Referred pain

Referred pain is a phenomenon used to describe pain perceived at a site adjacent to or at a distance from the site of an injury's origin. One of the best examples of this is during ischaemia brought on by an angina pectoris, or heart attack. Even though the heart is directly affected the pain is often felt in the neck, shoulders and back rather than the chest. The International Association for the Study of Pain, as of 2001, has not officially defined the term; hence several authors have defined the term differently. Despite an increasing amount of literature on the subject there is no definitive answer regarding the mechanism behind this phenomena.^[1] It is interesting to note that physicians and scientists have known about referred pain since the late 1880s and to this day there is no definitive evidence to prove conclusively that one of the many theories proposed is correct. Critics have stated that one reason for this is the lack of a good referred pain model, or the incomplete understanding of neuronal organization in the brain.

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Characteristics

• The size of referred pain is related to the intensity and duration of ongoing/evoked pain.^[1]
• Temporal summation is a potent mechanism for generation of referred muscle pain.^[1]
• Central hyperexcitability is important for the extent of referred pain.^[1]
• Patients with chronic musculoskeletal pains have enlarged referred pain areas to experimental stimuli. The proximal spread of referred muscle pain is seen in patients with chronic musculoskeletal pain and very seldom is it seen in healthy individuals.^[1]
• Modality specific somatosensory changes occur in referred areas, which emphasize the importance of using a multimodal sensory test regime for assessment.^[1]

Mechanism

There are several proposed mechanisms for referred pain. Currently there is no definitive consensus regarding which theory may be correct.

The Convergent-Projection Theory

This represents one of the earliest theories on the subject of referred pain. It is based on the work of W.A. Sturge and J. Ross from 1888 and later TC Ruch in 1961. This theory proposes that afferent nerve fibers from tissues converge onto the same spinal neuron. This theory explains why referred pain is believed to be segmented in much the same way as the spinal cord. Additionally, experimental evidence shows that when local pain (pain at the site of stimulation) is intensified the referred pain is intensified as well. Criticism of this model arises from its inability to explain why there is a delay between the onset of referred pain after local pain stimulation. Experimental evidence also shows that referred pain is often unidirectional. For example stimulated local pain in the anterior tibial muscle causes referred pain in the ventral portion of the ankle; however referred pain moving in the opposite direction has not been shown experimentally. Lastly, the threshold for the local pain stimulation and the referred pain stimulation are different, but according to this model they should both be the same.^[1]

The Convergence-Facilitation Theory

In 1893 J MacKenzie created an alternate theory based on the ideas of Sturge and Ross. He believed that the internal organs were insensitive to stimuli. Furthermore, he believed that nonnociceptive afferent inputs to the spinal cord created what he termed "an irritable focus". This focus caused some stimuli to be perceived as referred pain. However, the theory did not gain widespread acceptance from critics due to its dismissal of visceral pain. Recently this simple idea has regained some credibility under as a new term, central sensitization. This theory, therefore, explains why changes in somatosensory sensibility could be undergoing processes similar to the dorsal horn and the brainstem. Additionally, the delay in appearance of referred pain shown in laboratory experiments can be explained due to the time required to create the central sensitization.^[1]

The Axon-Reflex Theory

This theory suggests that the afferent fiber is bifurcated before connecting to the dorsal horn. Bifurcated fibers do exist in muscle, skin, and intervertebral discs. Yet these particular neurons are rare and are not representative of the whole body. Axon-Reflex also does not explain the time delay before the appearance of referred pain, threshold differences for stimulating local and referred pain, and somatosensory sensibility changes in the area of referred pain.^[1]

The Hyperexcitability Theory

Out of all the theories present on the subject of referred pain this one appears to be backed by the largest amount of evidence. This theory hypothesizes that referred pain has no central mechanism. However, it does say that there is one central characteristic that predominates. This theory is derived from experiments involving noxious stimuli and recordings from the dorsal horn of animals. Experiments revealed that referred pain sensations began minutes after muscle stimulation. Pain was felt in a receptive field that was some distance away from the original receptive field. According to the theory new receptive fields are created as a result of the opening of latent convergent afferent fibers in the dorsal horn. This signal could then be perceived as referred pain. Several characteristics are in line with this theory of referred pain such as dependency on stimulus and the time delay in the appearance of referred pain as compared to local pain. However, the appearance of new receptive fields, which is interpreted to be referred pain, conflicts with the majority of experimental evidence from studies including studies of healthy individuals. Furthermore, referred pain generally appears within seconds in humans as opposed to minutes in animal models. Some scientists attribute this to a mechanism or influence downstream in the supraspinal pathways. Neuroimaging techniques such as PET scans or fMRI may visualize the underlying neural processing pathways responsible in future testing. ^[1]

The Thalamic-Convergence Theory

The last theory suggests that referred pain is perceived as such due to the summation of neural inputs in the brain, as opposed to the spinal cord, from the injured area and the referred area. Experimental evidence on this theory is lacking. However, pain studies performed on monkeys revealed several pathways converging on both subcortical and cortical neurons.^[1]

Examples

• Myocardial ischaemia (the loss of blood flow to a part of the heart muscle tissue) is possibly the best known example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm or even hand.^[2]
• “Ice cream headache” or “brain freeze” is another example of referred pain, in which the vagus nerve is cooled by cold inside the throat. ^[2]
• Phantom limb pain, a type of referred pain, is the sensation of pain from a limb that has been lost or from which a person no longer receives physical signals. It is an experience almost universally reported by amputees and quadriplegics. ^[2]

Laboratory Testing Methods

Pain is studied in a laboratory setting due to the greater amount of control that can be exerted. For example the modality, intensity, and timing of painful stimuli can be controlled with much more precision. Within this setting there are two main ways that referred pain is studied.

Referred Muscle Pain Using Alogenic Substances

In recent years several different chemicals have been used to induce referred pain including bradykinen, substance P, capsaicin^[3], and serotonin. However before any of these substances became widespread in their use a solution of hypertonic saline was used instead. Through various experiments it was determined that there were multiple factors that correlated with saline administration such as infusion rate, saline concentration, pressure, and amount of saline used. The mechanism by which the saline induces a local and referred pain pair is unknown. Some researchers have commented that it could be due to osmotic differences, however that is not verified.^[1]

Referred Muscle Pain Using Electrical Stimulation

Intramuscular electrical stimulation (IMES) of muscle tissue has been used in various experimental and clinical settings. The advantage to using an IMES system over a standard such as hypertonic saline is that IMES can be turned on and off. This allows the researcher to exert a much higher degree of control and precision in terms of the stimulus and the measurement of the response. The method is easier to carry out than the injection method as it does not require special training in how it should be used. The frequency of the electrical pulse can also be controlled. For most studies a frequency of about 10 Hz is needed to stimulate both local and referred pain.^[4] Using this method it has been observed that significantly higher stimulus strength is needed in order to obtain referred pain relative to the local pain. There is also a strong correlation between the stimulus intensity and the intensity of referred and local pain. It is also believed that this method causes a larger recruitment of nociceptor units resulting in a spatial summation. This spatial summation results in a much larger barrage of signals to the dorsal horn and brainstem neurons. ^[1]

Use in Clinical Diagnosis and Treatments

Referred pain can be indicative of nerve damage. A case study done on a 63 year old man with a sustained injury during his childhood developed referred pain symptoms after his face or back was touched. After even a light touch the there was shooting pain in his arm. The study concluded that the reason for this man's pain was possibly due to a neural reorganization which sensitized regions of his face and back after the nerve damage occurred. It is mentioned that this case is very similar to what phantom limb syndrome patients suffer. This conclusion was based on experimental evidence gathered by V. Ramachandran in 1993. With the difference being that the arm that is in pain is still attached to the body.

Orthopedic Diagnosis

From the above examples one can see why understanding of referred pain can lead to better diagnoses of various conditions and diseases. In 1981 physiotherapist Robin McKenzie described what he termed centralization. He concluded that centralization occurs when referred pain moves from a distal to a more proximal location. Observations in support of this idea were seen when patients would bend backward and forward during an examination. Studies have reported that the majority of patients that centralized were able to avoid spinal surgery due to isolation of the area of local pain. However, the patients that did not centralize had to undergo surgery in order diagnose and correct problems. As a result of this study there has been a lot of research into the elimination of referred pain through certain body movements. One example of this is referred pain in the calf. McKenzie showed that the referred pain would move closer to the spine when the patient bent backwards in full extension a few times. More importantly, the referred pain would dissipate even after the movements were stopped. ^[5]

General Diagnosis

As with myocardial ischaemia referred pain in a certain portion of the body can lead to a diagnosis of the correct local center. Somatic mapping of referred pain and the corresponding local centers has led to various topographic maps being produced in order to aid in pinpointing the location of pain based on the referred areas. For example local pain stimulated in the esophagus is capable of producing referred pain in the upper abdomen, the oblique muscles, and the throat. Local pain in the prostate can radiate referred pain to the abdomen, lower back, and calf muscles. Kidney stones can cause visceral pain in the urethra as the stone is slowly passed into the excretory system. This can cause immense referred pain in the lower abdominal wall. ^[6] In addition to this, recent research has found that ketamine, a sedative, is capable of blocking referred pain. The study was conducted on patients suffering from fibromyalgia, a disease characterized by joint and muscle pain and fatigue. These patients were looked at specifically due to their increased sensitivity to nociceptive stimuli. Furthermore, referred pain appears in a different pattern in fibromyalgic patients than it does in normal people. Often this difference manifests as a difference in terms of the area that the referred pain is found (distal vs. proximal) as compared to the local pain. The area is also much more exaggerated owing to the increased sensitivity.^[7]

References