What is the best treatment for pain in hypermobile Ehlers‑Danlos syndrome?

Pain Management in Hypermobile Ehlers-Danlos Syndrome

Begin with a structured exercise program combined with physical therapy for myofascial release as the foundation of pain management, then layer in gabapentin (titrated to 2400 mg daily) or low-dose amitriptyline for persistent pain, while strictly avoiding NSAIDs and opioids. 1, 2

First-Line Non-Pharmacological Interventions

Exercise is the single strongest evidence-based intervention for pain management in hypermobile EDS, with graded aerobic and resistance training providing the most robust benefits. 1 Start with low-resistance exercise to improve joint stability through increased muscle tone—this addresses the underlying mechanical instability that drives much of the pain. 1, 2

Physical therapy with myofascial release techniques should precede or accompany exercise programs to facilitate participation, as many patients cannot tolerate exercise initially due to severe myofascial pain and muscle guarding. 1, 2 This sequential approach is critical: attempting exercise without addressing myofascial dysfunction first often leads to treatment failure.

Cognitive Behavioral Therapy (CBT) is strongly recommended as a core component of chronic pain management, promoting patient acceptance of responsibility for change and development of adaptive behaviors. 1 This is particularly important given the high rates of anxiety, psychological distress, and kinesiophobia in hEDS patients that amplify pain perception. 3

Additional beneficial modalities include:

• Yoga specifically for chronic neck/back pain, headache, and general musculoskeletal pain 1
• Meditative movement therapies and mindfulness-based stress reduction for pain and sleep disturbance 1

Pharmacological Management Algorithm

Step 1: Initiate Neuromodulators

Gabapentin should be initiated first, titrating to 2400 mg daily in divided doses for neuropathic pain components. 1, 2 This addresses the neuropathic pain that develops as hEDS progresses beyond the initial nociceptive pathology. 3

Alternatively, start low-dose amitriptyline (gradually titrating to 75-100 mg if tolerated) to address both pain and the non-refreshed sleep that is nearly universal in hEDS. 1, 2 This dual benefit makes it particularly valuable.

Pregabalin (75-300 mg every 12 hours) can be considered as an alternative to gabapentin, particularly if gabapentin is not tolerated. 2

Step 2: Add Antidepressants for Severe Pain

For severe pain with comorbid depression, add duloxetine or milnacipran (SNRIs) to the regimen. 1 These address both the pain pathways and the psychological comorbidities that worsen pain perception.

Step 3: Breakthrough Pain Management

Tramadol is recommended for breakthrough pain, though use cautiously given addiction potential—this should be reserved for acute flares, not chronic daily use. 1

Paracetamol (acetaminophen) appears safe and can be used for mild-to-moderate pain episodes. 4, 2

Critical Medications to Avoid

Never prescribe NSAIDs—they worsen gastrointestinal symptoms (which affect up to 90% of hEDS patients), increase fluid retention, and can precipitate autonomic dysfunction. 4, 2, 5 This is a hard contraindication, not a relative one.

Avoid opioids entirely for chronic pain management, especially when gastrointestinal manifestations are present, as they worsen outcomes, increase complications, and lead to dependency without addressing the underlying pain mechanisms. 2, 5 The evidence is clear that opioids should not be used for abdominal or chronic pain in hEDS. 2

Adjunctive Symptom Management

Sleep Optimization

Address non-refreshed sleep through sleep hygiene education, as poor sleep amplifies pain perception. 1 Low-dose amitriptyline or pregabalin specifically target sleep disturbance while also providing pain relief. 1

Autonomic Dysfunction (POTS)

Measure postural vital signs with active stand test to screen for POTS, which affects a significant proportion of hEDS patients and worsens pain through tissue hypoperfusion. 1, 2 If POTS is confirmed:

• Increase fluid intake to 2-3 liters daily 1, 5
• Increase salt intake to 6-10 grams daily 1
• Use compression garments 1, 5
• Implement graded exercise training 1

Gastrointestinal Pain

For gastritis/reflux: proton pump inhibitors, H2-blockers, or sucralfate 2

For irritable bowel symptoms: antispasmodics (hyoscyamine, dicyclomine, peppermint oil) 2

For abdominal pain specifically: neuromodulators (tricyclic antidepressants, SSRIs, SNRIs, pregabalin, gabapentin) rather than opioids 4, 2

Mast Cell Activation Syndrome (MCAS)

If MCAS is suspected (present in up to 10% of hEDS patients):

• H2 receptor antagonist (famotidine 20 mg twice daily) 4, 5
• Second-generation H1 antagonist (cetirizine 10 mg daily) 4, 5
• Mast cell stabilizer (cromolyn sodium, ketotifen) 4
• Leukotriene receptor antagonist (montelukast) 4

Nutritional Support

Vitamin C supplementation may improve hypermobility as it is a cofactor for collagen cross-linking, potentially addressing the underlying pathology. 1, 2

Calcium and vitamin D supplementation are recommended for bone health, as hEDS patients have increased fracture risk. 1, 2

Multidisciplinary Team Coordination

A multidisciplinary team is essential and should include:

• Pain management specialist 1, 2
• Physical therapist 1, 2
• Psychologist/psychiatrist 1, 2
• Gastroenterologist (for GI symptoms) 1, 2
• Cardiologist or neurologist (for POTS evaluation) 2, 5

This coordinated approach is necessary because hEDS pain is multifactorial—arising from joint instability, muscle weakness, proprioceptive disorders, autonomic dysfunction, and central sensitization. 3, 6 No single intervention addresses all these mechanisms.

Common Pitfalls to Avoid

Do not delay physical therapy in favor of medications alone—the mechanical instability must be addressed through strengthening, or pain will persist regardless of pharmacological interventions. 2

Do not perform orthopedic surgery as first-line treatment—outcomes are significantly worse in hEDS patients compared to those without EDS, with decreased stabilization and pain reduction. 2 Surgery should be delayed in favor of physical therapy and bracing.

Do not prescribe opioids for chronic pain, particularly with GI manifestations present. 2, 5 This cannot be overstated given the high risk of dependency and worsening of GI symptoms.

Ensure dietary interventions (if needed for GI symptoms) are delivered with appropriate nutritional counseling to avoid restrictive eating patterns and avoidant/restrictive food intake disorder (ARFID). 2, 5