What is the best approach to manage leg pain in a patient with multiple sclerosis (MS)?

Management of Leg Pain in Multiple Sclerosis

For leg pain in MS patients, start with pregabalin (75-300 mg every 12 hours) or gabapentin (300 mg at bedtime, titrating up to 2400 mg daily in divided doses) as first-line therapy, reserving tricyclic antidepressants like amitriptyline or nortriptyline as second-line options. 1

Determine the Pain Type First

The critical first step is distinguishing between neuropathic and musculoskeletal pain, as this determines your entire treatment approach 2:

• Neuropathic pain presents with burning, tingling, or shooting sensations in the legs and represents the most common chronic pain syndrome in MS 2, 3
• Musculoskeletal pain manifests as diffuse body aches without neurological features and may be related to spasticity, abnormal gait, or postural abnormalities 2, 4
• Mixed pain can occur when spasticity-related pain (originating from central motor pathway lesions) triggers muscle nociceptor activation 5

First-Line Treatment Algorithm

For Neuropathic Leg Pain (Most Common)

Start with calcium channel α2-δ ligands 1:

• Pregabalin: 75-300 mg every 12 hours 6
• Gabapentin: Start 300 mg at bedtime, increase to 2400 mg daily divided into 3 doses 6, 3

These medications bind to voltage-dependent calcium channels, reducing the hyperalgesia and allodynia characteristic of MS neuropathic pain 6.

Alternative first-line options include 1:

• Tricyclic antidepressants: nortriptyline or desipramine (preferred over amitriptyline due to fewer anticholinergic effects) 1
• SSNRIs: duloxetine or venlafaxine (up to 75 mg daily) 1, 6

For Musculoskeletal-Type Leg Pain

Begin with acetaminophen as the initial choice for non-neuropathic body aches 2. This is particularly appropriate when leg pain lacks neurological features and appears related to gait abnormalities or postural changes 3, 7.

For Spasticity-Related Leg Pain

When leg pain is clearly associated with spasticity or painful tonic spasms 4:

• Initiate adequate physiotherapy first 3, 7
• Add baclofen or tizanidine as antispastic agents 3, 7
• Consider gabapentin or levetiracetam specifically for phasic spasticity 3
• Reserve botulinum toxin injections or intrathecal baclofen for severe, refractory cases 3, 7

Second-Line and Combination Therapy

If inadequate response after 4 weeks of monotherapy 2:

• Add a second agent with a different mechanism of action 3
• Combine tricyclic antidepressants with anticonvulsants to reduce adverse effects while improving efficacy 3, 7
• Consider topical treatments (lidocaine patches 4-5% or compounded amitriptyline-ketamine) for localized peripheral neuropathic pain 1

Critical Pitfalls to Avoid

Do not assume all MS leg pain is neuropathic 2. Diffuse body aches without neurological features respond better to acetaminophen than neuropathic agents, and misclassification leads to treatment failure 2.

Avoid NSAIDs for chronic pain management in MS patients with fibromyalgia-like symptoms due to lack of efficacy and potential side effects 2, 3.

Do not use tizanidine for diffuse body aches without documented spasticity (increased muscle tone on examination), as it is specifically indicated for muscle spasticity, not generalized pain 2.

Screen patients over 40 years before starting tricyclic antidepressants with an electrocardiogram, and use caution in those with cardiac disease or ventricular conduction abnormalities 1.

Monitor for medication-specific side effects 6:

• Somnolence with gabapentin/pregabalin 6
• Lower limb edema with gabapentin (which can counteract benefits) 6
• Anticholinergic effects with tricyclic antidepressants 6

Escalation Therapy

For refractory cases after 12 weeks of appropriate treatment 6:

• Opioids may be considered, though their role should be limited 3, 7
• Cannabinoids show encouraging results but their definitive role remains to be determined 3, 7

Non-Pharmacological Approaches

Integrate these alongside pharmacotherapy 2:

• Cognitive-behavioral therapy for chronic pain management 2, 1
• Physical exercise programs 2
• Yoga or tai chi 2
• Manual acupuncture 2

Trial single agents for at least 4 weeks before adding combination therapy to avoid unnecessary polypharmacy 2.