protocols
ARA-290 for Nerve Pain and Injury Recovery
Some injuries don't heal because the nerves won't stop screaming.
The tissue looks fine on imaging. Structural repair is progressing. But burning pain, electric sensations, and allodynia persist. Guarding reflexes don't match tissue integrity. Movement feels effortful despite adequate strength. The brain keeps receiving "danger" signals from small nerve fibers that haven't recovered.
This is where ARA-290 (Cibinetide) fits. It's an 11-amino-acid peptide derived from the tissue-protective region of erythropoietin—designed to activate the innate repair receptor and quiet neuropathic symptoms without thickening the blood or raising hematocrit.
ARA-290 is not a healing peptide for tendons or collagen. It's a nerve-repair module for when small-fiber neuropathy is the bottleneck blocking rehab.
At a Glance
| Property | Details |
|---|---|
| What it is | Non-erythropoietic EPO fragment (11 amino acids) |
| Mechanism | Activates innate repair receptor (EPO-β + IL-4Rα) |
| Primary effect | Small-fiber nerve protection and regeneration |
| Secondary effect | Anti-inflammatory, M2 macrophage polarization |
| Dose | 4 mg subcutaneous daily |
| Cycle | 4–8 weeks (modeled on clinical trials) |
| When to use | Neuropathic symptoms blocking rehab progress |
Key principle: ARA-290 is a specialized nerve module, not a general-purpose repair peptide. Use it when burning/tingling/allodynia is the limiting factor.
Who This Is For
Use ARA-290 If:
- Burning, dysesthesia, or "electric" pain persists despite structural healing
- Allodynia (pain from light touch) at or near the injury site
- Guarding reflexes don't match tissue integrity—the brain thinks there's more damage than exists
- Ghost pain that MRI can't explain
- Movement feels effortful despite adequate strength
- Autonomic small-fiber features (temperature dysregulation, altered sweating) worsen with rehab
Skip ARA-290 If:
- Pain is mechanical/soreness-dominant (improves predictably with load management)
- Pain is clearly inflammatory (swelling, warmth, redness) → KPV or NSAIDs
- No sensory symptoms—just stiffness or weakness
- Symptoms are clearly structural (imaging shows ongoing damage)
- Tissue is still cold and poorly perfused → Need BPC-157/TB-500 first
Do I Need the Base Protocol First?
Not required, but often complementary. ARA-290 addresses a specific bottleneck—neuropathic symptoms—that the base protocol doesn't fully resolve.
| Scenario | Recommendation |
|---|---|
| Nerve symptoms are the clear, primary limiter | ARA-290 can be used early |
| Running base protocol with persistent nerve pain | Add ARA-290 |
| Tissue is still poorly perfused/healing | Start with BPC-157 + TB-500 |
| Multiple bottlenecks (energy, inflammation, nerves) | Use 5-compound base + ARA-290 |
ARA-290 is layered onto structural repair stacks when nerve symptoms are limiting. If tissue lacks blood flow or cellular mobility, address those first.
How ARA-290 Works
The Problem: Small-Fiber Nerve Damage
Injuries don't just damage tendons and ligaments—they damage the small nerve fibers that provide sensation, proprioception, and autonomic regulation. When these fibers are injured:
- They send persistent "danger" signals (burning, tingling, electric pain)
- Proprioception is impaired (movement feels uncertain)
- The brain maintains guarding reflexes even after tissue heals
- Rehab becomes "two steps forward, one step back" because the nervous system won't allow full loading
Standard repair peptides (BPC-157, TB-500, GHK-Cu) address vascular access, cellular mobility, and collagen quality—but they don't directly target small-fiber nerve regeneration.
What Makes ARA-290 Different
ARA-290 is engineered from the tissue-protective region of erythropoietin (EPO). But unlike full-length EPO:
| Full EPO | ARA-290 |
|---|---|
| Binds erythropoietic receptor | Binds innate repair receptor (IRR) |
| Raises hematocrit/hemoglobin | No erythropoietic effect |
| Thickens blood | No thrombotic signal |
| Red cell production | Tissue protection and nerve repair |
The Innate Repair Receptor (IRR) is a heterodimer of EPO-β and CD131. When activated by ARA-290:
| Pathway | Effect | What You Notice |
|---|---|---|
| Anti-apoptotic cascades | Protects small-fiber nerves from death | Burning and tingling fade |
| M1→M2 macrophage shift | Local inflammation resolves without immunosuppression | Less irritability at nerve sites |
| NF-κB downregulation | Reduces inflammatory cytokines (IL-6, TNF-α) | Calmer tissue; less flare |
| Nerve regeneration support | Promotes small-fiber nerve sprouting | Improved proprioception, less guarding |
| Microvascular protection | Restores blood-nerve barrier | Better perfusion to nerve endings |
The Clinical Evidence
ARA-290 has been studied in two main human settings:
Type 2 Diabetes with Painful Neuropathy (Brines 2014)
- 4 mg SC daily for 28 days vs placebo
- painDETECT scores dropped ~4 points vs ~1 point on placebo at 8 weeks
- Corneal nerve fiber density (CNFD) improved in the most affected subgroup
- Modest HbA1c improvement (indirect metabolic benefit)
- No erythropoietic or thrombotic signal
Sarcoidosis Small-Fiber Neuropathy (Heij 2012; Dahan 2013)
- 4-week IV/SC courses
- SFNSL symptom scores reduced by ~8–10 more points than placebo
- Corneal nerve fiber density improved
- 6-minute walk distance increased
- Benefits persisted months after dosing stopped
| Trial | Duration | Key Finding |
|---|---|---|
| Brines 2014 (T2D) | 28 days dosing, 8 wk follow-up | 4-point reduction in neuropathic pain vs placebo |
| Dahan 2013 (Sarcoid) | 4 wk dosing, 16 wk follow-up | 8-10 point SFNSL reduction; CNFD +15 fibers/mm² |
Who Responds Best
ARA-290 appears most effective for:
| Phenotype | Response |
|---|---|
| Burning, dysesthetic neuropathic pain | Strong |
| Diabetic or metabolic small-fiber neuropathy | Studied |
| Immune-mediated SFN (sarcoid-like, post-infectious) | Studied |
| Autonomic small-fiber features | Modest improvement |
| Mechanical/soreness pain | Unlikely to help |
Dosing Protocol
| Parameter | Recommendation |
|---|---|
| Dose | 4 mg |
| Frequency | Daily (morning) |
| Route | Subcutaneous |
| Cycle | 4–8 weeks |
| Timing | Morning, empty stomach |
Implementation Notes
- Morning dosing for nerve perfusion effects
- Empty stomach maximizes absorption
- Don't escalate beyond 4 mg daily—this matches the clinical trial protocol
- Inject alone—separate syringe from other peptides
- Short courses (4 weeks) often produce benefits that persist for months
Alternative Protocol (Modeled on Sarcoid Trials)
If subcutaneous daily isn't feasible:
- 2 mg IV 3× weekly for 4 weeks (requires clinical setting)
- Similar outcomes in sarcoidosis studies
Weekly Schedule (Example)
If running with base protocol, continue base compounds. Add:
| Compound | Mon | Tue | Wed | Thu | Fri | Sat | Sun |
|---|---|---|---|---|---|---|---|
| ARA-290 | 4 mg AM | 4 mg AM | 4 mg AM | 4 mg AM | 4 mg AM | 4 mg AM | 4 mg AM |
Combined with Tesamorelin (if both sleep timing and nerve symptoms):
| Compound | Mon | Tue | Wed | Thu | Fri | Sat | Sun |
|---|---|---|---|---|---|---|---|
| ARA-290 | 4 mg AM | 4 mg AM | 4 mg AM | 4 mg AM | 4 mg AM | 4 mg AM | 4 mg AM |
| Tesamorelin | 1.5 mg PM | 1.5 mg PM | 1.5 mg PM | 1.5 mg PM | 1.5 mg PM | 1.5 mg PM | 1.5 mg PM |
They work through completely different pathways and don't interfere with each other.
Timeline: What to Expect
Weeks 1–2
| What's happening | IRR activation; anti-apoptotic cascades engaging |
| What you notice | Sensory symptoms starting to quiet; less burning |
| Challenge | Stay consistent; effects build over time |
Weeks 2–4
| What's happening | Small-fiber protection established; M2 macrophage shift |
| What you notice | Tingling reduced; movement feels less guarded |
| Decision point | Most of the benefit occurs by week 4 |
Weeks 4–8
| What's happening | Nerve regeneration support |
| What you notice | Proprioception improving; can load more confidently |
| Stopping point | Clinical trials used 4-week courses with lasting benefit |
After Stopping
In clinical trials, benefits persisted months after the last dose:
- painDETECT improvements maintained at 8 weeks (4 weeks post-dosing)
- SFNSL improvements maintained at 16 weeks (12 weeks post-dosing)
- CNFD (corneal nerve fiber density) continued to improve after dosing stopped
This suggests ARA-290 triggers a repair process that continues after the compound is cleared.
Safety Profile
What the Trials Showed
| Domain | Finding |
|---|---|
| Hematologic | No erythropoietic stimulation; no rise in hematocrit |
| Cardiovascular | No thrombotic signal |
| Tolerability | Generally well-tolerated; similar to placebo |
| Common AEs | Mild injection site reactions; transient headache/flu-like |
| Metabolic | HbA1c and lipids improved or stable (T2D trial) |
What Remains Uncertain
- Long-term and repeated-course safety: Trials were 4–8 weeks; no multi-year data
- Very old or frail patients: Limited data in age ≥80
- Repeated cycles: Unknown if multiple courses have cumulative effects or risks
- Off-label preparations: Commercial ARA-290 may not match trial-grade purity
Practical Safety Posture
For injury recovery applications:
- Short-course ARA-290 (4–8 weeks) appears low-risk from hematologic and cardiovascular perspectives
- Conservative approach: use trial-style protocols, don't escalate beyond studied doses
- Avoid in: active malignancy, unstable cardiovascular disease, hypercoagulability
Managing Side Effects
| Issue | Primary Mitigation | Secondary Options |
|---|---|---|
| Mild dizziness | Usually first week only | Reduce frequency if persistent |
| Injection site reactions | Rotate sites | Rare; usually mild |
| Transient headache | Usually resolves | Hydration; reduce frequency |
| Flu-like symptoms | Usually first week | Self-limited |
Note: Serious side effects are rare in clinical trial data. The main safety concern is theoretical (untested in very old, frail, or immunocompromised populations outside trial contexts).
Contraindications
Do not use if:
- Severe hypotension
- Complex autonomic dysregulation (unrelated to injury)
- Active malignancy (theoretical concern; not studied)
- Unstable cardiovascular disease or hypercoagulability
Use with caution if:
- Advanced age (≥80) or frailty (limited data)
- Dense polypharmacy
- Severe renal or hepatic impairment (not formally studied)
What Comes Next
Signs ARA-290 Is Working
- Burning and tingling symptoms fading (usually by weeks 2–4)
- Movement feels less guarded
- Proprioception improving (balance, coordination)
- Can tolerate physical therapy without nerve-related flares
- Guarding reflexes diminishing
If Issues Persist
If nerve symptoms resolve but recovery timing issues persist (sleep disruption, unpredictable flares), consider Tesamorelin for GH timing support.
If you still experience relapse under load (progress then flare with intensity), consider SS-31 for mitochondrial stability.
Maintenance Options
ARA-290 is typically used as a defined 4–8 week course rather than ongoing therapy. Based on clinical trial patterns:
- Single course: Often sufficient; benefits persist months post-dosing
- Repeat course: If symptoms recur after 3–6 months, another 4-week course may help
- Maintenance use: Not established; trials didn't study continuous long-term dosing
FAQ
What is ARA-290?
ARA-290 (Cibinetide) is an 11-amino-acid peptide engineered from the tissue-protective region of erythropoietin. It activates the innate repair receptor (EPO-β + CD131) to protect and regenerate small-fiber nerves without stimulating red blood cell production.
How is ARA-290 different from EPO?
Full EPO binds the erythropoietic receptor and raises hematocrit/hemoglobin (thickening blood). ARA-290 binds a different receptor (the innate repair receptor) and has no effect on red blood cells. This makes it safe to use without the cardiovascular risks of EPO.
What kind of pain does ARA-290 help with?
ARA-290 is specifically for neuropathic pain—burning, tingling, electric sensations, allodynia (pain from light touch), and dysesthesia. It does not help with mechanical/soreness pain, inflammatory pain, or structural damage.
How quickly does ARA-290 work?
Most people notice sensory symptoms starting to quiet within 2–4 weeks. In clinical trials, significant improvements occurred by week 4 of dosing and continued to improve even after stopping.
Do benefits last after stopping ARA-290?
Yes. In clinical trials, benefits persisted months after the 4-week dosing course ended. This suggests ARA-290 triggers a repair process rather than just masking symptoms.
Do I need the base protocol to use ARA-290?
Not required. ARA-290 addresses a specific bottleneck (nerve-related symptoms) that the base protocol doesn't fully resolve. However, if tissue is still poorly perfused or structurally damaged, address those issues first with BPC-157/TB-500.
Can I use ARA-290 with Tesamorelin?
Yes. They work through completely different pathways and don't interfere with each other. Use Tesamorelin at night for GH timing; ARA-290 in the morning for nerve support.
What if my pain is both neuropathic AND structural?
Use both structural repair compounds (BPC-157, TB-500) and ARA-290. They address different bottlenecks and are complementary.
Is ARA-290 FDA-approved?
No. ARA-290 (Cibinetide) is investigational. It has been studied in Phase 2 clinical trials for diabetic neuropathy and sarcoidosis-associated small-fiber neuropathy but is not yet approved for any indication.
Are there long-term risks?
Unknown. Trial durations were 4–8 weeks with months of follow-up. No concerning signals emerged, but there are no multi-year safety datasets. The conservative approach is to use defined courses (4–8 weeks) rather than indefinite treatment.
A note on TB-500 vs TB-4 in the base protocol
If you're running the base protocol that includes TB-500: most vendors selling "TB-500" are actually selling full TB-4 (thymosin β4). Check your Certificate of Analysis—molecular weight ~800 Da is the fragment, ~4,900 Da is the full protein. Both work for tissue repair; the dosing recommendations account for either.
Related Guides
- 5-Compound Base Protocol — The foundation for structural repair
- BPC-157 + TB-500 Protocol — Simpler foundational option
- Tesamorelin for Injury Recovery — GH timing support
- SS-31 Add-On — Mitochondrial stability
- ARA-290 Overview — General peptide information
References
- ARA-290 in T2D with painful neuropathy: PMC4365069
- ARA-290 in sarcoidosis SFN (Heij 2012): Mol Med 2012
- ARA-290 with extended follow-up (Dahan 2013): Mol Med 2013
- Corneal nerve fiber & neuropathy trial: NCT02039687
- ARA-290 orphan drug review: Expert Opin Orphan Drugs 2013
This content is for educational purposes only. ARA-290 (Cibinetide) is investigational and not FDA-approved. Use in injury recovery is off-label extrapolation from neuropathy trials. Peptide therapy requires medical supervision. Consult a qualified healthcare provider before starting any protocol.