Pain Management in Multiple Sclerosis
John F. Foley, Ryan R. Metzger, Kara Menning, Cortnee Roman, and Emily N. Stuart
KEY POINTS FOR CLINICIANS
• Pain is a common symptom in multiple sclerosis (MS).
• Pain may occur with primary demyelination as well as indirect musculoskeletal compromise.
• Acute MS relapses may produce pain (e.g., optic neuritis, dysesthesia, or Lhermitte’s sign).
• Central neuropathic pain (CNP) occurs in up to 28% of MS patients, and most commonly involves the lower extremities.
• CNP is often associated with spinal cord plaque, and is most often amenable to treatment similar to that used to treat peripheral neuropathic pain.
• Trigeminal neuralgia is related to demyelination in the trigeminal nerve root entry zone, and is amenable to medical and surgical interventions.
PREVALENCE AND IMPACT OF PAIN IN MULTIPLE SCLEROSIS
Once thought to be an uncommon symptom in MS, we now know that pain is frequently reported by patients living with this disease. Pain may occur as a result of an acute relapse, or on a chronic daily basis as a result of long-standing neurological insult. It may represent the central presenting symptom of MS, or it may develop much later in the disease course. The estimated prevalence of pain in MS patients reported in the literature ranges from 29% to 86% (1–7). It has been estimated that almost one-half of MS patients report chronic pain, with some studies showing that its occurrence increases with age and disease duration (6,8,9). One study found pain to be present twice as often in women with relapsing-remitting MS (RRMS) compared to healthy women, with pain intensity over 7 days twice as high (10). A systematic review of 28 studies (7,101 subjects) estimated overall pain prevalence to be 63% in MS, with additional estimates of specific pain syndromes as follows: headache 43%, neuropathic extremity pain 26%, back pain 20%, Lhermitte’s sign 16%, painful spasms 15%, and trigeminal neuralgia (TN) 3.8% (6). This is reflected in clinical practice, as well, with many office visits centering on evaluating and treating a patient’s pain.
There is no doubt that pain adversely affects quality of life. For many MS patients, pain is often widespread, chronic, severe, and frequently interferes with sleep, occupational performance, and recreation (1,8). There also appears to be a connection between higher pain levels and worsened fatigue and depression (10–12). Pain also creates an economic burden resulting from direct medical expenses and productivity loss. One year’s financial expenditure for patients with neuropathic pain is up to three times higher than those without pain, with far more frequent office visits per year (13).
MECHANISMS OF PAIN IN MS AND CLINICAL PRESENTATIONS
Multiple potential pain generators exist with MS. Pain can occur as a primary result of demyelination along the neuraxis, and is often mediated by dorsal root neurons radiating via the spinothalamic tract to the thalamus. Projections from the thalamus include the medial system with radiations to the locus coeruleus, periaquaductal gray matter, thalamic nuclei, insula, secondary somatosensory cortex, hippocampus, amygdala, and hypothalamus (14). This system processes the emotional and cognitive aspects of pain. The lateral system processes the sensory discriminative elements of the signal and flows through the lateral thalamus, somatosensory cortex, parietal operculum, and insula (14).
Abnormal amplification of normal axonal pain transmission can produce enhanced pain perception. MS plaque 226may interrupt descending inhibitory pain fibers (15). The immune process may also directly produce a central pain response (16,17). Generation of pain produced by activation of nonpain sensory receptors is called allodynia. Exaggeration of painful stimuli is known as hyperalgesia. This central sensitization phenomenon is poorly understood. Secondary pain syndromes can be related to asymmetric load carrying or hypertonicity-producing musculoskeletal activation of peripheral pain receptors. Headache seems to also occur with increased frequency in MS, though pathophysiological mechanisms remain poorly understood and certain disease-modifying treatments may increase prevalence (18–21). Recognition of pain type by the clinician is important for appropriate intervention, keeping in mind that different pain types often coexist in the same patient. Specific pain syndromes are listed in Table 25.1.
Central neuropathic pain
Chronic, worsened with relapse
Dysesthetic extremity pain
Chronic or paroxysmal
Chronic or paroxysmal
Chronic or paroxysmal
Optic neuritis paina
Associated with relapse
Painful tonic spasma
MS, multiple sclerosis.
aDiscussed in other chapters.
ASSESSMENT OF PAIN IN MS
The management of MS-related pain can be a challenge, and often requires patient-specific tailoring, trial and error, and frequent reassessment. When assessing pain severity in patients, quantification is helpful, even if the responses obtained are ultimately subjective. A number of simple pain scales exist to help with the quantification of a patient’s pain perception, such as the pain Visual Analogue Scale (VAS), Numeric Rating Scale, and Verbal Rating Scale (22). Questionnaires such as the Brief Pain Inventory and the McGill Pain Assessment Questionnaire can be utilized to assess in more detail the characteristics of the pain (23). In addition, patient-reported outcome (PRO) surveys that address how pain impacts quality of life and everyday functioning can help the clinician better ascertain the degree to which the patient is affected by their pain. Such instruments include PROMIS (Patient-Reported Outcomes Measurement Information System) measures, the Medical Outcomes 36-Item Short-Form Health Survey (SF-36), and the Pain Effects Scale (PES) (24). The PES is a six-item self-report questionnaire that can be completed by the patient within a few minutes (see Figure 25.1). This scale provides insight into the way pain interferes with mood, mobility, sleep, and activities of daily living, and can be readministered to assess changes over time (25). Patients with upper extremity or visual impairments can have questionnaires administered as an interview.
CENTRAL NEUROPATHIC PAIN
The prevalence of CNP in the MS population may be as high as 28% (26). In one study, among those reporting CNP, pain occurred in the lower extremities in 87% of cases, and in the upper extremities for 31%. Pain was bilateral in most cases (76%), and occurred daily in the far majority (88%) (26). Dysesthesias are described as a constant, burning discomfort, which can be symmetric or asymmetric, usually affecting the lower limbs, and can also present as increased sensitivity to touch. Paresthesias are most often described as a “pins and needles” sensation, but can also present as aching, throbbing, stabbing, shooting, tightness, or numbness (24). Dysesthesias and paresthesias are most commonly felt in the limbs, but may also occur elsewhere.
CNP management requires frequent assessments, managing expectations, and finding a regimen that is effective without causing too many treatment-related debilitating side effects. Nonpharmacological interventions may also be beneficial. Physical therapy, regular exercise, relaxation, stretching, massage therapy, hypnotherapy, and psychological intervention should be introduced where felt appropriate. Most therapeutic agents utilized for treatment of CNP have been coopted from the peripheral pain trials, or from studies in other central nervous system conditions. Dysesthesias and paresthesias can usually be treated with antiepileptics or tricyclic antidepressants. Sometimes, combinations of medications with different mechanisms of action are needed to adequately control pain symptoms without causing side effects such as sedation (23). Figure 25.2 describes the treatment algorithm utilized by our clinic.
Of particular importance, the use of opioids for treatment of pain should be reserved for third-line pharmacological therapy due to the significant potential for drug dependence, overdose, and impact on quality of life. Furthermore, when prescribing opioids, it is suggested that clinicians follow the most up-to-date recommendations for best practices that have been developed in response to the recent opioid-related public health emergency. Such guidelines include elements to help ensure safe and effective therapy such as a patient treatment agreement, screening for prior or current substance abuse or misuse, screening for depression, tracking pain and function to recognize tolerance and effectiveness, and tracking daily morphine-equivalent doses using an online dosing calculator (27).
Currently, class 1 clinical trials for pharmacological management of MS-related CNP by cannabinoid therapies are being conducted (28–32). Though there are greater than 60 cannabinoid compounds present in Cannabis sativa (cannabis), the main psychoactive ingredient, tetrahydrocannabinol (THC), and the nonpsychoactive ingredient, cannabidiol (CBD), are the current agents of medical interest for MS (33,34). Between 2004 and 2015, four out of five clinical trials investigating the impact of THC/CBD on CNP in MS reported a statistically significant reduction in pain (28–32). However, this does not necessarily mean cannabinoids are a suitable therapy for CNP. Although the reductions in CNP observed with cannabinoid treatment reached statistical significance in these trials, the actual clinical reduction of pain was small, and likely no better than that achieved by other agents currently utilized for pain 228(28,30–32,35). In addition, methodological issues were present in many of these studies, including small sample size, nonstandard follow-up periods, large placebo effect, and a wide range of doses utilized (35). And though serious adverse effects were rare in these studies, cannabinoids may still carry a significant risk of cognitive impairment and psychotic illness (36,37). Thus, the American Academy of Neurology currently supports continued rigorous research to evaluate the safety and effectiveness of cannabinoid therapies, but does not advocate for the use of such therapies for neurological disorders such as MS at this time (38).
TN occurs more frequently (typically 2%–4%) (3,6,39) and more often is bilateral (up to 18%) (40) in the MS population. TN may be the presenting symptom at the time of MS diagnosis (41). Lesions in the region of the trigeminal nerve root entry zone (REZ), and possibly the nerve nucleus itself, are felt to be causal to the condition, and vascular compression may further complicate the pathophysiology. Lesions in the REZ may also remain asymptomatic or produce only dysesthesia or hyperalgesia without classic TN (42). Clinical symptoms of TN may include hyperesthesia or hyperalgesia of one or several facial nerve segments. The pain occurs unilaterally along the path of the trigeminal nerve (V1–V3 distribution), and is described as lancinating, burning, shock-like, stabbing, or electrical pain. It is often precipitated by an external stimulus such as a puff of air to the face, chewing, drinking, shaving, brushing one’s teeth, or touching the affected side. The pain is typically extremely short in duration, although lower level dysesthesia may persist in the same distribution as the more severe shock-like sensations. TN is one of the most severe pain syndromes of MS.
The mainstay of pharmacological treatment remains carbamazepine, though pain control may diminish with long-term use. If partial control is achieved, the addition of baclofen, imipramine, or valproate to the regimen is sometimes useful. Alternative therapies may include oxcarbamazepine, phenytoin, lamotrigine, or benzodiazepines. In patients refractory to pharmacological therapy, the options of radiofrequency or glycerol rhizotomy can sometimes provide lasting relief (42). In very unusual cases, nerve decompression may also be of benefit (see Figure 25.3).
Jean Lhermitte presented the review paper on this phenomenon to the Neurological Society of Paris entitled Pain of an Electric Character Discharge Following Head Flexion in Multiple Sclerosis (43). Lhermitte’s sign is described as a brief, electric, shock-like sensation extending down the spine, sometimes into the lower extremities, typically triggered by forward flexion of the head. It is a common complaint in the MS population, occurring with a frequency of 9% to 41% (6,44,45). It is generally felt to be related to a lesion of the ascending spinothalamic tract at the cervical level, with MRI showing a cervical spinal cord plaque in more than 95% of patients (45). An increase in pressure on the dorsal columns with neck flexion is postulated to produce a transient conduction block, resulting in the dysesthetic sensation radiating down the spine. Therapy involves treatment of the primary MS cervical plaque with steroids if the plaque is acute or subacute, and treatment of the disease with immunomodulators. Symptomatic therapy is generally of limited utility.