The Pain of Multiple Sclerosis: Is it Real and Is it Treatable?
Multiple sclerosis (MS) is an incurable autoimmune disease of the central nervous system characterized by pathophysiological abnormalities of inflammation and demyelination. The disease affects approximately 350,000 people in the United States1 and is most commonly seen in young adults: The typical age of onset is between 20 and 40 years old. In fact, MS is the most common neurologic cause of disability in young adults.2 However, MS is not limited to young adults—children and adults as old as 70 can develop it, too. Multiple sclerosis appears to be more common in women (1.77 to 1.0, female to male ratio), and the overall risk of first-degree relatives developing MS is 5%.3
The clinical course of MS is characterized by 4 distinct types:
- Primary progressive
- Secondary progressive
(began as relapsing-remitting type)
- Relapsing progressive
The question of whether patients with MS experience pain has been controversial. Though first
described by Jean-Martin Charcot in 1872, the occurrence of pain in MS patients has probably been under-reported. In fact, in Neurology in Clinical Practice, a well-known textbook published in 2008, the section on “Relief or Modification of Symptoms” listed spasticity, tremor, fatigue, bladder dysfunction, depression, sexual dysfunction, cognitive impairment, and paroxysmal symptoms as common MS symptoms. But there was no mention of pain.³
The reported estimates of MS patients experiencing pain vary from 29% to 86%, based on the various definitions of pain and population size studied. However, one large epidemiological study of 1,672 MS patients reported the occurrence of at least one type of pain in 43% of patients.4 Of these 719 patients, there was a correlation between the occurrence of pain with disease course, duration of illness, level of disability, and patient age—but not gender. Another study noted that 8% of patients reported pain as their chief symptom.5
Table 1 outlines the major pain syndromes associated with MS.
Effective management of MS pain should be based on incorporating the Douleur Neuropathique 4 Questions (DN4), which helps differentiate neuropathic pain from non-neuropathic pain, and the Expanded Disability Status Scale (EDSS). A meticulous physical examination should also be performed that includes testing for neuropathic pain (quantitative sensory testing).
Treatment of Pain
Treating pain in patients who have MS should be based on the ABC model.
- Anti-convulsants: Pregabalin,6 gabapentin are often used first-line for most neuropathic pain conditions (no significant drug interaction risk; improved sleep). Topiramate, lamotrigine, and levetiracetam are also used.7 Carbamazepine is usually first-line therapy for trigeminal neuralgia, but adverse effects can mimic an MS exacerbation.8
- Anti-depressants: Tricyclic anti-depressants and serotonin–norepinephrine reuptake inhibitors, such as duloxetine,9 with analgesic effects through the enhancement of diffuse noxious inhibitory control, are used.
- Botulinum toxin-A injections:10 These medications are typically used for treatment of spasticity.11 They have also been used off-label for neuropathic pain (intra-dermal injections)12,13 and nociceptive pain (intra-muscular and intra-articular injections).14,15 Botulinum toxin-A for MS can also be helpful in treating MS-related conditions (eg, overactive bladder, tremor, sialorrhea, hyperhidrosis).
- Cannabinoids: These are available in 3 pharmaceutical forms: nabilone,16 dronabinol,17 and the sublingual spray (eg, Sativex), which has the most randomized controlled trial (RCT) evidence.18-21 Prescribed medical marijuana22,23 (cannabis is used by 10% to 12% of MS patients24) is also now available in some states.
- Drug combinations: There is evidence supporting a synergistic relationship when opioids are combined with gabapentinoids 25 and cannabinoids.26-28
- Emerging new therapies: This includes transcranial29 and invasive neurosurgical stimulation30 for the treatment of central neuropathic pain (CNP). There is a need for greater research not only in the area of ph armacotherapies, but also in physical therapeutics31 and complementary medicine for the treatment of CNP.32 One recent paper suggests a synergism between cannabinoids and omega 3 fatty acids.33
Central Neuropathic Pain
In reviewing the literature on treatments for central neuropathic pain—the most common type of disabling pain seen in patients who have MS—the drug group with the best evidence and clinical experience is pharmaceutical cannabinoids.34 (See Table 2.)
Efficacy of Cannabinoids: Case Studies
To document the effectiveness of cannabinoids for treating CNP, we present 9 patients with MS. All of the patients were referred to the University of Toronto’s hospital outpatient clinic by their primary care physician or neurologist. Patients were pre-screened with the DN4 questionnaire and the EDSS.
Patient outcomes were measured using the numerical rating scale for pain, Short-form McGill Pain Questionnaire, Pain Disability Index, Neuropathic Pain Scale, and Pain Diagram. Physical examinations also included jamar grip dynamometry and neurological assessment.
The patients were started on low-dose nabilone, starting with 0.5 mg at night. Seven patients required higher doses and were titrated up to 1 mg/day. Two patients were highly sensitive to medication (groggy, sedated) and
responded better to a sublingual aqueous mixture of nabilone at 0.2 mg/mL. All related medications and therapies were monitored. Duration of treatment varied from 1 to 18 months.