Understanding Chronic Pain

Robert Bennett MD

Professor of Medicine OHSU

The Problem

Pain is a universal experience that serves the vital function of triggering avoidance. A few unfortunate individuals have a congenital absence of pain sensation; they do not fare well due to repeated bodily insults that go unnoticed. As a rheumatologist I see patients with an acquired deficiency in pain sensation (e.g. diabetic neuropathy or neuro-syphilis) who develop a severe destructive arthritis — a result of repeated minor joint injuries that are overlooked. Thus pain sensation is a necessary part of being human. As a matter of fact pain sensation is a fact of all life. Even the primitive ameba takes avoiding action in the face of adverse events. However in such primitive life forms pain avoidance is a purely reflex action, as they do not have the complexity of a highly developed brain to feel pain in the sense that humans do. Thus every day experience teaches us that there are at least two components to pain in humans: 1. The unconscious reflex avoidance reaction that is so rapid that it occurs before the actual awareness of the pain sensation (as in all life forms), 2. the actual experience of the pain sensation (that can only occur in highly complex organisms). This is an important point that we will come back to later, as it implies that different parts of the brain are involved in these two consequences of a pain reaction.

Acute versus chronic pain

The expectation is that injuries get better over time. This is the experience of all human beings. Fortunately for most of us this situation a life-long. Importantly there is an obvious relationship between the external manifestations of the injured part (e.g. a burned hand) and the amount of pain experienced; as the healing process proceeds so the pain recedes. If you are unfortunate enough to develop an incurable cancer you may experience severe pain (hopefully it would be reduced by morphine etc.), that would only be ended by death. But even in this example you would understand that there was a relationship between the amount of pain and the extent of the cancer. Importantly your spouse, relatives and friends would also understand this link and would be sympathetic to your plight. If there is not an obvious relationship between the subjective perception of pain and the source of the pain there is an instinctive temptation to suspect that there is nothing really wrong with the patient – for instance most FM patients usually look normal. Thus the problem must be in the psyche. Is there some hidden agenda for these claims? Is the patient getting some secondary gain for this behavior? Maybe they are escaping the stresses of a boring job, receiving more attention, getting an early pension or are they just bucking the system? Such invidious thoughts are not only the province of health care providers; family members, co-workers and friends often harbor the same suspicions. Are FM patients ever truly disabled and if so, what is the nature of their impairment?

The crucial difference between acute pain and chronic pain is that there is no apparent link between the experience of pain and an obvious injury or cancer etc. It has been difficult to understand chronic pain at a physiological level as most people, including many physicians, have viewed the nervous system as being "hard wired" – that is stimulation of a nerve ending (say a needle prick) always produces the same response by traveling along the nerves to the brain to produce the pain sensation of skin being pierced.

This concept implies that the same intensity of pain stimulus will always elicit the same degree of nerve stimulation and hence the same subjective experience of pain. This is what is meant by the concept of the nervous system being "hard wired". It is now understood that this concept is wrong. Basic research has now convincingly demonstrated that the nervous system demonstrates "plasticity" – in order to fully understand chronic pain one must understand the physiological basis of neuro-plasticity.

The "wind-up" phenomenon

In 1965 Mendell and Wall noted that when stimulation of a peripheral nerve at sufficient intensity to activate C-fibers was performed repetitiously there was a progressive build up of the amplitude of the electrical response recorded in the corresponding dorsal horn neurons of the spinal cord. They termed this phenomenon "wind-up. It is now appreciated that the phenomenon of wind-up is crucial to understanding the problem of chronic pain. Furthermore the biochemical basis for this phenomenon is now being unraveled. This will eventually lead to new and more effective treatments for chronic pain conditions. An example of an experiment demonstrating wind-up is shown below:

This experiment also demonstrates an important property of wind-up – it is dependent on activation of NMDA receptors (as the prior treatment of the animal with AP5, an NMDA receptor antagonist) prevented the summation of the signal at the level of the spinal cord.

Wind-up is one cause of increased pain susceptibility called "central sensitization". It is now thought that central sensitization is an important mechanism in the pain experience of fibromyalgia patients.

Muscle Pain

Muscle pain travels in myelinated A-delta fibers (Group III) and in unmyelinated Type C fibers (Group IV). The free nerve endings are concentrated around small arterioles and capillaries between the muscle fibers. The cell bodies for these nerves are found in the dorsal root ganglion and synapse in lamina I and IV-V of the dorsal horn of the spinal cord. Activation of peripheral nociceptors leads to a release of neurotransmitters in the spinal cord -- prominent transmitters are substance P and calcitonin gene-related peptide (CGRP). There is also a prominent retrograde migration of substance P which is released in the region of the free nerve endings. This retrograde flow sensitizes the tissues and makes them more responsive to less intense stimuli. Muscle nociceptors are activated by mechanical stimuli (stretching or pressure), bradykinin, 5-hydroxytryptamine and potassium ions. They are not activated by normal muscle movement or even increased muscle tension. Sensory input from muscle, as opposed to skin, is a much more potent effector of central sensitization. This may be the clue to the role of muscle pain in the total spectrum of the fibromyalgia syndrome. A classical experiment demonstrating this phenomenon was reported by Wall et al. in 1984. These investigators used a decerebrate rat model to explore the effects on reflex withdrawal of the hind limb to a noxious stimulus (pinching the toes), before and after stimulating either the sural nerve (a purely cutaneous nerve) or the gastrocnemius-soleus nerve (a predominantly muscle afferent) at 1 Hz for 20 seconds. Stimulation of the sural nerve induced an increased excitability of the withdrawal reflex that lasted for about 10 minutes. Stimulation of the gastrocnemius-soleus nerve produced a prolonged increase in reflex activity that lasted up to 90 minutes. Importantly these results were also seen in the contralateral limb -- indicating a central rather than a peripheral etiology. It was surmised that intra-spinal changes evoke the observed long lasting reflex that occurs after stimulation of muscle C afferent fibers. The authors opined, " at present we know nothing of the reason for the difference in the central excitability increase elicited by muscle and cutaneous nerves, which is regrettable because it might be related to the important clinical phenomenon of widespread and prolonged tenderness following tissue injury in deep tissue". Ten years later the answer is known. A synergism between substance P and NMDA (N-methyl D-aspartate) receptors appears to be of critical importance in the perpetuation of chronic pain states. The term for this increased pain sensitivity is "central sensitization".

Central Sensitization

Patients with severe FM have a reduction in pain threshold (allodynia), an increased response to painful stimuli (hyperalgesia) and an increase in the duration of pain after nociceptor stimulation (persistent pain). These features are found in central pain amplification states generally referred to as "central sensitization". There is good evidence that central sensitization is relevant to the pain experience in fibromyalgia patients. Arroyo and Cohen, using the technique of electrocutaneous stimulation, found that the upper limbs of FM patients could be characterized as regions of secondary hyperalgesia. Gibson et al have reported amplified cerebral evoked potentials in FM patients using a laser heat source . Mountz et al have reported that FM patients, characterized by low pain thresholds, have a decreased regional cerebral flow compared to healthy controls. The decreased perfusion was particularly prominent in the thalamic and caudate nuclei (structures involved in the processing of nociceptive stimuli), and it was hypothesized that the lowered pain tolerance of FM patients may result from functional abnormalities within the central nervous system – presumably a result of neuroplastic changes inducing a state of central sensitization.

It is seen that severe or persistent pain from any source (e.g. injuries, arthritis, surgery etc.) can potentially lead to a state of pain centralization and result in a heightened sensitivity to pain itself, the perception of formerly non-painful stimuli as now being painful and the spread of pain beyond the site of the originating impetus.

The spread of pain from the original site of "injury' is due to a diffusion of substance P within the spinal cord in a manner that sensitizes neighboring dorsal horn neurons that subserve other anatomical locations. Substance P is one of the major neurotransmitters released in the dorsal horn of the spinal cord on activation of muscle nociceptors. It synergises to activate NMDA receptors.

Unlike excitatory amino acids (e.g. NMDA) Substance P can diffuse over long distances without losing activity. There is experimental evidence that diffusion of Substance P to synaptic connections in adjacent myotomes can unmask formerly "silent" interspinal connections. This leads to an expansion of the receptive field to regions that were not injured.

The Psychology of Chronic Pain

An official definition of pain is as follows:

Pain is an unpleasant sensory and emotional experience associated
with actual or potential tissue damage, or described in terms of
such damage.

It was seen in the preceding section that chronic pain can occur in the absence of ongoing tissue damage – this is an explanation for the sensory component of pain. It was noted previously that one component of pain is a reflex avoidance behavior that can occur before the conscious appreciation of pain. In terms of brain physiology this implies that more primitive parts of the brain are being activated (i.e. the areas below the cerebral cortex). These sub-cortical areas of the brain contain several discrete areas known as nuclei (e.g. the thalamus, cingulate gyrus, hippocampus, amygdyala, locus coerulus) which interact to form a functional unit called the limbic system. This is the part of the brain that subserves many reflex phenomenon, including the association of sensory imput with specific mood states (e.g. sexual pleasure, migraine displeasure). These facts form the basis for considering the emotional aspect of pain.

Most fibromyalgia patients are reluctant to consider the psychological component of pain as in the past they had been led to believe that the pain was all in their head – i.e. the pain was purely psychological in nature. Unfortunately many health care professionals still convey this impression. But remember pain is both a sensory and emotional experience. To consider just the sensory component is equally as wrong as to focus entirely on the psychological component. The emotional component of pain is multifactorial and includes past experiences, genetic factors, general state of health, the presence of depression and other psychological diagnoses, coping mechanisms, and beliefs and fears surrounding the pain diagnosis. Importantly thoughts as well as other sensations can influence the sensory pain input to consciousness as well as the emotional coloring of the pain sensation.

The term given for this modulation of pain impulses is the "gate control theory of pain". A good example of the practical application of this theory is the use of counter-stimulation to minimize a painful event – such as rubbing a finger you have just mistaken for a nail! This is also why electrical transcutaneous stimulation of the skin (TENS) often reduces pain.

As thoughts (beliefs, fears, depression, anxiety, anger, helplessness etc.), as well as peripherally generated sensations, can both dampen or amplify pain, the role of the mind in influencing the total response to pain is an important subject to understand. Indeed in many chronic pain conditions (that lack any really effective therapy), the reduction of pain and the resulting suffering can only be effected by modulating the psychological aspects of pain. As the psychological contribution to pain varies enormously from patient to patient this approach to helping chronic pain patients has to be individualized. However there are some general principles that are worth noting.

There are important consequences of having pain that will not go away (as is the expected experience for most pain in most people). The unsettling realization that the problem may well be life-long generates a varied mix of emotions and behaviors that are often counterproductive to coping with a chronic problem. Many of these changes (which are partly reflex in origin) would be appropriate for dealing with acute self healing pain events, but become a liability when dealing with chronic pain.

Thus altering the consequences of having chronic pain will eventually help minimize (but never completely cure) the suffering involved in having a persistent, incurable pain state. This is the theory underlying the psychological approach to helping pain patients. In fact patients have to learn to modify their thoughts, beliefs and behaviors with the help of a skilled therapist. This approach to helping pain patients is called cognitive behavioral therapy.

Ideally the treatment of chronic pain would be to prescribe effective pain medications. There is hope in the near future that drugs that target the NMDA receptor will afford such relief. Until that time comes it is still going to be important for patients to pay close attention to the altering the consequences of having chronic pain. This is the theory underlying cognitive behavioral therapy—some important areas to modify are shown in the figure to the right.