Abstract
Chronic pain that is associated with multiple sclerosis (MS) can be a challenging entity to the treating clinician. A number of chronic pain conditions affecting patients with MS have been described, including headache, musculoskeletal pain, low back pain, and neuropathic pain. This prevalent condition within the population with MS requires an appropriate evaluative approach, including a thorough history, a targeted physical examination, and appropriate use of radiologic imaging and diagnostic testing. A multitude of management approaches exist, including nonpharmacologic, rehabilitative, pharmacologic, and interventional approaches. The chapter provides an overview of the epidemiology, classification, evaluation, and management of MS-associated pain.
Keywords
Headache, Multiple sclerosis, Musculoskeletal pain, Neuropathic pain, Spasticity
Introduction
Multiple sclerosis (MS) results in a number of serious impairments including paralysis, sensory loss, spasticity, cognitive impairment, and neurogenic bowel/bladder dysfunction, but perhaps no MS-associated condition is more vexing to the treating clinician than chronic pain. Although some of these MS-related impairments can be accommodated with compensatory strategies, neuropathic pain associated with MS often remains quite recalcitrant. In addition to the expected challenges in treating any chronic pain condition, treatment of MS-related pain has the added difficulty of disruption of normal neural pathways that subserve pain transmission and attenuation. This chapter endeavors to describe the classification, epidemiology, evaluation methods, and treatment strategies for this and often confounding pain syndrome.
Classification
The most recent classification described in the medical literature proposed five major categories of pain that effects the patient with MS: nociceptive, neuropathic, psychogenic, idiopathic, and mixed. These categories are generally well described in the literature and are depicted graphically in Fig. 20.1 .
Perhaps the biggest distinction in this taxonomy is nociceptive pain, which is pain that arises from actual or threatened damage to nonneural tissue and is due to the activation of nociceptors, versus neuropathic pain, which is caused by a lesion or disease of the somatosensory nervous system. Of note, both neuropathic and nociceptive pain can demonstrate peripheral or central sensitization, which is a process of increased responsiveness of neurons to their normal input and/or recruitment of a response to normally subthreshold inputs. Although this distinction is obvious in some individuals, many patients with MS demonstrate characteristics of both neuropathic and nociceptive pain. Patients with MS can demonstrate nociceptive pain that is prevalent in the non-MS patients, such as degenerative joint disease, as well as nociceptive pain that is associated directly with the disease process, such as abnormal joint biomechanics secondary to spastic hypertonia. Trigeminal neuralgia, a relatively common neuropathic pain condition, has a higher prevalence in the population with MS. Optic neuritis is a neuropathic pain condition that is almost exclusively associated with MS.
Among the five categories of pain, perhaps the most challenging to define is psychogenic pain. This term refers to both primary psychiatric conditions such as somatoform pains associated with anxiety and depression and the superimposed psychogenic components that often develop in patients with chronic refractory pain. Somatoform pain disorder is defined as a form of mental illness that causes one or more bodily symptoms that causes excessive and disproportionate levels of distress. An example of this disorder would be a middle-aged female with a 10-year history of stable MS with refractory back pain despite relatively benign imaging and extensive trials of oral medication who displays catastrophic behavior and demands inappropriate interventions (such a high doses of opiates).
Idiopathic pain embodies several complex and perhaps poorly understood chronic pain conditions, including fibromyalgia, irritable bowel syndrome, interstitial cystitis, and persistent idiopathic facial pain. Of note, these disorders are not exclusive to MS but may have a higher prevalence in this patient population. These syndromes may share a common genetic predisposition.
The two most common mixed pain syndromes in patients with MS are headache and low back pain. For both of these conditions, there is evidence to suggest that MS-related factors can increase the occurrence of these entities.
Pain can be a consequence of or related to MS treatment. The β-interferons and glatiramer acetate are given as subcutaneous injections and have been associated with local acute pain. Systemic pain syndromes, particularly myalgias, have been associated with interferons. A potential increase in the frequency of preexisting headaches can occur after starting treatment with interferons. Dalfampridine, an agent that is used to improve walking capacity in patients with MS, has been reported to potentially activate trigeminal neuralgia.
Epidemiology
Given the potential ambiguity of chronic MS-related pain described earlier, attempts at epidemiology can be problematic. Potential confounders include oversampling (because patients may have more than one pain syndrome), adequate pain description, criteria used for chronicity/severity, and appropriate inclusion/exclusion criteria. Based on relatively broad definitions, the prevalence of chronic pain in the population with MS has ranged from 29% to 86%. If one applies a more stringent approach to epidemiology (diagnoses of definite MS, prospective study design, and strict assessment measures), the prevalence range narrows considerably, from 57% to 65%. It is not uncommon for pain to present at the time of initial MS diagnosis, with a reported prevalence from 11% to 21%. Roughly 20% of patients report increased pain during an exacerbation. With regard to pain intensity, a general rule of thumb is that about half of patients with MS would self-report their pain as moderate, a quarter would rate their pain as severe, and a quarter would rate their pain as mild. The presence of pain in an individual with MS is associated with decreased emotional and physical functioning. Risk factors reported to be associated with a greater likelihood of pain in patients with MS include older age, longer disease duration, and greater disease severity. Men and women with MS seem to have a comparable risk for pain, although women may have greater severity of pain. The etiology of these observations appears to be multifactorial in nature.
Evaluation
The approach to MS-related pain should commence in a fashion similar to that of all chronic pain conditions—history, physical examination, and judicious use of diagnostic testing. Information should be obtained regarding the patient’s disease onset, course, and progression. Descriptors should be obtained regarding pain history, including time of onset from initial diagnosis, time course, pain location, intensity, quality, alleviating and aggravating factors, past evaluations, treatments (including effectiveness), and pharmacologic assessment. Inquiry into the presence or change in upper motor neuron signs, such as clonus or spasticity, is reasonable. Functional, occupational, and recreational history should be acquired for two reasons. First, these activities may be a contribution factor to the development of pain (e.g., shoulder pain in a wheelchair-dependent individual). Second, the degree of pain interference with these activities allows the clinician to judge the functional impact of the patient’s pain condition. Some degree of psychological assessment is warranted with exploration into possible depression, anxiety, personality disorders, substance use, and cognitive impairment. In selected cases, a more formal psychological assessment, including psychometric testing, by either a psychologist or psychiatrist may be appropriate. Lastly, the patient should be queried into what diagnostic tests have been undertaken previously. Newly occurring pain is a potential warning sign that should be thoroughly diagnosed and not “automatically” be attributed to MS. One serious example is spinal cord compression in patients with MS that results from various causes such as vertebral deterioration, tumor, or other anatomic causes.
It is also reasonable to attempt assessment of the multidimensional nature of pain in terms of interference with daily activities. Of note, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group recommended that measures of pain severity, physical functioning, and emotional functioning be included in all clinical trials of chronic pain interventions. The impact of pain on physical functioning may be obtained through a number by pain interference scales such as the Graded Chronic Pain Disability scale and the Brief Pain Inventory. These scales have demonstrated reasonable reliability and validity in the populations with MS.
Many patients with chronic pain disorders and MS have comorbid psychological disorders, including depression, anxiety, anger, psychosis, eating disorders, substance dependence, cognitive impairment, and personality disorders. At a minimum, treating physicians should discuss the existence and severity of these behavioral problems with the patient. Cotreatment with mental health professionals is often warranted for more in-depth neuropsychological assessments. Examples of standardized psychological assessments used in this population include the Beck Depression Inventory and Hospital Anxiety and Depression Scale.
The physical examination of the individual with MS-associated pain should focus on the neurologic and musculoskeletal systems. Assessment should include reflex testing, assessment sensory abnormalities (allodynia, hyperalgesia, hyperpathia), motor control (tremor, ataxia), and muscle overactivity (spasms, spasticity, clonus). One particular maneuver is worthy of note: the Lhermitte phenomenon, which is an electrical sensation that runs down the back and into the limbs elicited by bending the head forward. Although this is often considered a classic finding in MS, it can be caused by a number of conditions. Focal examination of a particular pain area would then proceed in a manner similar to that utilized for all pain complaints. Items to be included are inspection, palpation, active and passive range of motion, and provocative maneuvers. Observation of wheelchair propulsion, posture, and gait may be appropriate in selected patients. Appropriate comfort and fit of assistive devices (cane, walker, crutch) and orthotic devices should be undertaken if this equipment appears to be contributing to the pain syndrome. A survey of mood, behavior, personality, and cognition is certainly reasonable given their potential impact on chronic pain treatment.
Although the use of neuroimaging is paramount in the diagnosis and management of MS, the use of imaging modalities for the detection of potential pain generators is less clear. The literature suggests that imaging is often undertaken in the presence of headache and facial pain. Brainstem lesions on MRI appear to be associated with a higher frequency of headache. Given the possible unreliability of abdominal/pelvic examinations in an insensate patient, imaging may also be warranted if visceral pain is suspected. In addition to the traditional MRI and CT imaging modalities, specialized techniques may be warranted for potential pain generator relative to neurogenic bowel and bladder. Examples in this arena might include colonoscopy, cystoscopy, urodynamics testing, etc. Triple phase bone scanning could be appropriate for the evaluation of unsuspected fractures or complex regional pain syndrome.
Similarly, judicious use of laboratory testing is a reasonable undertaking. Care must be exerted with regards to interpretation so as not to “over-read” the importance of a particular abnormality. An example of this pitfall would be to attribute asymptomatic urinary bacterial colonization as the sole cause of visceral pain. Potential laboratory tests in this population might include a complete blood count, erythrocyte sedimentation rate, HbA1c, C-reactive protein, and hormonal assessment (including thyroid/testosterone levels, pregnancy testing). Subtherapeutic vitamin B 12 and vitamin D have been implicated in neuronal dysfunction and represented potentially reversible abnormalities.
Management
Nonpharmacologic
A generalized exercise program in the form of global strength training, cardiovascular training, or recreational physical activities has the potential to be beneficial for a number of MS-related conditions (e.g., spasticity, muscle atrophy, bone health), but its effect on global pain in this population has not been very satisfactory. Animal studies have suggested that antinociceptive behaviors can be reduced with weeks of exercise training. Extrapolation from these experiments to the human condition has not been straightforward. Some human trials have suggested that a long-term exercise program can attenuate global pain complaints but these effects may not persist if regular exercise is discontinued. More targeted exercise programs for specific pain complaints have a much higher likelihood of success. Van der Linden et al. suggested that Pilates was a safe and feasible form of exercise for wheelchair-bound individuals with MS, which resulted in decreased back and shoulder pain. Doulatabad and colleagues suggested the positive effects of yoga on MS-related pain during a randomized clinical trial.
In addition to generalized and specified exercise programs, referral to physical or occupational therapy may be appropriate for the patient with MS with musculoskeletal pain in an effort to address biomechanical abnormalities that can be associated with mobility aids. Modification of orthotics, canes, walkers, crutches, and wheelchairs has the potential to influence detrimental ergonomics. Perhaps the best example of this intervention is adjustment of the rear wheel of a manual wheelchair in an effort to modify the forces about the shoulder that can occur as a result of wheelchair propulsion.
Therapeutic modalities have the potential to be effective in treating MS-related pain. A review of transcutaneous electrical nerve stimulation has suggested that it is a safe and effective treatment of central neuropathic pain. A randomized controlled trial (RCT) of massage therapy suggested enhanced pain reduction compared with a generalized exercise program. Reflexology, which is the application of pressure to the feet and hands with specific thumb, finger, and hand techniques without the use of oil or lotion, failed to demonstrate significant difference compared with nonspecific massage during an RCT. However, both groups exhibited pain relief compared with baseline.
One nonpharmacologic pain intervention that is particularly popular for both the general patient and the population with MS is acupuncture. In 1997 a report from the National Institutes of Health supported the use of acupuncture for certain conditions, including pain. There have been at least 12 studies that have examined the capacity of acupuncture to attenuate MS-related symptoms, including pain. Although the majority of these studies suggest benefit, there is a significant lack of scientific rigor in these investigations.
Pharmacologic
Antiepileptic drugs (AEDs) are considered first-line therapy for central neuropathic pain associated with MS. The most common medications discussed include pregabalin, gabapentin, and lamotrigine. Pregabalin and gabapentin binds to voltage-gated calcium channels. It is hypothesized that this binding that reduces the influx of calcium into the hyperexcited neuron in turn results in a reduction in the release of several neurotransmitters, including glutamate, noradrenaline, serotonin, dopamine, and substance P. Both gabapentinoids have analgesic, anticonvulsant, anxiolytic, and sleep-modulating activities. Lamotrigine is a sodium channel blocker and is thought to exert its pain-modulating activity by enhancing γ-aminobutyric acid and reducing glutamatergic neurotransmission. Less common AEDs utilized in patients with MS include carbamazepine, oxcarbazepine, topiramate, and phenytoin. The most common adverse events associated with pregabalin and gabapentin are mild or moderate and typically transient. Edema, somnolence, and dizziness are the most commonly reported adverse events, with edema being the most likely reason for discountenance of therapy. Hyponatremia can be seen with oxcarbazepine. AEDs are most commonly utilized in MS-related neuropathic pain, including trigeminal neuralgia, glossopharyngeal neuralgia, and paroxysmal dysesthesias.
The use of antidepressants for neuropathic pain has a long-standing tradition. It would appear that this class of medication is less well tolerated than AEDs. The classic group of medications is the tricyclic antidepressants (TCAs). They can be quite beneficial but can have a significant side-effect profile, including anticholinergic adverse effects such as urinary retention, constipation, dry mouth, cognitive dysfunction, weight gain, cardiac arrhythmia (prolonged QTc), and increased fatigue. These medications may be particularly useful for treating hyperactive detrusor in cases of bladder dysfunction and may reduce sleep disorders. The so-called second-generation TCAs (i.e., secondary amines such as nortriptyline, desipramine, and protriptyline) are preferred because the analgesic efficacy is equivalent and tolerability is better than that of first-generation TCAs (i.e., tertiary amines such as amitriptyline, clomipramine, and doxepin). All TCAs are considered to have a ceiling effect. Thus, once a therapeutic effect is achieved, further increase in dosing should be avoided to minimize adverse effects. When adverse events or effects are encountered with the TCAs, there is a suggestion that additive therapy with AEDs can be beneficial.
One of the more recent additions to the armamentarium of antidepressant use for chronic pain is the dual serotonin and norepinephrine reuptake inhibitors. Medications in this class include duloxetine, milnacipran, levomilnacipran, venlafaxine, and desvenlafaxine. Pain modulation appears to be independent of their antidepressant properties. Duloxetine, the first medication approved for use in the United States within this class, has Food and Drug Administration indication for chronic musculoskeletal pain, fibromyalgia, and diabetic neuropathy. Two trials of this agent with patients with MS have suggested a positive therapeutic effect, although tolerability was somewhat of a concern. There are no reports of using any of the other medications for chronic MS-associated pain. One interesting observation is the potential for venlafaxine to be immunomodulatory in preclinical models.
Opioid medications have been suggested as a reasonable option for chronic nociceptive and perhaps neuropathic pain. Perhaps no other decision in medicine causes more anxiety than prescribing opiates for patients with chronic, noncancer pain. Concerns over diversion, misuse, dependence, addiction, monitoring, and cost can make the analysis of utilizing chronic opiate therapy troublesome for even experienced clinicians. In the patient with MS, concerns over the potential exacerbation of neurogenic bowel caused by opioid-related constipation makes this decision even more challenging. There are several new strategies for the management of opioid-related constipation, including peripheral opioid receptor antagonists and prokinetic agents. A review of the use of opioids in neuropathic pain suggested clinical efficacy of this medication class for long-term use. It is relevant to note that this review has a large preponderance of periphery-based neuropathic pain (diabetic neuropathy or postherpetic neuropathy), but some subjects with MS were included. There are several developments within the opioid class medications that may be of specific interest to clinicians treating MS-related pain. Tapentadol is a centrally acting analgesic with dual mechanism of action—agonist activity at the μ-opioid receptor and inhibition of norepinephrine reuptake. A potential therapeutic advantage of this agent is its utility in neuropathic pain. This benefit has been studied with both low back pain with a neuropathic pain component and diabetic peripheral neuropathy. There are no specific reports on the use of this agent in MS. In addition, this medication may also have therapeutic advantages over other opiates, including a lower incidence of withdrawal symptoms and decreased frequency of gastrointestinal side effects. However, owing to the activity that this agent has with monoamine metabolism, there is a potential to exacerbate or precipitate serotonin syndrome. Another dual-acting product is tramadol, which is a combination of a serotonin and noradrenaline reuptake inhibitor and a μ-opioid agonist. This medication is noteworthy because its mechanism of action is distinct from those of other opioids. Tramadol has been shown to demonstrate benefit in osteoarthritis, fibromyalgia, and neuropathic pain; however, there is insufficient evidence to definitely define tramadol as more effective than other opioids. There is also some evidence to suggest that opiate use can be detrimental for patients with MS. This hypothesis is supported by the observation that low-dose naltrexone therapy can improve many symptoms of MS, including fatigue, cognition, mood, and pain. The theory behind the mechanism of action of low-dose naltrexone is that this agent transiently inhibits opioid receptors at low doses, causes the body to increase the production of endorphins, and upregulates the immune system. As with any patient who receives opiates, a screening must be performed to elucidate which patient may be at risk for abuse or diversion. There are several survey instruments available to clinicians that can assist in the decision making relative to chronic opiate therapy. These include the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), the Opioid Risk Tool (ORT), and the DIRE score (Diagnosis, Intractability, Risk and Efficacy) score. The validity, reliability, sensitivity, and predicative value of these tools are considered fair to good. Additional measures that should be utilized if a clinician is going to engage chronic opiate therapy includes narcotic agreement, query of state prescription drug databases, and in-office drug testing (such as urine, saliva, serum, or hair sampling). Thus the decision to utilize opiates in the patient with MS must undergo a careful risk-benefit analysis.
The relationship between pain and spasticity is complex. Reduction of spasticity may reduce the pain associated with biomechanical pain. Modulation of spasticity may not be effective in reducing neuropathic pain. There are several oral medications that can accomplish spasticity reduction, including baclofen, tizanidine, diazepam, and dantrolene. Of particular interest, tizanidine has a dual mechanism of action, an α2 adrenergic agonism at the spinal level and an influence on descending noradrenergic pathways. The latter mechanism may be of particular interest in the management of MS-related pain. Similarly, botulinum toxins have the potential to reduce muscle overactivity in a focally directed manner. Over and above their antispasticity activities, botulinum toxins have the capacity to exert a therapeutic effect on neuropathic pain. However, there are no formal studies examining the effects of botulinum toxin on MS-related pain independent of their spasticity reduction properties.
Medicinal marijuana and synthetic cannabinoids represent intriguing pharmacologic choices for the management of MS-associated pain. Cannabis contains 60 or more cannabinoids, the most abundant of which are δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). At the time of submission of this chapter, roughly half of US states had legalized some form of medicinal marijuana, although it is illegal under federal law. Many states have qualifying conditions for medicinal marijuana use. One of the most common qualifying condition is pain as well as muscle spasms. Some states also use damage to the nervous tissue of the spinal cord a qualifying condition. Availability is a concern in many locations given this legal ambiguity. Several clinical trials have examined the use of cannabinoids for the population with MS. Using a crossover design, it was noted that dronabinol (a synthetic THC product) reduced pain and improved certain quality of life measures but was associated with a high frequency of side effects. In a parallel group trial, a mixture of THC and CBD reduced pain, improved sleep quality, and was reasonably well tolerated in a group of patients with MS with central pain. The use of a THC/CBD oromucosal spray (Sativex) suggested efficacy in open-label and enriched enrollment trials but had somewhat equivocal results during an RCT when used in combination with patients’ existing treatment regimen. Nabilone (a synthetic THC analogue) showed promise as additive therapy to gabapentin during an RCT in 15 patients with MS. Side effects may have compromised the blinding in some of these trials, which would make interpretation of the results problematic.
Interventional
Perhaps the most common neuropathic pain syndrome that appears to be the most amenable to interventional procedures is trigeminal neuralgia. Approaches include thermocoagulation in Meckel cave, percutaneous retrogasserian glycerol rhizotomy, radiosurgery with the Gamma Knife, and microvascular decompression. These procedures are typically reserved for recalcitrant cases and appear to the capacity for dramatic pain relief. Recurrence is possible. The most common adverse event is persistent facial numbness.
Spinal cord stimulation (SCS) is defined as posterior epidural stimulation of the dorsal columns. The proposed mechanisms of action of this therapy involve the gate theory of pain, enhancement of parasympathetic activity, inhibition of sympathetic activity, upregulation of descending inhibitory pathways, and downregulation of ascending pain pathways. Owing to concerns over MRI compatibility of SCS devices and the need for routine surveillance MRI to assess disease burden in MS, this intervention has not been utilized very often. Provenzano et al. reported on the successful reduction of neuropathic pain in a patient with MS with the use of an MRI-compatible SCS system.
Intrathecal drug delivery provides direct administration of therapeutic agents to the subarachnoid space where they have enhanced access to receptor sites. Intrathecal baclofen is a well-established technique for the reduction of spasticity associated with MS. To the extent that spasticity is related to musculoskeletal pain, this technique has the capacity to attenuate pain in this population. However, the use of intrathecal baclofen as a pure pain-modulating agent is limited. The utility of more traditional intrathecal analgesic agents has not been overwhelmingly successful. Combination therapy with baclofen and clonidine, morphine and clonidine, baclofen and morphine, baclofen and ziconotide, and hydromorphone and ziconotide have resulted in varying degrees of success. Intrathecal gabapentin failed to demonstrate a therapeutic effect in a population with generalized pain.
Peripheral field stimulation is a form of neuromodulation that involves placement of an electrical stimulator that targets small nerve fibers in the subcutaneous tissue, beneath the skin. This technique has been utilized for the management of trigeminal neuralgia and other facial pain in patients with MS. Deep brain stimulation has also been suggested as a potential therapeutic modality for facial pain in this population. The MRI compatibility of these devices has similar concerns to those of the SCS devices described earlier.
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