Understanding Pain Mechanisms in MS
Summary
Although pain is not considered a typical symptom of multiple sclerosis, more than 50% of patients with MS present with pain syndromes. In the setting of an incurable disease, symptom control and particularly pain control is very important in achieving an enhanced quality of life. For paroxysmal pain syndromes such as trigeminal neuralgia or painful tonic seizures, carbamazepine, and other anticonvulsive drugs are the cornerstone of treatment. In dysesthetic extremity pain (the most common type of chronic pain), the treatment of choice is amytriptyline. Painful leg spasms which worsen with increasing disability and spasticity respond to tizanidine or baclofen, the latter either orally or intrathecaly. Transcutaneous electrical nerve stimulation (TENS) may be sometimes useful for the control of chronic pain. All these treatments may be combined. If, however, they do not alleviate pain, regular physiotherapy may relieve pain symptoms.
Introduction
Multiple Sclerosis (MS) is conventionally thought of as a disease that can bring physical disability, but cognitive function may not escape the effects of the disease. Cognitive difficulties may occur with memory, concentration, and other mental skills.
There are three reasons why information about cognitive aspects of the disease should be readily available to patients, carers and professionals:
to ensure as complete an understanding as possible, so that all areas of function likely to be vulnerable to MS are considered and monitored;
to increase awareness of the impact of cognitive dysfunction on all aspects of daily life, including physical activity;
to facilitate the dissemination of management strategies and treatment options relating to cognitive dysfunction.
Multiple Sclerosis - a Painless Disease?
Pain has received little attention in popular or scientific texts on multiple sclerosis and the opinion is still widespread that pain is not a typical symptom of MS. More and more it is being recognized that MS is not the 'painless disease' it was once thought to be. Figures in recent literature indicate that clinically significant pain occurs in more than fifty percent of patients with MS. (Vermote et al, 1986) However, it is important to note that pain in MS is not always directly due to demyelinating lesions. People with MS, like everyone else, are also subject to other conditions which are not related to MS (e.g. arthritis, migraine headaches, or low back pain due to degenerative conditions). Therefore, it should not be assumed that any pain experienced by patients with MS is a symptom of MS. Before describing the different pain syndromes occurring in patients with MS a simplified overview of the multiple existing pain mechanisms will be given.
What is Pain?
Pain is purely subjective, often difficult to describe and there is no 'objective' measure of pain. It is defined as an unpleasant sensory and emotional response to a stimulus associated with actual or potential tissue damage. (International Association for the Study of Pain, 1986) However, pain intensity is not proportional to the amount of physical injury and it is extensively influenced by anxiety, depression, expectation, and other psychological or social variables. Pain is a complex experience where the physical characteristics of the stimulus become interwoven with the motivational, affective, and cognitive functions of the individual as well as with the memory of past pain experiences.
Pain Pathways (or how pain is transmitted from the injured tissue to the brain)
In the initial phase, peripheral receptors (so called nociceptors) are stimulated by inflammatory substances released through tissue damage. This stimulation results in impulses ascending from the injury site to the spinal cord along the myelinated A-delta fibres and the unmyelinated C fibres which are embedded in the peripheral nerves. Stimuli that activate pain receptors vary from one tissue to another. While the adequate stimuli for skin is injury of tissue through pricking, cutting, crushing, burning, or freezing, the same stimuli are ineffective when applied to the stomach, the intestine, or the bladder where pain is produced by distension of the organ, by spasms of the smooth muscles or by inflamed mucosa. In skeletal muscle, pain is caused by ischemia, injury of the connective tissue sheets and prolonged contraction of the muscle as can occur with severe spasticity.
The fast conducting A delta fibres originate in the skin all over the body surface. They respond to strong mechanical stimulation as well as damaging heat and transmit the initial, or 'first pain' message, which lasts as long as the painful stimulus does. This fast pain seems to be functionally concerned with helping the body to avoid tissue damage since it provokes an immediate flexor withdrawal reflex and evokes rapid, well localized conscious awareness. (Bowsher, 1982)
Having reached the central nervous system at the level of the dorsal horn of the spinal cord the A-delta fibre synapses to the next neuron, whose axon crosses to the opposite side to ascend directly (oligosynaptic transmission) through the neospinothalamic tract of the spinal cord to the posterio- ventral nuclei of the thalamus. From there a further neuron passes the information to the post-central cortex, where the pain is perceived. This oligosynaptic pathway is fast conducting and has a somatotopic organisation resulting in rapid transmission of nociceptive information regarding site, intensity and duration of the painful stimulus. It subserves the sensory-discriminative aspects of pain (Adams & Victor, 1993). The free nerve endings of the C fibres are found in all innervated body tissue except the central nervous system. They seem to be sensitive to many kinds of stimuli: mechanical, chemical, and heat - but particularly to the chemicals released from tissue damage by any stimulus. In painful lesions due to tissue damage there is a release of proteolytic enzymes which liberate substances like kinin, histamine, and prostaglandins. These substances excite peripheral nociceptors. Paracetamol (Panadol®), Aspirin (Alcacyl®) and the other NSAIDs (Nonsteroidal anti- inflammatory drugs) reduce pain by inhibiting the prostanglandin synthesis and by decreasing other inflammatory reactions due to tissue damage. These drugs are used to treat acute and chronic somatic pain of low to moderate severity.
The C fibers are unmyelinated, slower conducting fibers, and they carry the sensation of 'second pain', which is a more diffuse and persistent sensation lasting beyond the termination of painful stimuli. Functionally, it appears to enforce inactivity of damaged tissue in order to allow healing to occur. It is thus associated with muscle spasms. The increased spasticity observed in patients with MS in the presence of skin irritation, bladder distension, infections, fractures, or fecal impaction could be explained by a hyper-reactivity to such exteroceptive stimuli.
The C fibers synapse with interneurones and neurones in the substantia gelatinosa of the dorsal horn of the spinal cord. After having crossed to the opposite side the signals are transmitted through many different neurones (poly-synaptic transmission) to the intralaminar nuclei of the thalamus via the reticular formation. Here they connect with further neurons passing to all parts of the cerebral cortex but especially to the prefrontal cortex and to the limbic system. This polysynaptic pathway is slow conducting, lacks somatotopic organisation, and results in poorly localized, dull, and burning sensations. This pathway is involved with the emotional and affective- motivational aspects of pain, i.e. the unpleasant feelings engendered by pain.(Adams and Victor, 1993)
Can the Brain Modify the Incoming Painful Impulses?
Fortunately, the ascending nociceptive information on its way to the cerebral cortex is controlled and modified by several descending pain control systems. The A-delta nociceptors in the spinothalamic tract give off branches to the periaquaductal grey matter (PAG) in the midbrain. Stimulation of the neurones in the PAG and the subsequent descending impulses result in the release of so called endorphins. These end-ogenous,morphine-like compounds are generally referred to as endorphins, meaning 'the morphins within. They activate the release of monoaminergic substances (serotonin, respectively nor-adrenaline) in the brain stem, in the nucleus raphe magnus (NRM) and at the nucleus locus ceruleus (NLC). From there other neurones descend to the dorsal column of the spinal cord where they activate other opioid-secreting inter-neurones which inhibit the activity of the ascending A-delta and C fibers (Fields et al, 1991). These interneurones may function either by pre- or post-synaptic inhibition at the level of the substantia gelatinosa or/and by preventing the release of substance P, a substance known to transmit pain impulses to the brain at the level of the spinal cord. Morphine given orally, parenterally or intrathecally and other narcotic drugs such as Pentazocin (Fortalgesic ®) or Tramadol (Tramal®) presumably produce analgesia by acting as 'false' neurotransmitters at receptor sites in the dorsal horn of the spinal cord and in the brain stem - sites that are normally activated by endogenous opioid peptides. Not only do opioids act directly on the central pain conducting sensory systems, but they also exert a powerful action on the affective component of pain.
Electrical Current for Pain Control?
As suggested in the 'gate control theory' by Melzack and Wall in 1965 there are low-threshold mechanoreceptors in the skin - A beta fibers- which pass without synapsing up the posterior columns of the spinal cord and give off collateral branches in the posterior horn (Melzack & Wall, 1965). These collateral effects impinge on nociceptor cells of the A-delta and C fibers of the posterior horn reducing effectively the excitability of these cells to pain generated stimuli. Thus the electrical pulses which stimulate the A-beta fibres may be effective in reducing pain perception. The gate control model has provided the theoretical basis for the use of elecrical current in pain control: low-intensity, high frequency (100- 200Hz) TENS (Transcutaneous Electrical Nerve Stimulation) can hence inhibit transmission of painful impulses. TENS has been tried in many painful conditions including MS with variable results (Johnson et al, 1991).
Does Pain Also Exist Without Visible Tissue Damage?
The pain pathways previously described are relatively straightforward and represent the probable mechanism for nociceptive pain which originates from tissue damage, (such as pain from cancer, degenerative joint disease pain, myofascial pain and trauma pain). However, when the neuronal structures are damaged after a cerebrovascular accident, a spinal cord injury, or in MS, another type of pain, called neurogenic or central pain occurs. This neurogenic pain is caused by neural dysfunction and not by stimulation of nociceptors in the periphery. Unlike nociceptive pain, neurogenic pain does not follow peripheral and central pain pathways and does not respond to systemic administration of conventional analgesics, including opiates, which act at the synapses of the classic pain pathway (Bowscher, 1991). It is also not always susceptible to destructive procedures designed to interrupt such pathways such as spinothalamic tractotomy. It is probably due to the disruption of descending inhibitory pathways resulting in a unmodulated activity of afferent A-delta and C fibers. The dysesthetic extremity pain is of neurogenic origin and is the most common non-paroxysmal pain in MS.
The quality of this pain shows a large inter-individual variation, and most patients experience more than one pain quality, often difficult to describe. In a recent review about dysethetic pain in MS, burning and aching pains were most frequent, occurring in about half of patients with MS, with pricking, stabbing, and squeezing being next in frequency (Boivie, 1994). Sometimes multiple localizations are found and one patient in this study had pains of three different kinds: The first was a burning pain down from the waist, the second was a tight belt-like pain just above the waist which felt tight as armour, the third pain was described as if sitting on a tennis ball. Patients with MS suffering central pain of this kind have very often a disturbed somatic sensibility as an indication of a dysfunction in the spino-thalamic pathways. The aberrations most often found are abnormal temperature and pain sensibility. To a lesser degree the vibration sense is affected, whereas the threshold to touch is often preserved. Typically there is allodynia in the skin involved with non-noxious stimuli such as light touch provoking pain.
What Drug Acts on Neurogenic Pain?
Neurogenic pain is very difficult to treat. Tricyclic antidepressants, such as amitryptilin are often used in the treatment of this pain. Probably the primary mechanism of tricyclic compounds is to block the re-uptake of the neurotransmittor serotonin in the CNS, a substance which enhances pain inhibition in the descending pathways (Thompson et al, 1992). In addition, amitryptilin is a potent sedative drug that may be used as sleeping medication. This compound is not always effective and sometimes anticonvulsive drugs such as clonazepam (Rivotril®) or carbamazepine (Tegretol®) are utilised. As in any chronic pain syndrome in which pharmacotherapy is of limited value, cognitive-behavioural approaches are very effective in providing coping techniques and distraction from pain (Clifford et al, 1984).
Are There Some Other Typical Pain Syndromes in MS?
Whereas dysesthetic extremity pain results directly from the demyelinating process, painful leg spasms, pain caused by pressure sores or low back pain are of secondary origin. For the last condition relief is sometimes possible with the use of non-steroidal anti- inflammatory drugs and physiotherapy. In this respect regular exercises at home or in a rehabilitation clinic are very important to maintain functional strength and posture to relieve the mechanical stress on the spine and the surrounding muscles (Stenager et al, 1991).
What About the Acute Pain Syndromes Typical of MS?
Acute pain syndromes include many of the paroxysmal symptoms of MS. They often occur at the beginning of the disease and are less frequent than the chronic pain syndromes described previously. Acute pain syndromes in patients with MS are characterised by brief sensory phenomena occurring in a stereotyped and paroxysmal fashion.
The best known paroxysmal pain disorders are:
· trigeminal neuralgia
· tonic seizure (also called painful tonic spasm) and
· Lhermitte's sign
Although highly characteristic of MS, the frequency of these acute pain syndromes is less than 15% (Moulin et al, 1988).
Trigeminal Neuralgia
Trigeminal neuralgia, the most common paroxysmal pain syndrome encountered in patients with MS, is a very intense and sharp sensation usually felt in the upper part of the face and which only lasts for a couple of seconds. Some patients, however, experience additional atypical prolonged facial pain. Very often the painful paroxyms are triggered by anodin sensory or motor stimuli such as touching the face, chewing or speaking. The intervals between the sometimes repeatedly (many times a day) occurring attacks are usually pain free. Although there is a tendency for spontaneous temporary remission, persistent spontaneous relief is rare.
Except for the fact that it tends to occur at a much earlier age and on both sides of the face the clinical features of trigeminal neuralgia in MS are indistinguishable from those of 'tic douloreux' or idiopathic trigeminal neuralgia of elderly patients. Since trigeminal neuralgia occurs about 300 times more frequently in people with MS than in the general population, the diagnosis of MS should be considered in patients under the age of 50 (Twomey & Espir, 1980).
Whereas idiopathic trigeminal neuralgia is most probably caused by a vascular loop pulsating against the trunk of the trigeminal nerve, focal demyelination at the entry zone of the trigeminal nerve in the pons has been postulated to explain pain in trigeminal neuralgia of MS patients.
Carbamazepine (Tegretol ®) is the drug of choice for trigeminal neuralgia and 70% of patients respond well. Small doses of 50 mg can be effective and it is recommended to start treatment with 50 mg twice a day or three times a day and to increase according to the clinical response. Maintenance doses are individually different, doses between 100 mg and 600 mg being sufficient in most cases. If the increase is too rapid, giddiness may occur, aggravating previously present ataxia. Sometimes the usefulness of carbamazepine may be limited by the effects of sedation and weakness. The drug is known to have haematological and hepatic side effects and initially blood counts and liver function have to be controlled. In cases of intolerance or when Carbamazepine is ineffective Baclofen (Lioresal®) or Phenytoin have been shown to be useful alternatives. For the rare cases not reacting to medication, glycerol injections in the nerves or thermocoagulation can be proposed. This last method leaves a less disturbing numbness in its place.
Tonic Seizures (Spasms)
During tonic spasms, which are not pathognomonic but strongly suggestive of MS, the arm and the leg of the same side of the body contract in a very painful manner which may last many seconds but rarely for minutes (Buchholz & Mumenthalter, 1987). Consciousness is preserved throughout the attacks. These symptoms can occur repeatedly in a day and may be brought about by changes in body position or by hyperventilation. Here again anticonvulsive drugs such as Carbamazepine work effectively.
Lhermitte's Sign
Although not always painful Lhermitte's sign is unpleasant enough to figure among the acutely painful features of MS (Lhermitte et al, 1924). When bending the neck patients experience an electric tingling sensation spreading rapidly down the spine to the legs and sometimes reaching both arms as well. Coughing and sneezing may also trigger Lhermitte's sign. This unpleasant sensation, quite typical for MS, can also be observed in other disorders involving the neck region such as tumour of the spinal cord and malformation. Most often this paroxysmal sensory disorder disappears spontaneously and medical treatment is not necessary. If it persists wearing a neck brace should be considered.
What is the Pathogenesis of the Acute Painful Syndromes?
Abnormal electrical conductivity in the demyelinated fibers seems to be at the origin of these paroxysmal phenomena in MS. Normally the integrity of the myelin sheath assures a rapid and continuous transmission of electrical impulse from one nerve to another. In a demyelinated axon, however, the impulses may leak out and spread to another adjacent demyelinated fibers giving rise to painful sensations if these fibers belong to the sensory pathway (Hess, 1989). This non-synaptic transmission of electrical impulse is called ephaptic spread. The pain of the trigeminal neuralgia provoked by chewing is related to a 'cross talk' between the motor branch and the sensory branch of the mixed trigeminal nerve, very much like a 'short circuit' between two badly isolated electrical wires. Because of their unique property of reducing the excitability of nerves through stabilisation of the electrical membrane, anticonvulsant drugs are very efficient in the treatment of these and other paroxysmal conditions.
Conclusion
This overview is by no means exhaustive and covers only the main forms of pain encountered in patients with MS. It is important to remember that MS is not a painless disease and that various painful syndromes, acute and chronic, can occur. Whereas the treatment of the paroxysmal pain syndromes has become rewarding thanks to the use of anticonvulsive drugs, the management of chronic pain syndromes of central origin, such as dysethetic extremity pain, is not always easy. Since there is no generally effective treatment it is recommended to try the different drugs in a systematic way, keeping the patient well informed and monitored closely for potential side effects. It is also wise to inform the patient that the treatment may not relieve the pain completely.
Avoiding obesity and pursuing a healthy life style with regular exercise may contribute to diminishing the consequences of immobility. If pain becomes a constant companion it will be important to plan the day such that social contact alternates with periods of rest. A long-lasting solid relationship with the physician will help the patient in periods of despair. Furthermore to increase activity a physiotherapy treatment should be included into the programme.