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8 Articles in Volume 11, Issue #2
Preventive Therapies for Cluster Headaches
The Pain of Multiple Sclerosis: Is it Real and Is it Treatable?
Antidepressants in the Treatment of Chronic Pain
Genetic Screening for Defects in Opioid Metabolism: Historical Characteristics and Blood Levels
Post-operative Patient-controlled Analgesia in Pediatric Patients
Pharmacogenetics in Pain Care: Consideration of Economic Impediments and Ethical Imperatives
Are Opioids More Harmful Than NSAIDs for Elderly Patients?
How Genetics Can Complicate Pain Treatment

The Pain of Multiple Sclerosis: Is it Real and Is it Treatable?

More than 40% of multiple sclerosis (MS) patients experience at least one type of pain. The most common disabling pain MS patients encounter is central neuropathic pain. Most MS patients who are treated for pain respond to a regimen based on the ABC model: anti-convulsants/anti-depressants, botulinum toxin-A injections, and pharmaceutical cannabinoids.

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:

  1. Relapsing-remitting
  2. Primary progressive
  3. Secondary progressive
    (began as relapsing-remitting type)
  4. Relapsing progressive

The question of whether patients with MS experience pain has been controversial. Though first 

Electromyography-guided botulinum toxin-A injections for treatment of spasticity-related pain.

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.

Ultrasound-guided platelet-rich plasma therapy for back painDiagnosing MS Pain

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.

The results of the study found that all 9 patients improved significantly in most outcome measures. In several cases, the use of opioids and psychotropic medications were reduced or eliminated. There were no major adverse reactions reported, and no reports of habituation or drug tolerance. Quality of life and sleep were also improved subjectively in patient diaries. (See Table 3.)

Discussion

Why are the most severe cases of MS often refractory to the standard therapy, yet quite receptive to low-dose sublingual cannabinoid therapy? There are many possible reasons. First, the mechanism of cannabinoids—they have been shown to have immunomodulatory effects, including anti-inflammatory properties, down regulation of T helper 1: cytokines and enhancement of the production of TH-2 (protective) cytokines. This shift has also been shown to be a therapeutic benefit for patients who have MS. Also, cannabinoids exert a neuromodulatory effect on neurotransmitters involved in the neurodegenerative phase of MS and reduce expression of major histocompatibility complexes—type II (MHC—II).37

Second, in terms of pain management, the synergy between cannabinoids and opioids is modeled as a utilization of some different and some similar receptor sites. An opioid-sparing effect was also seen in this case series.27,28 Lastly, the cannabinoids additive/medication-sparing effect results in the need for fewer non-opioid medications (eg, anxiolytics, NSAIDS).34

It is the case of MS patients, especially the more severe cases, that they are refractory or experience adverse drug reactions with the standard therapy for their condition. It is in this particularly difficult population that cannabinoids shine most brightly as a promise for future research.

It is hypothesized that the documented effectiveness with this patient population is by gently stimulating the brain’s own manufacture of endocannabinoids. This case series and the

more recently published randomized controlled trials appear to substantiate the endocannabinoid model of the etiology of MS neuropathic pain, and they suggest a new paradigm and model for further research.

 

 

Table 1. Major Pain Syndromes Associated With Multiple Sclerosis

Classification

Type

Prevalence

Characteristics

Treatment

Nociceptive Pain

Painful tonic spasms

11% of MS patients

PQRST:

• Provocative factors: movement, sensory stimuli

• Quality: cramping, pulling pain

• Region: in the legs (more than the arms)

• Symptoms associated: distinct from pain related to spasticity

• Timing: often during the night

Anecdotal use of baclofen, diazepam, gabapentin, carbamazepine, tiagabine, and Botulinum toxin-A injection (BTX-A)11

Low back pain

Most common type of somatic nociceptive pain 16.4%

Contributing factors include poor posture, loss of core strength, abnormal stance and gait, ill-fitting wheelchairs.

Management should incorporate pharmacological and non-pharmacological therapies. Newer emerging treatment approaches include the use of platelet-rich plasma and stem cell injections to strengthen ligamentous support.35

Pelvic pain

2.9%

Visceral nociceptive and neuropathic pain problem seen in MS

BTX-A, carbamazepine

Spasticity-related pain10

The frequency of spasticity is reported to be 73-100% of MS patients. Pain is seen with the more severe cases.

Motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks due to hyperexcitability of the stretch reflex; it is one component of the upper motor neuron syndrome.

BTX-A is helpful for focal muscle spasticity, BTX-A also used to treat co-morbid problems, such as neurogenic overactive bladder, neuro-ophthalmological problems, tinnitus, neuropathic pain-trigeminal neuralgia (through intra-dermal injections) facial myokymia, sialorrhea, and hyperhidrosis. Phenol motor point ablative injections can also be done. For generalized spasticity, oral medications include baclofen, tizanidine, diazepam, dantrolene. More severe cases may be managed with intrathecal baclofen.

Table 1. Major Pain Syndromes Associated With Multiple Sclerosis (Cont)

Classification

Type

Prevalence

Characteristics

Treatment

Neuropathic Pain

Central neuropathic pain

Most common type of disabling pain, occurring in 25% of MS patients.

PQRST:

• Provoking factors: allodynia, hyperalgesia is NOT frequently noted

• Quality: burning pain

• Region: usually affects lower limbs, may be symmetric or asymmetric

• Symptoms associated: signs of spinal cord involvement (spasticity, neurogenic bladder) and sensory loss

• Timing: constant

Cannabinoids, gabapentin, pregabalin, lamotrigine, and levetiracetam

Trigeminal
neuralgia

1.9% to 4.9%

Widely recognized and studied pain syndrome in MS patients.

Compared to non-MS cases, MS-related neuralgia often present at a younger age, with brainstem signs (such as diminished facial sensation), and with bilateral involvement more frequently.

First-line therapy: carbamazepine; other trials include lamotrigine, gabapentin, and combination lamotrigine and gabapentin

Atypical facial pain

Probably similar to above for trigeminal neuralgia

Pain is described as dull and continuous—not paroxysmal.

First-line treatment: amitriptyline 25 to 100 mg QHS

Optic neuritis

19% of MS onset symptoms with a mean age of 31.1 years and a mean time delay to final MS diagnosis of 6.1 years.36

Acute visual loss and retrobulbar pain worse with eye movement; caused by inflammation of the optic nerve

Corticosteroids and non-steroidal anti-inflammatories

L’ hermitte’s sign

9.1%

Neck flexion resulting in paroxysmal radiating pain down the spine to the legs

May be improved with low doses of carbamazepine

Glossopharyngeal neuralgia

Rare

Severe pain in the posterior pharynx down to the tongue

Treated with carbamazepine

Complex
regional pain syndrome

Very Rare

IASP 2005 criteria includes symptoms (3/4) and signs (2/4) of the 4 categories: sensory, vasomotor, sudomotor-edema, motor-trophic changes.

Treatment as per guidelines for neuropathic pain. Early interventional approaches include stellate ganglion and lumbar sympathetic blocks.

 

Conclusion

Multiple sclerosis neuropathic pain is an often overlooked and poorly treated complication of the most common cause of neurological disability in young adults. About 40% of MS patients will describe the burning CNP in their lower extremities and yet, the literature suggests that the clinical classical signs of allodynia and hyperalgesia are often absent.3 Another commonly overlooked condition is nociceptive low back pain, particularly in the setting of severe generalized spasticity. Treatment of MS patient’s pain should be directed at the type of pain—nociceptive or neuropathic—and should contain a multimodal approach to best improve patient outcomes.

Last updated on: August 5, 2016
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