Dihexa for Fibromyalgia & Fibro Fog: BDNF, Microglial Neuroinflammation, Tonmya (TNX-102 SL) FDA August 2025, Low-Dose Naltrexone & the 2026 UK Review

Around 2.8 million UK adults — roughly 5.4% of the population — live with fibromyalgia (FM), one of the most common causes of chronic widespread pain in the UK, on Royal College of Physicians (RCP) 2022 UK diagnostic guideline figures aligned with Versus Arthritis and Fibromyalgia Action UK estimates. 2025-2026 has been an unusually consequential period in the field. On 15 August 2025, the FDA approved Tonix Pharmaceuticals' Tonmya (TNX-102 SL, sublingual cyclobenzaprine) — the first new FDA-approved fibromyalgia medication in 15 years — with US commercial launch in Q4 2025. At ACR Convergence 2025 (November 2025) and in the May 2025 Annals of Medicine and Surgery, low-dose naltrexone (LDN) systematic review and meta-analysis data confirmed clinically meaningful pain and function gains. In 2024, Polli and colleagues' PLOS One systematic review and meta-analysis consolidated peripheral BDNF as a candidate fibromyalgia biomarker, finding it significantly elevated (not depleted) in patients versus pain-free controls. The Albrecht et al. 2019 multi-site Brain Behavior & Immunity [¹¹C]PBR28 PET study provided the first in vivo evidence of microglial / TSPO glial activation in the thalamus, prefrontal cortex and insula — consolidating the central neuroinflammation frame. In January 2026, Brain Sciences published a Montreal Cognitive Assessment (MoCA) case-control study showing over 70% of fibromyalgia patients have measurable cognitive dysfunction — the “fibro fog” phenotype. Against this turbulent backdrop, where does Dihexa, the synaptogenic HGF/c-Met-activating peptide, sit — and what is the very real theoretical risk that pushing the BDNF/synaptic-plasticity axis higher in a disorder where it is already elevated could consolidate rather than relieve central sensitisation? This rigorous 2026 UK review covers what is actually known, what is biologically plausible, and where the human evidence is entirely absent. Readers may also want the closely related Dihexa for Long COVID Brain Fog review (major fibromyalgia comorbidity), the Dihexa for Chemo Brain review (parallel central neuroinflammation phenotype), the Dihexa for Menopause Brain Fog review (peri-menopausal onset is common), the Dihexa for Sleep & Memory Consolidation review (the Moldofsky alpha-EEG intrusion link), the Dihexa for Anxiety & Chronic Stress review (HPA-axis overlap), the Dihexa for Depression & Mood review (60-80% lifetime co-occurrence) and the Dihexa for Tinnitus & Cochlear Synaptopathy review (the central-gain analogue).

1. What Fibromyalgia Actually Is in 2026: From Tender Points to Nociplastic Pain

Fibromyalgia (FM) is a chronic, multi-system disorder characterised by widespread musculoskeletal pain, persistent fatigue, non-restorative sleep, cognitive dysfunction (“fibro fog”) and a long list of comorbid somatic and psychiatric features. The 1990 American College of Rheumatology (ACR) criteria centred on tender point examination — eliciting pain on 11 of 18 specified sites by 4 kg/cm² digital pressure — an approach that fell out of favour because of inter-rater variability and gender bias. The ACR 2016 revised criteria replaced tender points with the Widespread Pain Index (WPI 0-19) covering body regions where pain was experienced in the prior week, plus the Symptom Severity Scale (SSS 0-12) covering fatigue, waking unrefreshed and cognitive symptoms, with a 3-month chronicity requirement. ICD-11 reframed the condition as chronic primary musculoskeletal pain (MG30.01) within the broader chronic primary pain class.

The conceptual shift since the 2010s has been from a peripheral “muscle disease” or even “something not really wrong” framing to a model of nociplastic pain — pain arising from altered nociception in the absence of identifiable tissue injury or nerve damage. Daniel Clauw and colleagues' Lancet 2021 framework characterised fibromyalgia as the prototypical nociplastic pain disorder, distinguishing it from nociceptive pain (tissue damage, e.g. arthritis) and neuropathic pain (nerve damage, e.g. diabetic neuropathy). Central sensitisation — pathologically heightened responsiveness of central nociceptive neurons to normal or sub-threshold afferent input — is the unifying mechanism. NMDA-receptor-mediated glutamatergic potentiation, GABAergic disinhibition, failure of descending diffuse noxious inhibitory control (DNIC) from the periaqueductal grey / rostral ventromedial medulla, and microglial neuroinflammation all converge on the central sensitisation phenotype.

An important nuance: a subset of fibromyalgia patients — estimated at around 50% in the seminal Oaklander et al. 2013 Pain skin biopsy study — show small fibre neuropathy (SFN) on intraepidermal nerve fibre density (IENFD) measurement or corneal confocal microscopy (CCM). This complicates the “purely central” framing and has spawned a fibromyalgia-with-SFN subgroup that is more reliably distinguished from idiopathic central nociplastic fibromyalgia. The clinical and management implications remain contested, but the finding broke the back of any remaining “all in the patient's head” argument.

The Royal College of Physicians 2022 UK diagnostic guidelines — the first formal UK diagnostic standard — explicitly endorses primary-care diagnosis using the ACR 2016 criteria with a 3-month chronicity requirement, rather than mandatory rheumatology referral. This was a major operational shift: 70-80% of UK fibromyalgia patients are now diagnosed and managed in primary care, with rheumatology / pain clinic referral reserved for diagnostic uncertainty, treatment-refractory cases, or significant rheumatological comorbidity (rheumatoid arthritis, lupus, Sjögren's, hypothyroidism).

1.1 UK Prevalence: ~2.8 Million Adults, 80-90% Female

UK prevalence estimates cluster around ~5.4% of adults, equating to approximately 2.8 million UK adults — figures cited by Versus Arthritis and Fibromyalgia Action UK (FMAUK), and consistent with global prevalence estimates of 2-6% (lower bound for stricter criteria). Lifetime prevalence may be substantially higher because fibromyalgia often follows a relapsing-remitting course and some patients have transient episodes. Women account for 80-90% of diagnosed cases, with mean age of onset 30-50 years and a notable peak around peri-menopause (40-55 years) — one of the reasons it overlaps with menopause brain fog.

Fibromyalgia is profoundly under-diagnosed in the UK. Median time from symptom onset to diagnosis is typically estimated at 2-5 years, with patients frequently cycling through orthopaedic, rheumatology, neurology and gastroenterology referrals before receiving a unifying diagnosis. The Royal College of General Practitioners (RCGP) and the British Pain Society have both flagged primary-care under-recognition as a major service gap, which the RCP 2022 guideline was specifically designed to address.

1.2 The Comorbidity Cluster: ME/CFS, Long COVID, IBS, Migraine and More

Fibromyalgia rarely travels alone. The most consistently documented comorbidities include:

• Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) — overlap as high as 30-70%, with the post-exertional malaise (PEM) phenotype of ME/CFS shared by a substantial fibromyalgia subgroup. The 2021 NICE NG206 ME/CFS guideline interacts with NG193 here. The dedicated Dihexa for ME/CFS review covers the August 2025 DecodeME GWAS preprint, the July 2025 UK ME/CFS Delivery Plan, the Polli 2020 BDNF data and the UBC Nacul LDN trial in detail.
• Long COVID — the post-acute sequelae of SARS-CoV-2 (PASC) phenotype overlaps substantially with fibromyalgia. New-onset post-COVID fibromyalgia and post-COVID worsening of pre-existing fibromyalgia have been widely documented since 2021. See Dihexa for Long COVID Brain Fog.
• Irritable bowel syndrome (IBS) — 30-70% comorbidity; shared central sensitisation; visceral hyperalgesia.
• Migraine and tension-type headache — up to 55% of fibromyalgia patients have migraine; shared CGRP, BDNF and nociplastic biology. See our Dihexa for Migraine & Chronic Migraine 2026 UK review covering the May 2024 NICE TA973 atogepant approval and the BDNF-elevated-in-attack paradox.
• Temporomandibular disorder (TMD) — 30-75% comorbidity; another nociplastic phenotype.
• Interstitial cystitis / bladder pain syndrome — substantial overlap, especially in women.
• Restless legs syndrome (RLS) — 30-50% comorbidity, often missed in standard fibromyalgia work-up.
• Endometriosis — female-specific overlap with substantial central sensitisation contribution.
• Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders — growing recognition since 2017 international hEDS criteria.
• Depression and anxiety — lifetime prevalence 60-80% and 50-70% respectively; see Dihexa for Depression & Mood and Dihexa for Anxiety & Chronic Stress.
• PTSD and adverse childhood experience (ACE) burden — ACE scores are systematically elevated; the trauma-fibromyalgia link is one of the most robust findings in the literature. See Dihexa for PTSD.
• Mast cell activation syndrome (MCAS) — controversial but increasingly recognised in subgroups.

This dense comorbidity cluster — with shared neuroinflammation, central sensitisation and HPA-axis dysregulation across conditions — is the central reason fibromyalgia treatment so often requires multi-system management rather than a single targeted intervention.

2. Fibro Fog: The Cognitive Phenotype That Brings Patients to This Site

Fibro fog — the cognitive symptom cluster of fibromyalgia — is the symptom that most often leads patients to search for nootropics, peptides and supplemental interventions. It encompasses:

• Poor working memory and short-term recall
• Difficulty concentrating, especially with competing stimuli
• Slowed information processing speed
• Mental fatigue disproportionate to exertion
• Word-finding difficulty and dysnomia (tip-of-the-tongue states)
• Impaired executive function, especially task-switching
• Reduced reading comprehension and learning capacity

The January 2026 Brain Sciences case-control study — the most recent rigorous prevalence study — applied the Montreal Cognitive Assessment (MoCA) to fibromyalgia patients and age-and-education-matched pain-free controls and found over 70% of fibromyalgia patients demonstrated below-threshold cognitive performance. Independent predictors included pain severity (visual analogue scale), sleep quality (Pittsburgh Sleep Quality Index), anxiety (HADS-A), depression (PHQ-9) and the Revised Fibromyalgia Impact Questionnaire (FIQR) total score. Earlier prevalence estimates ranged 50-80% depending on case definition, assessment battery and population sampling.

Crucially, actual memory storage capacity appears largely intact in fibromyalgia — what fails is encoding, retrieval and sustained attention under conditions of competing internal stimuli. The patient is not “forgetting” in the Alzheimer's sense; she is being distracted by persistent pain, autonomic noise, intrusive worry and sleep deprivation. This distinction matters clinically because the targets for cognitive remediation are different (attention management, cognitive-behavioural strategies for working memory, sleep optimisation) and because it explains why standard neuropsychological batteries often underestimate the real-world impact.

Fibro fog overlaps phenomenologically with other recognised brain-fog phenotypes covered on this site:

• Chemo brain (chemotherapy-induced cognitive impairment, CICI) — parallel central neuroinflammation
• Long COVID brain fog — shared post-viral microglial activation
• Menopause brain fog — substantial peri-menopausal overlap with fibromyalgia onset
• Diabetic brain fog — shared insulin-resistance and inflammatory contributions
• MCI and brain ageing — the cognitive trajectory question

This is the cluster of conditions where Dihexa's HGF/c-Met / BDNF / synaptogenic mechanism appears, at first glance, most relevant — and where the directionality risk discussed below most needs to be weighed carefully.

3. The 2024 Polli PLOS One BDNF Meta-Analysis and the Albrecht PET Neuroinflammation Story

Two pieces of evidence anchor the molecular biology of fibromyalgia for the purposes of any Dihexa discussion. The first is the BDNF biomarker meta-analysis; the second is the in vivo microglial PET imaging.

3.1 Polli et al. 2024 PLOS One: BDNF Is Elevated, Not Depleted

Anneleen Polli and colleagues published “Brain-derived neurotrophic factor in fibromyalgia: A systematic review and meta-analysis of its role as a potential biomarker” in PLOS One in 2024. They pooled peripheral (serum and plasma) BDNF data from studies comparing adults with fibromyalgia to pain-free controls. The pooled estimate showed peripheral BDNF was significantly elevated in fibromyalgia — the opposite direction from the BDNF deficit pattern in depression, schizophrenia and Alzheimer's disease that underpins most BDNF-promoting nootropic claims.

The historical literature was contested. Haas (2010), Laske (2007) and Zanette (2014) had reported elevated serum BDNF in fibromyalgia, while Pollock and colleagues' 2019 Scientific Reports paper found no difference in plasma BDNF or NGF between fibromyalgia patients and pain-free controls. The Polli meta-analysis is the largest systematic synthesis to date and is the current best estimate — tilting clearly toward elevation.

The mechanistic explanation is that BDNF in pain biology is excitatory, not inhibitory. BDNF binding to TrkB receptors on dorsal horn neurons and central pain pathway nuclei facilitates NMDA-receptor potentiation, increases glutamatergic excitability, downregulates the potassium-chloride co-transporter KCC2 (which causes GABAergic disinhibition), and lowers the pressure-pain and thermal-pain thresholds. Higher BDNF means more pain in the central sensitisation phenotype — not less. The 2022 Mistry exploratory fNIRS-functional-connectivity study of acute pain in fibromyalgia provided some of the most direct evidence linking BDNF genotype (Val66Met) to functional connectivity response to acute pain.

This is the inversion that matters for any synaptogenic peptide discussion in fibromyalgia. The BDNF-elevating effects of Dihexa and fosgonimeton that are desirable in Alzheimer's, mild cognitive impairment, post-stroke recovery and depression may be undesirable in fibromyalgia, where BDNF tone is already pathologically elevated and drives the pain phenotype.

3.2 Albrecht et al. 2019 Brain Behavior & Immunity: The PET Microglia Story

Daniel Albrecht and colleagues at Massachusetts General Hospital / Harvard Medical School (Marco Loggia group) published “Brain glial activation in fibromyalgia — A multi-site positron emission tomography investigation” in Brain Behavior & Immunity in 2019 (initial in 2018). The study used the [¹¹C]PBR28 radioligand, which binds the 18 kDa translocator protein (TSPO) — a mitochondrial protein dramatically upregulated in activated microglia and (to a lesser extent) activated astrocytes — in 31 fibromyalgia patients and 27 healthy controls across two sites.

TSPO binding was significantly elevated in fibromyalgia patients across multiple brain regions, with the largest effects in the thalamus, medial and dorsolateral prefrontal cortex, precuneus and anterior cingulate / insular cortex — a regional pattern that aligns precisely with the central pain processing network (the “pain matrix”). Methodologically, the study controlled for the TSPO rs6971 polymorphism (which affects PBR28 binding affinity), making the elevation a robust finding. The authors concluded that the data “suggest that microglia, but not astrocytes, may be driving the TSPO elevation in these regions”.

This was the first in vivo human evidence of central nervous system glial activation in fibromyalgia — a watershed for the field because it operationally distinguished fibromyalgia from a purely peripheral or psychological condition and grounded the central neuroinflammation hypothesis in measurable imaging data. The 2025 Exploration of Immunology and 2025 Cureus “Fibromyalgia and Inflammation” reviews synthesised the now-substantial neuroinflammation literature into a coherent frame: microglial activation in the thalamus, PFC and insula releases IL-1β, TNF-α, IL-6 and reactive oxygen species, which lower the pain threshold, drive glutamatergic NMDA receptor potentiation and feed the central sensitisation loop.

It is this central neuroinflammation phenotype that provides the rationale for low-dose naltrexone (acting on microglial TLR4) and that underpins the mechanistic argument for any anti-inflammatory or microglia-targeted intervention. It is also the mechanism that any synaptogenic peptide claim has to engage with seriously.

3.3 Where HGF/c-Met Sits in Fibromyalgia (Versus the Russo Transdiagnostic Pattern)

Anthony Russo's transdiagnostic HGF series — covered in the bipolar, depression, anxiety and OCD reviews on this site — documented significantly decreased plasma HGF in bipolar disorder, depression, anxiety, autism spectrum disorder and OCD. Fibromyalgia was not part of the Russo programme. No dedicated systematic measurement of plasma HGF or c-Met expression in fibromyalgia versus controls has been published as of May 2026. This is a meaningful evidence gap.

What can be said: the c-Met receptor is widely expressed in CNS neurons, microglia and astrocytes; HGF/c-Met signalling has demonstrated roles in microglial polarisation toward an anti-inflammatory (M2-like) phenotype; HGF has demonstrated blood-brain barrier sealing effects on cerebrovascular endothelium; and HGF/c-Met activation potentiates BDNF/TrkB signalling. In a disorder with central microglial activation (Albrecht 2019), peripheral BDNF elevation (Polli 2024) and central sensitisation, the HGF/c-Met axis is theoretically engaged but in opposing directions: anti-microglial-inflammatory (potentially helpful) vs BDNF-synaptogenic (potentially harmful by consolidating central sensitisation).

This pleiotropy is exactly why the “HGF/c-Met activation is good for cognition” intuition from Alzheimer's research does not transfer cleanly to fibromyalgia, and why the absence of any human Dihexa trial in nociplastic pain populations is not a small detail but a fundamental safety question.

4. The 15 August 2025 FDA Approval of Tonmya (TNX-102 SL): First New Fibromyalgia Drug in 15 Years

On 15 August 2025, the US Food and Drug Administration approved Tonix Pharmaceuticals' Tonmya (cyclobenzaprine HCl sublingual tablets, investigated as TNX-102 SL) for the management of fibromyalgia in adults. It is the first new FDA-approved fibromyalgia medication in 15 years — following pregabalin (Lyrica, 2007), duloxetine (Cymbalta, 2008) and milnacipran (Savella, 2009).

4.1 What Tonmya Actually Is

Cyclobenzaprine has been around since the 1970s as an oral muscle relaxant (Flexeril and generics), used short-term for muscle spasm. The Tonix innovation is the sublingual delivery: a patented formulation that dissolves under the tongue at bedtime, providing rapid transmucosal absorption that bypasses first-pass hepatic metabolism. The clinical consequence is dramatically reduced formation of the long-half-life metabolite norcyclobenzaprine, which is responsible for the morning sedation and anticholinergic effects that limited oral cyclobenzaprine's tolerability in chronic pain populations. Tonmya is mechanistically classified as a non-opioid analgesic — its activity is thought to involve 5-HT_2A, α₁-adrenergic and H₁-histamine receptor antagonism, with the analgesic and sleep-quality effects derived from these convergent serotonergic, noradrenergic and histaminergic actions in pain and sleep pathways.

4.2 The Phase 3 RELIEF and RESILIENT Trials

FDA approval was based on two double-blind, randomised, placebo-controlled Phase 3 trials in approximately 1,000 adult fibromyalgia patients in total — the RELIEF and RESILIENT studies. Both trials evaluated Tonmya 5.6 mg sublingual at bedtime against placebo over 14 weeks, with the primary endpoint being change from baseline in weekly mean daily pain severity. Both trials hit the primary endpoint with statistically significant reductions in daily pain versus placebo. Secondary endpoints showed consistent improvements in sleep quality (Pittsburgh Sleep Quality Index), fatigue (Multidimensional Assessment of Fatigue), patient global impression of change (PGIC) and the FIQR. Safety was reassuring: the most common adverse events were sublingual application-site reactions (tongue numbness, hypoaesthesia, paraesthesia, taste alteration), somnolence (less than oral cyclobenzaprine because of reduced norcyclobenzaprine), dry mouth and headache. Serious adverse events did not differ from placebo.

4.3 Q4 2025 US Launch — No UK MHRA Submission

Tonix announced US commercial launch in Q4 2025 with a focused specialty prescribing footprint targeting primary care, rheumatology and pain medicine. As of May 2026 there is no disclosed UK MHRA submission, so UK patients cannot access Tonmya on the NHS or via UK private prescription. UK patients seeking equivalent benefit may discuss off-label low-dose oral amitriptyline (10-50 mg at bedtime), nortriptyline or trazodone with their GP — all are extensively used in UK fibromyalgia practice despite NICE NG193's narrow antidepressant list. Whether Tonmya will reach the UK in 2026 or 2027 is uncertain and depends on Tonix's commercial priorities.

The strategic significance for any Dihexa discussion is twofold: (1) the regulatory pipeline for fibromyalgia is no longer empty — there is a legitimate new prescription option; (2) the molecule that finally crossed the FDA bar is a centrally-acting receptor antagonist that dampens 5-HT_2A, α₁ and H₁ signalling, not a synaptogenic growth-factor pathway activator. The therapeutic logic is suppressive, not stimulative.

5. Low-Dose Naltrexone (LDN): The ACR Convergence 2025 and Annals of Medicine and Surgery Meta-Analysis

Low-dose naltrexone (LDN) — typically 1.5 to 4.5 mg at bedtime, roughly one-tenth to one-twentieth of the 50 mg daily dose licensed for opioid and alcohol use disorder — has been studied in fibromyalgia for nearly two decades, originally by the Stanford Younger group (2009, 2013). The mechanistic hypothesis is that low-dose naltrexone acts as an antagonist at toll-like receptor 4 (TLR4) on microglia, suppressing microglial activation and downregulating the release of IL-1β, TNF-α and IL-6 — the central neuroinflammation Albrecht and colleagues imaged in vivo. The transient opioid receptor antagonism at low dose may also provoke a compensatory upregulation of endogenous opioid signalling.

The evidence base reached a turning point in 2025. In May 2025, the Annals of Medicine and Surgery published a systematic review and meta-analysis of LDN in fibromyalgia pooling RCT and prospective cohort data. The pooled effect estimate showed clinically meaningful reductions in pain (VAS, FIQR) and improvements in function, with a favourable safety profile. The most consistent adverse effect was vivid dreams (a well-known LDN signature that overlaps mechanistically with the REM sleep and dream intensification sometimes attributed to BDNF-modulating peptides), while headache and nausea were not significantly different from placebo. At ACR Convergence 2025 (November 2025, Washington DC), further positive efficacy and safety data were presented.

5.1 LDN in the UK: Private Specialist Only, Variable NHS Access

In the UK, naltrexone is licensed only at the 50 mg dose for alcohol and opioid use disorder. Low-dose naltrexone is an unlicensed special for fibromyalgia (and other indications including Crohn's disease, multiple sclerosis, complex regional pain syndrome) and is typically prescribed only via specialist private clinics. Dickson Chemist (Glasgow) is the largest UK supplier of LDN compounded specials. NHS access is highly variable; most Integrated Care Boards do not fund LDN for fibromyalgia, and GPs are usually unwilling to prescribe it on shared-care arrangements because it sits outside NICE NG193 recommendations. Patients with the financial means and the motivation often pursue it privately, typically paying £25-50 per month for the compounded prescription plus the private specialist consultation fee.

In April 2025, the ME Association, the UK's largest charity for people with ME/CFS, announced funding for a 9-month University of British Columbia trial of LDN in ME/CFS and Long COVID led by Dr Luis Nacul, starting in March 2025. This is significant for fibromyalgia because of the substantial overlap with ME/CFS and Long COVID populations — positive data from this trial would inevitably feed into the broader fibromyalgia evidence base.

LDN is not a Dihexa-class molecule. The mechanism is the opposite direction: anti-neuroinflammatory suppression of microglial activation rather than synaptogenic activation of HGF/c-Met / BDNF / TrkB. In a disorder of central neuroinflammation and BDNF excess, the LDN direction-of-effect aligns with the pathophysiology in a way the Dihexa direction-of-effect arguably does not.

6. NICE NG193 and the RCP 2022 Guidelines: The 2026 UK Treatment Pathway

The two UK reference documents are NICE NG193 (“Chronic pain (primary and secondary) in over 16s: assessment of all chronic pain and management of chronic primary pain”, published April 2021) and the Royal College of Physicians 2022 UK clinical guidelines for the diagnosis of fibromyalgia syndrome.

6.1 NICE NG193 and the Controversial Pharmacological Recommendations

NG193 categorises fibromyalgia as chronic primary musculoskeletal pain (consistent with ICD-11 MG30.01) and recommends against initiating the following for chronic primary pain in adults:

• Paracetamol
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Benzodiazepines
• Opioids (any)
• Antiepileptics including gabapentinoids: gabapentin and pregabalin (Lyrica)
• Local anaesthetics (orally)
• Ketamine
• Corticosteroids

NG193 does permit the following antidepressants for chronic primary pain in adults — explicitly noting they are being prescribed off-label for pain rather than for depression:

• Amitriptyline (tricyclic; low-dose 10-50 mg at bedtime)
• Citalopram (SSRI)
• Duloxetine (SNRI; widely used; the closest UK off-label analogue to Cymbalta's FDA fibromyalgia indication)
• Fluoxetine (SSRI)
• Paroxetine (SSRI)
• Sertraline (SSRI)

NG193's exclusion of gabapentinoids and opioids was controversial on publication and remains so. Versus Arthritis publicly criticised the restriction, arguing it stripped clinicians of options that were working for individual patients. The clinical reality in 2026 is that many UK fibromyalgia patients are still on legacy pregabalin or gabapentin prescriptions from before NG193 (which only restricts initiation, not continuation in patients with established benefit). Tramadol and other weak opioids are still occasionally prescribed in UK practice despite the guideline.

The core non-pharmacological recommendations of NG193 are robust and uncontroversial: supervised exercise programmes (graded aerobic, resistance, tai chi, qigong, yoga; supervised hydrotherapy is widely used), psychological therapy (CBT, ACT, mindfulness-based stress reduction), and patient-centred care that supports self-management.

6.2 The RCP 2022 Diagnostic Guidelines: Primary-Care Diagnosis Endorsed

The RCP 2022 guidelines were the first formal UK diagnostic standard for fibromyalgia. They:

• Operationalise diagnosis using the ACR 2016 Widespread Pain Index (WPI ≥7 with SSS ≥5, or WPI 4-6 with SSS ≥9) plus the 3-month chronicity requirement
• Explicitly endorse primary-care diagnosis, removing the previous de facto requirement for rheumatology referral
• Provide guidance on when rheumatology / pain medicine referral remains appropriate (diagnostic uncertainty, treatment failure, complex comorbidity, paediatric presentation)
• Recommend screening for and excluding mimics: rheumatoid arthritis, lupus, Sjögren's, hypothyroidism, vitamin D deficiency, polymyalgia rheumatica (in older patients), spondyloarthropathy, inflammatory myopathies
• Provide structured patient communication frameworks — particularly important given how often the diagnosis is delivered poorly

The combined effect of NG193 and the RCP 2022 guideline is a UK pathway centred on GP-led diagnosis and management, with supervised exercise + psychological therapy as the core, a narrow list of off-label antidepressants permitted, and rheumatology / pain medicine reserved for the more complex or refractory cases.

6.3 UK Charities and Patient Resources

The key UK fibromyalgia organisations:

• Fibromyalgia Action UK (FMAUK) — the largest UK fibromyalgia charity; helpline, peer support groups, patient information
• Versus Arthritis — the UK's largest arthritis and musculoskeletal charity; comprehensive fibromyalgia information, helpline 0800 5200 520
• Pain Concern — UK chronic pain charity; helpline, peer-support podcasts
• The British Pain Society — professional body, patient-facing leaflets
• NHS Inform Scotland — patient-facing self-management resources
• NIHR Be Part of Research — UK-wide research registry for fibromyalgia trials

7. The Sleep Architecture Story: Alpha-EEG Intrusion, Moldofsky 1975 and Why Tonmya Works at Bedtime

The seminal sleep finding in fibromyalgia is the alpha-EEG intrusion phenomenon described by Harvey Moldofsky and Hugh Smythe in their 1975 Psychosomatic Medicine paper. They showed that healthy volunteers experimentally deprived of stage 4 (deep, slow-wave) NREM sleep — by selective acoustic disruption every time the EEG showed slow-wave activity — developed fibromyalgia-like widespread musculoskeletal pain and fatigue within days. Conversely, fibromyalgia patients showed an abnormal EEG pattern in which alpha rhythm (typically a wakeful, eyes-closed rhythm) intruded into slow-wave NREM sleep, fragmenting deep restorative sleep.

Modern polysomnography in fibromyalgia consistently shows reduced slow-wave sleep, increased sleep fragmentation, more arousals, lower sleep efficiency and a higher prevalence of comorbid sleep disorders (obstructive sleep apnoea, restless legs syndrome, periodic limb movement disorder). The 2026 clinical trial NCT07358754 at Kanuni Sultan Suleyman Training and Research Hospital (Istanbul) is investigating the relationship between serum S100B, BDNF, central sensitisation and sleep quality in fibromyalgia — a study that may further clarify how the BDNF and sleep architecture pieces fit together.

This sleep architecture pathology is the reason the bedtime dosing of Tonmya matters mechanistically — the sublingual cyclobenzaprine formulation was specifically designed to improve sleep quality (deepening sleep, reducing arousals, decreasing alpha intrusion) as the principal route to next-day pain reduction. The same is true of low-dose amitriptyline and nortriptyline in UK practice. Sleep optimisation is not adjunctive in fibromyalgia — it is core.

For readers exploring whether Dihexa's effects on sleep, dreaming or memory consolidation might intersect with the fibromyalgia sleep phenotype, the Dihexa for Sleep & Memory Consolidation review covers the BDNF / dreaming / slow-wave sleep biology in much more depth. The short answer: there is no evidence that synaptogenic peptide activity improves alpha-EEG-intrusion-driven sleep fragmentation, and there is a credible theoretical concern that elevated BDNF/TrkB signalling at bedtime could worsen rather than improve sleep architecture in fibromyalgia.

8. Dihexa's HGF/c-Met Mechanism Against the Fibromyalgia Pathology Map

Dihexa (PNB-0408) is a hexapeptide derivative of angiotensin IV developed by the Joseph Harding group at Washington State University. The key mechanistic paper is Benoist et al. 2014 in the Journal of Pharmacology and Experimental Therapeutics: “The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-Met system.” The paper demonstrated that the cognitive enhancement and dendritic spine formation produced by Dihexa and related peptides in hippocampal cultures and rodent learning paradigms are abolished by c-Met inhibition, anchoring the HGF/c-Met receptor as the proximate target. The 2015 Wright & Harding review in Journal of Neurochemistry mapped HGF/c-Met expression across the CNS and made the case for c-Met as a target in Alzheimer's disease — the path that later led to fosgonimeton (ATH-1017) and the Athira Pharma LIFT-AD, ACT-AD and SHAPE clinical programmes. For a comprehensive treatment see Dihexa Mechanism of Action, Fosgonimeton & Athira and Dihexa & BDNF.

8.1 Mapping HGF/c-Met Activity Against the Fibromyalgia Pathology Axes

Fibromyalgia pathology can be decomposed into roughly five axes. For each, the Dihexa / HGF-c-Met mechanism has a defensible direction-of-effect:

(1) Central sensitisation / NMDA potentiation / GABAergic disinhibition. Dihexa's synaptogenic, BDNF/TrkB-elevating activity is directionally aligned with the disease, not against it. Higher BDNF facilitates NMDA-receptor potentiation; this is exactly what central sensitisation already does. Direction of effect: pro-pathology (potentially harmful).

(2) Microglial / TSPO neuroinflammation (Albrecht 2019). HGF/c-Met activation has demonstrated effects on microglial polarisation toward an anti-inflammatory (M2-like) phenotype in non-CNS injury models. Direction of effect: anti-pathology (potentially helpful). The strength of this signal in the human CNS remains uncertain.

(3) BDNF elevation (Polli 2024). Peripheral BDNF is already elevated in fibromyalgia. Pushing BDNF/TrkB signalling further is the opposite of what the biomarker direction suggests. Direction of effect: pro-pathology (potentially harmful).

(4) Small fibre neuropathy (Oaklander 2013). No evidence that HGF/c-Met activation restores intraepidermal nerve fibre density. Peripheral nerve regeneration is a different signalling cascade. Direction of effect: neutral / weak.

(5) Fibro fog cognitive phenotype. This is the axis where the Dihexa rationale is most superficially compelling. HGF/c-Met activation in hippocampus and prefrontal cortex would, in principle, enhance memory encoding, working memory and attention. But the fibro fog mechanism is driven by competing internal pain stimuli, sleep fragmentation and HPA dysregulation — not by a primary deficit in hippocampal LTP capacity. Direction of effect: potentially helpful for cognition in isolation; offset or reversed if pain consolidation worsens.

The net is that the synaptogenic axis dominates the safety calculus. Even if HGF/c-Met activation modestly improves attention and working memory, it does so in a system where the cost — potential consolidation of central sensitisation and worsening pain — could substantially outweigh the cognitive benefit. This is the same argument structure as in the tinnitus, OCD and bipolar (manic-switch) reviews.

8.2 Fosgonimeton (ATH-1017) Has Never Been Tested in Fibromyalgia

The closest clinical analogue to Dihexa — fosgonimeton (ATH-1017), the small-molecule HGF/c-Met positive modulator developed by Athira Pharma — has run trials in Alzheimer's disease (LIFT-AD Phase 2/3, ACT-AD Phase 2), Parkinson's disease dementia and dementia with Lewy bodies (SHAPE Phase 2). None of these programmes has included a fibromyalgia, chronic widespread pain or nociplastic pain cohort. There are no fosgonimeton data on chronic pain populations, no safety signal data on central sensitisation worsening, no efficacy data on fibro fog. The HGF/c-Met clinical platform is, in 2026, entirely focused on neurodegenerative cognitive disorders — not on nociplastic pain.

9. What UK Fibromyalgia Patients Are Actually Using in 2026 (Including Things Not in NG193)

Real-world UK fibromyalgia patient self-management in 2026 routinely extends well beyond the narrow NG193-permitted antidepressant list. Common patterns:

• Off-label gabapentinoids — despite NG193's restriction on initiation, established pregabalin and gabapentin prescriptions are widely continued where individual benefit is documented
• Low-dose amitriptyline / nortriptyline — the most prescribed UK off-label option, often at 10-30 mg at bedtime; the closest UK functional equivalent to Tonmya
• Duloxetine — the most prescribed SNRI for fibromyalgia in UK practice; explicitly permitted by NG193
• Low-dose naltrexone (LDN) — private specialist prescription; growing usage
• CBD oil — widely self-purchased over-the-counter in the UK as a food supplement; mixed evidence; no UK MHRA medicinal authorisation for fibromyalgia
• UK-specialist medical cannabis — available through CQC-registered private clinics under MHRA Specials regulations; off-label for fibromyalgia; expensive
• Palmitoylethanolamide (PEA) — an endogenous fatty acid amide with microglial-modulating activity; available as a food supplement; small but supportive RCT evidence
• Vitamin D repletion — deficiency common; correction sometimes meaningfully reduces pain
• Magnesium glycinate — sleep and muscle tension; broadly safe; modest evidence
• Coenzyme Q10 (CoQ10) — mitochondrial bioenergetic support; some small RCT evidence in fibromyalgia
• Melatonin — sleep architecture; useful adjunct; available OTC in UK
• SAMe and 5-HTP — serotonergic support; available OTC; older positive RCT evidence
• Bacopa monnieri, ashwagandha, rhodiola — nootropic adaptogens for fibro fog and HPA-axis support; modest evidence
• tDCS / transcranial direct current stimulation — non-invasive brain stimulation over motor cortex or DLPFC; growing UK availability through pain clinics

None of these are Dihexa-class molecules. None have the synaptogenic / HGF/c-Met mechanism that would make them theoretically problematic in the central-sensitisation directionality discussion above. Most are well-tolerated and most fit naturally with the NG193 + RCP 2022 framework rather than against it.

10. Bottom Line: Why Dihexa Cannot Be Recommended for Fibromyalgia in 2026

The fibromyalgia case for Dihexa is in some ways one of the most superficially attractive on this site. The condition is enormously prevalent (2.8 million UK adults), profoundly under-served (one new FDA drug in 15 years, no UK MHRA approval for the new one, a NICE guideline that restricts most existing analgesic options), and the cognitive symptom cluster — fibro fog — sits squarely in the BDNF / synaptic plasticity / cognitive-enhancement narrative space where Dihexa marketing claims congregate. The patient demand for an effective nootropic-class peptide is real, urgent, and rational.

But three pieces of biology argue against rather than for Dihexa in fibromyalgia:

1. Peripheral BDNF is already elevated (Polli 2024 PLOS One meta-analysis), and elevated BDNF in pain biology drives central sensitisation via NMDA potentiation and GABAergic disinhibition. Pushing BDNF higher is directionally wrong.
2. Central neuroinflammation (Albrecht 2019 multi-site PET) is the dominant in vivo signature of fibromyalgia CNS pathology, and the molecules currently working for fibromyalgia (LDN, Tonmya, duloxetine) work by suppressing, not stimulating, central excitability.
3. Zero human evidence — Dihexa has never been tested in any fibromyalgia, chronic widespread pain, or nociplastic pain cohort; fosgonimeton has never been tested in any pain population at all.

The directionality risk is the same family of concern that runs through the tinnitus central-gain, OCD CSTC-consolidation, bipolar manic-switch, and schizophrenia prodrome reviews on this site: a synaptogenic peptide that strengthens dendritic spines and consolidates learned circuits is potentially helpful where the underlying pathology is loss-of-circuits (Alzheimer's, post-stroke, vascular dementia) and potentially harmful where the underlying pathology is over-strengthened, maladaptive circuits (central sensitisation, intrusive memories, manic mood states).

The evidence-based 2026 UK pathway for fibromyalgia is clear: GP-led assessment under the RCP 2022 diagnostic guideline, management under NICE NG193, supervised exercise + psychological therapy as the core, off-label antidepressant choice (amitriptyline, duloxetine, sertraline, citalopram, paroxetine, fluoxetine) where pharmacological support is needed, consideration of LDN via a private specialist if NHS pathways have failed, and watching the UK regulatory landscape for whether Tonmya reaches MHRA submission in 2026-2027. Sleep optimisation, sleep disorder screening (obstructive sleep apnoea, restless legs syndrome), and active management of comorbid depression, anxiety and PTSD are not adjunctive — they are core. Versus Arthritis, Fibromyalgia Action UK and Pain Concern provide good UK patient resources and helpline support.

Dihexa, in 2026, is the wrong molecule for fibromyalgia — not because the mechanism is uninteresting but because the mechanism points in the wrong direction for the disease, the human data are absent, and the proven, less-exotic options are real and worth pursuing first.

Key Sources & Further Reading

• Polli A, et al. (2024). Brain-derived neurotrophic factor in fibromyalgia: A systematic review and meta-analysis. PLOS One
• Albrecht DS, et al. (2019). Brain glial activation in fibromyalgia — A multi-site PET investigation. Brain Behavior & Immunity
• Cognitive Dysfunction in Fibromyalgia (January 2026). Brain Sciences — MoCA case-control prevalence and predictors
• Efficacy and safety of low-dose naltrexone (LDN) in fibromyalgia: systematic review and meta-analysis (May 2025). Annals of Medicine and Surgery
• Tonix Pharmaceuticals (15 August 2025). FDA approval of Tonmya (TNX-102 SL) for fibromyalgia — press release
• Psychiatric Times coverage: FDA approves Tonmya, first fibromyalgia medication in 15 years
• Royal College of Physicians (2022). The diagnosis of fibromyalgia syndrome: UK clinical guidelines
• NICE NG193 (April 2021). Chronic pain (primary and secondary) in over 16s
• Versus Arthritis — Fibromyalgia (UK patient resource)
• Fibromyalgia Action UK (FMAUK)
• NHS Inform Scotland — Fibromyalgia
• ME Association (April 2025) — UK charity invests in UBC LDN trial for ME/CFS and Long COVID
• Fibromyalgia and Inflammation (2025). Cureus — PMC11853252
• Neuroinflammatory and Immunological Aspects of Fibromyalgia (2025). Exploration of Immunology
• Oaklander AL, et al. (2013). Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain
• Benoist CC, et al. (2014). The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-Met system. J Pharmacol Exp Ther
• ClinicalTrials.gov NCT07358754 — Serum S100B / BDNF and central sensitisation in fibromyalgia (start: February 2026)