed into terms of sensory experience. A chronic irritation of sensory nerves may initiate clinical states that are characterized by pain and a spreading disturbance of function in both somatic and visceral structures. If such disturbances are permitted to continue, profound and perhaps unalterable organic changes may result in the affected part. A vicious circle is thus created[3].
In 1942 Paul Sudeck suggested that the signs and symptoms of RSD/CRPS including sympathetic hyperactivity might be provoked by an exaggerated inflammatory response to injury or operation of an extremity. His theory found no followers, as many doctors incorrectly believe that RSD/CRPS is solely initiated by a hyperactive sympathetic system.
In 1965, collaboration between Canadian psychologist Ronald Melzack and British physiologist Patrick Wall produced the gate control theory. Their paper, “Pain Mechanisms: A New Theory,[4] has previously been described as “the most influential ever written in the field of pain. ” Melzack and Wall suggested a gating mechanism within the spinal cord (substantia gelatinosa of the dorsal horns) that closed in response to normal stimulation of the fast conducting A-beta “touch” nerve fibers; but opened when the slow conducting C “pain” fibers transmitted a high volume and intensity of sensory signals. The gate could be closed again if these signals were countered by renewed stimulation of the large fibers. By opening or closing in varying degrees, the neural gate modulates incoming pain signals before they reach the brain. The opening and closing of the gate is determined by the amount of activity in the pain fibers, the amount of activity in other peripheral fibers, activity of descending inhibitory pathways from neurons in the brainstem and cortex. In summary, the Gate Theory proposed that small (C) fibres activated excitatory systems that excited output cells—these latter cells had their activity controlled by the balance of large-fibre (A-beta) mediated inhibitions and were under the control of descending systems. Wall went on to add to and refine the theory to include changes in afferents, prolonged central excitability, and changes in these systems after nerve damage. The concepts of convergence and modulation espoused by the Gate Control Theory reduced the emphasis on destruction of pathways and led to the idea that pain could be controlled by modulation—reduce excitation or increase inhibition. The Gate Control Theory explains why massage or applying heat reduces some pain and why people who are hypnotized or distracted may not notice pain. However, in a 1965 article, Melzack himself stated that the gate control theory is not able to explain several chronic pain problems[5]. The Gate Control theory does not provide an explanation of the biochemical and molecular mechanism of neuronal activation and transmission, does not explain the pathophysiology of pain syndromes and does not provide a road map for treatment of all pain syndromes.
More recently, Pain is currently defined by the International Association for the Study of Pain (IASP) as ‘an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. This definition was adapted in 1979, and published in the paper ‘Pain terms; a list with definitions and notes on usage. Recommended by the IASP Subcommittee on Taxonomy’, in the journal Pain in 1979[6]. This definition was subsequently considered elusive, and the following statement was added in order to make the position more clear: ‘Pain is always subjective. Each inpidual learns the application of the word through experiences related to injury in early life. It is unquestionably a sensation in a part of the body but it is also unpleasant and therefore also an emotional experience. Many people report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons. There is no way to distinguish their experience from that due to tissue damage, if we take the subjective report. If they regard their experience as pain and if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. This definition avoids tying pain to the stimulus…’
Pain is also currently classified as being peripheral or central in origin. Peripheral pain originates in muscles, tendons, etc., or in the peripheral nerves. Pain originating in the peripheral nerves, i.e. via trauma to the nerves, is classified as neurogenic pain. Central pain is currently thought to arise from central nervous system pathology: a “primary” CNS dysfunction. Some of this has been thought to arise due to maladaptive thought processes, true “psychogenic” pain[7]. But most of it has been thought to be due to structural changes in the CNS, e.g., spinal cord injury, multiple sclerosis, stroke and epilepsy (Boivie, 1996)[8] [9].
Another current classification, that distinguishes between normally functioning nerves and nerves whose function has been altered by pathology is as follows: Nociceptive pain is pain in which normal nerves transmit information to the central nervous system about trauma to tissues. Neuropathic pain is pain in which there are structural and/or functional nervous system adaptations secondary to injury, that take place either centrally or peripherally (Jensen, 1996)[10]. The IASP defines central pain as “pain initiated or caused by a primary lesion or dysfunction in the central nervous system” (Merskey, and Bogduk, 1994)[11].
Current theories of Pain state that physiological pain arises from damage to tissue (inflammatory pain), whereas neuropathic pain results from changes in damaged nerves[12]. When tissue is damaged, peripheral chemicals sensitize the sensory endings and after neuropathic pain, excitability changes occur within the nerve itself. These peripheral changes then alter activity in central systems[13]. The current theories further state that inflammation will produce peripheral sensitization[14] in that the system will be driven harder for a given stimulus. Ongoing ectopic activity in damaged peripheral nerves will continually produce transmitter release into the spinal cord, and this will cause subsequent neuronal activity[13].[15] [16] After tissue and nerve injury, there are increases in the activity of calcium channels within the spinal cord responsible for both presynaptic transmitter release and postsynaptic neuronal excitability. Current theories on wind-up and central sensitization explain central pain on the basis of augmented transmitter release, an increased release of glutamate and enhanced activation of the glutamate receptors for glutamate, especially the N-methyl-D-aspartate (NMDA) receptor.[13] Central sensitization is said to occur when peripheral sensory neuron activity drives central spinal systems that amplify and prolong the incoming sensory messages.
The variations in the current treatment of pain syndromes reflect a lack of a unifying theory of pain. Depending on the physician, a patient with severe back pain and an MRI showing a 4 mm herniated disc may be given heat or cold therapy, trigger point injections, epidural steroid injections, radiofrequency (RF) neurotomy, cryotherapy of the lumbar facet medial branch nerve, heating of the intervertebral disk with intradiscal electro-thermal therapy (IDET), spinal cord stimulation, implantation of an intrathecal infusion pump, surgical laminectomy or surgical fusion. This demonstrates significant differences in understanding of the pathophysiology and treatment of pain syndromes. Current medical theories place an over reliance on structural abnormalities to explain pain syndromes. This is not surprising because our current imaging technologies are structure based. Physicians are comfortable treating what they see. Patients who have structural abnormalities such as a osteoarthritis or herniated disk on MRI scans get operated upon often times needlessly and end up with more joint, back or neck pain. Patients with severe pain who do not have structural abnormalities on MRI scans e.g. patients with fibromyalgia are referred for psychiatric intervention. The fallacy of this approach has been confirmed in numerous published studies. In one of these studies[17], the authors performed magnetic resonance imaging on sixty-seven inpiduals who had never had low-back pain, sciatica, or neurogenic claudication. The scans were interpreted independently by three neuro-radiologists who had no knowledge about the presence or absence of clinical symptoms in the subjects. About one-third of the subjects were found to have a substantial abnormality. Of those who were less than sixty years old, 20 per cent had a herniated nucleus pulposus and one had spinal stenosis. In the group that was sixty years old or older, the findings were abnormal on about 57 per cent of the scans: 36 per cent of the subjects had a herniated nucleus pulposus and 21 per cent had spinal stenosis. There was degeneration or bulging of a disc at least one lumbar level in 35 per cent of the subjects between twenty and thirty-nine years old and in all but one of the sixty to eighty-year-old subjects. In view of these findings in asymptomatic subjects, the authors concluded that abnormalities on magnetic resonance images must be strictly correlated with age and any clinical signs and symptoms before operative treatment is contemplated. In another study[18], the authors examined the prevalence of abnormal findings on magnetic resonance imaging (MRI) scans of the lumbar spine in people without back pain. 52 percent of the asymptomatic subjects were found to have a bulge at least at one level, 27 percent had a protrusion, and 1 percent had an extrusion. Thirty-eight percent had an abnormality of more than one intervertebral disk. The prevalence of bulges, but not of protrusions, increased with age. The most common nonintervertebral disk abnormalities were Schmorl’s nodes (herniation of the disk into the vertebral-body end plate), found in 19 percent of the subjects; annular defects (disruption of the outer fibrous ring of the disk), in 14 percent; and facet arthropathy (degenerative disease of the posterior articular processes of the vertebrae), in 8 percent. The findings were similar in men and women. The authors concluded that on MRI examination of the lumbar spine, many people without back pain have disk bulges or protrusions but not extrusions. The authors went further to state that given the high prevalence of these findings and of back pain, the discovery by MRI of bulges or protrusions in people with low back pain may frequently be coincidental. In another study[19], which tracked the natural history of inpiduals with asymptomatic disc abnormalities in magnetic resonance imaging the authors stated that the high rate of lumbar disc alterations recently detected in asymptomatic inpiduals by magnetic resonance imaging demands reconsideration of a pathomorphology-based explanation of low back pain and sciatica. . In another controlled trial of arthroscopic surgery for osteoarthritis of the knee[20], 180 patients with osteoarthritis of the knee were randomly assigned to receive arthroscopic débridement, arthroscopic lavage, or placebo surgery. Patients in the placebo group received skin incisions and underwent a simulated débridement without insertion of the arthroscope. Patients and assessors of outcome were blinded to the treatment-group assignment. Outcomes were assessed at multiple points over a 24-month period with the use of five self-reported scores — three on scales for pain and two on scales for function — and one objective test of walking and stair climbing. A total of 165 patients completed the trial. The study results were astounding. At no point did either of the intervention groups report less pain or better function than the placebo group. For example, mean (±SD) scores on the Knee-Specific Pain Scale (range, 0 to 100, with higher scores indicating more severe pain) were similar in the placebo, lavage, and débridement groups: 48.9±21.9, 54.8±19.8, and 51.7±22.4, respectively, at one year (P=0.14 for the comparison between placebo and lavage; P=0.51 for the comparison between placebo and débridement) and 51.6±23.7, 53.7±23.7, and 51.4±23.2, respectively, at two years (P=0.64 and P=0.96, respectively). Furthermore, the 95 percent confidence intervals for the differences between the placebo group and the intervention groups exclude any clinically meaningful difference. The authors concluded that in this controlled trial involving patients with osteoarthritis of the knee, the outcomes after arthroscopic lavage or arthroscopic débridement were no better than those after a placebo procedure. This is further confirmation of the fallacy of a structure-based approach to the treatment of pain.
Medical treatment of pain syndromes has vastly improved with a greater recognition of the need to effectively control pain through the use of a variety of medications including NSAIDs, Corticosteroids, Opioids, Anti-seizure drugs, Antidepressants e.t.c. However the vast majority of physicians have no experience in the utilization of inflammatory mediator blockers in the treatment of pain syndromes.
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