Medications and Supplements in hEDS

See below for Medication Metabolization and Low-Dose Naltrexone

Hypermobile Ehlers-Danlos syndrome (hEDS) is a complex, multisystem connective tissue disorder with no disease-modifying treatment. Management is highly individualized and relies on symptom control through a combination of medications, supplements, and nonpharmacologic strategies. This article synthesizes current clinical guidance, emerging therapies, and theoretical considerations across the full spectrum of hEDS and its common comorbidities, including postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), gastrointestinal dysmotility (abnormal movement of the digestive tract), psychiatric comorbidities, and nutritional deficiencies. It covers both acute and long-term issues across all age groups.

Overview of Medication Use in hEDS

While there is no one-size-fits-all treatment, understanding the types of medications and supplements commonly used can help patients and providers build a safer, more effective plan. Medications are typically selected to reduce symptom burden and improve function. A multidisciplinary, symptom-targeted strategy is essential.

• Pain management includes acetaminophen, NSAIDs (used cautiously), SNRIs, anticonvulsants, and occasionally opioids.

• Fatigue and cognitive dysfunction are addressed with supportive care and off-label agents such as low-dose naltrexone.

• Psychiatric comorbidities (especially anxiety and depression) are commonly treated with SSRIs, SNRIs, or tricyclic antidepressants.

• GI issues require a combination of standard agents, prokinetics, reflux treatments, and dietary strategies.

• Supplements support correction of common deficiencies, especially when malabsorption is present.

• POTS and MCAS require dedicated pharmacologic strategies and often interact with the broader hEDS medication plan.

Regular medication review, consideration of route and formulation, and attention to age- and tissue-specific vulnerabilities are all necessary to reduce harm and maximize benefit.

Medications by Symptom Domain

Pain

Chronic pain is often the first and most persistent concern in hEDS. A multimodal approach using pharmacologic and nonpharmacologic interventions is best. Pain in hEDS is often multifactorial—nociceptive, neuropathic, and centrally sensitized—and typically responds poorly to simple analgesics alone.

• First-line agents: Acetaminophen, NSAIDs (or COX-2 inhibitors, used cautiously due to gastrointestinal and bleeding risks)

• Neuropathic pain: SNRIs (e.g., duloxetine), TCAs, gabapentin, pregabalin

• Refractory (resistant to treatment) cases: Long-acting opioids, tramadol (short term), topical lidocaine, topical capsaicin

• Theoretical adjunct: Low-dose naltrexone (LDN) has shown promise in small studies. (See below following Medication Metabolization for information on LDN)

Because connective tissue fragility may increase the risk of gastrointestinal bleeding, tendon injury, and bruising, NSAID use should be closely monitored. Opioids should be limited to select cases with regular reassessment.

Fatigue and Sleep Disturbance

Fatigue in hEDS is profound, disabling, and multifactorial in origin. Contributing factors include pain, deconditioning, poor sleep, hormonal dysregulation, nutritional deficits, and autonomic dysfunction.

• Supportive care: Physical therapy, energy conservation, and psychological strategies

• Underlying contributors: Treat pain, insomnia, anxiety, POTS, MCAS, and screen for thyroid/adrenal dysfunction

• Medications: Low-dose amitriptyline or trazodone may improve sleep and mood

• Modafinil: Sometimes used off-label, but may worsen insomnia or anxiety

• Endocrine testing is recommended for those with unexplained fatigue. The results of this testing may lead to medication options to treat fatigue (see below).

• Stimulants and Caffeine

The role of stimulants and caffeine in hEDS remains controversial due to overlap with existing symptoms.

• Prescription stimulants (e.g., methylphenidate, amphetamines, modafinil) may help in co-occurring ADHD but are not recommended for general fatigue due to risks of

  • Insomnia

  • Anxiety

  • Appetite suppression

  • Tachycardia and blood pressure elevation

  • Mood instability and rebound fatigue

• Caffeine is widely used.

  • Use may cause palpitations.

  • Use may worsen GI symptoms.

  • Use may worsen sleep disturbances.

  • Regular use can lead to tolerance and dependency.

• Stimulants may also disrupt hormone regulation, including suppression of cortisol (a key stress hormone) or interference with appetite-related hormones such as leptin and growth hormone—effects that may be especially problematic in people with hEDS due to their sensitivity to hormonal shifts and vulnerability to fatigue, weight fluctuation, and autonomic imbalance.

Headaches

Recurrent headaches in hEDS are common and may be migraine, tension-type, or cervicogenic in origin.

• Abortive treatments: NSAIDs, acetaminophen, triptans

• Preventive medications: TCAs, SNRIs, anticonvulsants

• Cervical instability-related: Gentle physical therapy, soft collars, postural adaptations

Headache care should account for the presence of cervical spine instability, medication overuse, and comorbid POTS or MCAS, which can exacerbate vascular headaches.

Psychiatric Symptoms

Mood and anxiety symptoms are common and may reflect chronic illness stress, trauma, medical invalidation, or neurodevelopmental overlap.

• Medications:

  • SSRIs (e.g., sertraline, fluoxetine)

  • SNRIs (e.g., duloxetine, venlafaxine)

  • TCAs (used cautiously due to anticholinergic and cardiovascular risks)

• ADHD and ASD: Treated per standard protocols

• Risks: Monitor for orthostatic hypotension, drug interactions, suicidality, and sedative burden

Adjunctive therapy such as ACT, DBT, or trauma-informed psychotherapy is often essential for long-term mental health outcomes.

Autonomic Dysfunction and Mast Cell Activation

POTS (Postural Orthostatic Tachycardia Syndrome)

Many individuals with hEDS have co-occurring POTS, requiring specific medications to manage tachycardia, fatigue, and lightheadedness

• Beta-blockers (e.g., propranolol, atenolol)

• Fludrocortisone: Increases blood volume

• Midodrine: Alpha agonist to raise blood pressure

• Pyridostigmine: Improves autonomic tone

• Ivabradine (off-label): Selective heart rate control without lowering BP

These drugs require individualized titration and should be balanced with fluid intake, salt loading, and compression garments.

MCAS (Mast Cell Activation Syndrome)

MCAS affects a subset of patients with hEDS and requires careful medication management, often with attention to excipients and routes of administration

• H1 antihistamines: Cetirizine, fexofenadine

• H2 blockers: Famotidine, ranitidine (discontinued in some regions)

• Mast cell stabilizers: Cromolyn sodium (oral or nebulized)

• Leukotriene inhibitors: Montelukast

• Emergency medications: Epinephrine auto-injector for anaphylaxis

• Compounding: Dye-free, preservative-free formulations may be necessary

Medications that release histamine (e.g., opioids, some antibiotics) should be avoided when possible.

Gastrointestinal and Endocrine Considerations

Connective tissue dysfunction in the GI tract can lead to poor motility, reflux, constipation, and malabsorption of both nutrients and medications.

• Motility management: Prokinetic agents, osmotic laxatives, antispasmodics, dietary strategies (e.g., small meals, fiber modification)

• Reflux: PPIs, H2 blockers, sucralfate

• Malabsorption

  • Consider sublingual, transdermal, or injectable routes for essential meds (e.g., B12, iron)

  • Avoid relying solely on oral absorption when absorption is poor

Endocrine disorders may be overlooked or misattributed. Screen for:

• Thyroid dysfunction (hypothyroidism, subclinical hypothyroidism)

• Adrenal insufficiency

• Hormonal imbalance, especially in menstruating individuals or those with weight fluctuations

Nutritional Supplements

Due to dietary restrictions, GI dysfunction, or chronic inflammation, hEDS patients often have low levels of essential nutrients

• Common deficiencies: Iron, vitamin D, calcium, B12, folate

• Delivery routes

  • Oral when tolerated

  • Sublingual or parenteral (injections/IV) when malabsorption is present

• Protein supplementation: May aid recovery in underweight or deconditioned patients

Avoid megadoses or untargeted supplementation without lab confirmation. Some supplements may interact with medications (e.g., calcium and thyroid hormone).

Tissue and Medication-Specific Risks

Tissue Fragility

• Increased risk of bruising, hematoma, and skin tearing with injections or adhesive patches

• IM or SC injections may require smaller needles or alternative routes

• Vascular access may be more difficult; fragile veins prone to rupture

Medication Classes of Concern

• Fluoroquinolones: Risk of tendon rupture, especially in weight-bearing joints; avoid unless no alternatives

• Long-term corticosteroids: Accelerated bone loss, impaired wound healing

• PPIs: May reduce calcium and magnesium absorption, especially in long-term use

Hormonal Medications

• Oral contraceptives and HRT

  • May worsen migraines

  • Potential interaction with vascular instability

  • Consider non-oral or progestin-only methods in high-risk individuals

Other Considerations

OTC and Topical Agents

• Diphenhydramine: Anticholinergic burden, sedation, falls in older adults

• Pseudoephedrine: May worsen POTS symptoms

• Topical pain creams: Lidocaine, capsaicin, arnica, or menthol may aid focal pain

• Barrier creams or wound-healing ointments: Important for fragile skin

Polypharmacy and Safety Concerns (Polypharmacy means taking multiple medications at the same time, often five or more.)

Patients with hEDS are frequently prescribed multiple medications, raising the risk of interactions and adverse effects.

• Medication review: Reassess at every visit

• Deprescribing: Prioritize elimination of ineffective or harmful agents

• Monitoring:

  • Interactions (especially CNS depressants, serotonergic agents, and cardiovascular meds)

  • Fall risk

  • Nutrient-drug competition

Age-Specific Considerations

• Children: Use weight-based dosing; avoid growth-inhibiting medications

• Adults: Adjust for comorbidities and long-term side effects

• Older adults: Start low, go slow; avoid high-anticholinergic burden, benzodiazepines

Summary

Effective medication and supplement use in hEDS depends on individualized, symptom-based care that integrates autonomic, gastrointestinal, psychiatric, and connective tissue factors. Special attention to medication safety, delivery routes, excipients, and polypharmacy risks is essential. Regular reassessment, interdisciplinary collaboration, and patient-led decision-making are key to achieving safe and sustainable symptom management in this complex, multifaceted condition.

Medication Metabolization in hEDS

Hypermobile Ehlers-Danlos syndrome (hEDS) is the most common subtype of the Ehlers-Danlos syndromes, a group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. It is a multisystem disorder with complex symptoms including chronic pain, gastrointestinal dysmotility, autonomic dysfunction, and frequent comorbidities like mast cell activation disorders (MCAD). Given the high symptom burden and frequent medication use, there is growing interest in whether hEDS patients metabolize medications differently or require unique approaches to pharmacologic management.

While high-quality pharmacokinetic (PK, how the body absorbs, distributes, metabolizes, and excretes drugs) and pharmacodynamic (PD, how the drug affects the body, including therapeutic effects and side effects) studies in hEDS are lacking, there are both theoretical and observational data suggesting that medication absorption, distribution, metabolism, and response may be atypical in this population. These considerations vary across age groups and medication classes and are further complicated by hEDS-associated conditions such as GI dysfunction, dysautonomia, and MCAD. This overview synthesizes current knowledge and identifies key gaps.

Theoretical Factors Affecting Medication Response in hEDS

Empirical Evidence for PK/PD Differences in hEDS

• Limited data available

  • No published studies directly measuring PK or PD differences in hEDS.

  • Most existing literature identifies the absence of data rather than documenting findings.

• Large cohort studies show higher medication usage in hEDS

  • Pediatric and adult EDS populations demonstrate higher rates of prescriptions, especially opioids and GI medications.

  • Example: Opioid use was double in children with EDS (27.5% vs. 13.5%) and higher in adults (62% vs. 34.1%).

• Reduced efficacy of local anesthetics

  • Common clinical finding in hEDS, especially in dental settings.

  • Mechanism unknown; may involve tissue permeability or vascularity.

Theoretical Mechanisms Impacting Medication Response

• Connective tissue abnormalities

  • ECM disarray may affect distribution, especially for injected or depot drugs.

• Gastrointestinal dysmotility (abnormal movement of the digestive tract)

  • Delayed gastric emptying, constipation, and reflux are common.

  • May lead to delayed or reduced oral medication absorption.

• Autonomic dysfunction

  • Alters circulation and organ perfusion.

  • May impact drug delivery and metabolism, especially in IV medications.

• Mast cell activation disorders (MCAD)

  • May cause allergic or non-IgE-mediated reactions to medications or additives.

• Enzyme variability

  • Some speculation exists around CYP450 pathway variation in hEDS, but no confirmation.

Medication Class-Specific Observations

Age-Specific Considerations

Impact of MCAD (Mast Cell Activation Disorder - Mast Cell Activation Syndrome is a subset of Mast Cell Activation Disorder) on Drug Response

• MCAD can lead to

  • Increased hypersensitivity reactions

  • Poor tolerance of excipients (fillers, dyes, preservatives)

• Treatment strategies include

  • Trigger avoidance (e.g., heat, stress, alcohol)

  • Antihistamines: H1 (e.g., cetirizine), H2 (e.g., famotidine)

  • Mast cell stabilizers (e.g., cromolyn sodium)

  • Escalation to biologics in refractory cases

Clinical Guidelines and Implications

• No current guidelines recommend specific hEDS-related dosing or medication protocols.

• Management is based on standard practices with individual titration based on tolerability and response.

• Multidisciplinary collaboration is encouraged, especially when managing pain, GI symptoms, and MCAD.

Conclusion

Although rigorous pharmacologic studies are lacking, theoretical mechanisms and observational trends support the need for individualized medication management in hEDS. Clinical experience shows altered responses, particularly to anesthetics and opioids, and patients often require lower starting doses, slower titration, or alternative formulations. Until better evidence is available, careful monitoring, symptom-based management, and multidisciplinary coordination remain best practices.

Low-Dose Naltrexone (LDN)

Low-dose naltrexone (LDN) is an emerging off-label option for people with widespread pain, fatigue, and central sensitization—features common in hEDS.

What is it?

• A very low dose (1.5–4.5 mg) of the drug naltrexone, traditionally used in much higher doses for opioid or alcohol dependence.

• In low doses, it works very differently, modulating pain and inflammation through unique mechanisms.

• Must be obtained at a compounding pharmacy.

• Often is not covered by insurance due to being prescribed off-label. Off-label prescribing is when a healthcare provider prescribes a medication for a use, dose, or population that is not specifically approved by the FDA but is supported by clinical judgment or evidence from research.

How might it help in hEDS?

• LDN is not a standard therapy for hEDS, but it is increasingly used off-label for chronic pain conditions involving central sensitization, such as fibromyalgia, which shares overlapping features with hEDS.

• Proposed mechanisms

  • Inhibition of microglial activation in the central nervous system

  • Toll-like receptor 4 (TLR4) antagonism

  • Reduction of neuroinflammation, possibly helping to dampen pain amplification and brain fog

• Patients often report improvements in

  • Chronic widespread pain

  • Fatigue

  • Sleep quality

  • Cognitive clarity

Evidence base

• Evidence for LDN in hEDS specifically is limited to anecdotal reports and clinician experience.

• However, systematic reviews and meta-analyses show modest benefit in fibromyalgia and related centralized pain conditions, with a good safety profile.

• Most published studies are small or preliminary; high-quality randomized controlled trials in hEDS are currently lacking.

Tolerability

• LDN is generally well-tolerated.

• May have mild and temporary side effects such as vivid dreams or sleep disruption early on.

Formulations

Because commercial manufacturers do not produce tablets in low doses, LDN must be specially prepared by compounding pharmacies. Common formulations include:

• Capsules – The most typical option, often filled with microcrystalline cellulose or another neutral filler. Available in precise strengths (e.g., 1.5 mg, 3 mg, 4.5 mg).

• Tablets – Less commonly compounded but sometimes preferred for patients who have trouble swallowing capsules.

• Liquid formulations – Useful for those who require very gradual dose titration (e.g., starting below 1 mg and increasing slowly). Allows for flexible adjustment in 0.1–0.5 mg increments.

• Sublingual drops or lozenges – Occasionally used when gastrointestinal absorption is a concern, though less standardized.

• Topical creams – An experimental option prepared by some pharmacies, typically for patients who cannot tolerate oral forms; evidence is minimal.

Because inactive ingredients vary between pharmacies, patients with sensitivities to dyes, fillers, or excipients (inactive ingredients) may need to request specific formulations. Prescribers can work with the compounding pharmacist to adjust both dosage and formulation to the patient’s needs.

Insurance and Prescription Access

• Insurance coverage is inconsistent. Many insurers consider LDN experimental or non-essential due to its off-label use and will not reimburse for compounded versions.

• Prior authorization or appeal letters from a provider may be required for coverage, and even then, success varies by plan.

• Compounding pharmacies are typically required because low-dose tablets are not commercially manufactured. Prices can range from $30–90/month depending on formulation and location.

• Patients should

  • Ask whether their prescriber can fax the prescription directly to a known compounding pharmacy.

  • Inquire about discount programs or bulk pricing through pharmacies.

  • Save receipts for out-of-pocket costs, which may be reimbursable through FSA/HSA accounts.

• Some patients also find better prices at online or mail-order compounding pharmacies, though quality and licensing should be verified.