Hi Friend,
Last week we got into the biology. Central sensitisation, wind-up, microglial activation, the sleep loop that keeps the whole thing running. This week I want to talk treatment, and none of it makes sense without that foundation, which is why I spent two issues laying it down first.
I'm going to be honest with you, which means this is not a tidy list of five things to try. The treatment landscape for fibromyalgia is messy. Things get recommended constantly on weak evidence, and things with genuinely decent evidence barely get mentioned because they don't fit a ten-minute appointment. I'd rather you had the real picture than a comfortable one.
Start with what doesn't work, because this matters
Conventional painkillers, paracetamol, ibuprofen, codeine, opioids, have consistently poor outcomes in fibromyalgia. Not because your pain isn't real. Because the pain isn't coming from where those drugs are aimed. If the problem is an amplifier stuck on high, reducing peripheral inflammation does very little to the signal being amplified.
Opioids deserve a specific mention. Still prescribed for fibromyalgia despite poor evidence, and there's a condition-specific problem called opioid-induced hyperalgesia, where long-term use can wind the central system up further rather than calming it. If you're on them, I'm not telling you to stop, and you should never stop opioids abruptly without medical support. But it's a conversation worth having with whoever prescribes for you.
Repeated imaging, joint injections, passive physiotherapy as a standalone treatment. Poor outcomes when the central nervous system is the actual driver. Aimed at the wrong level of the problem.
What the evidence genuinely supports
Two long-standing medications have a real evidence base and are used at lower doses than people expect. Amitriptyline, a tricyclic used well below antidepressant dosing, where it works on sleep architecture and descending pain inhibition rather than mood. And duloxetine, which acts on the serotonin and noradrenaline systems we covered, the same systems that run depleted in central sensitisation. Neither is a cure. Each helps a meaningful subset of people. The skill is matching the drug to which part of your picture is loudest rather than working through them at random, which is the entire reason for understanding your individual biology first.
There is also now, for the first time in over fifteen years, a medication developed and licensed specifically for fibromyalgia rather than borrowed from another condition. It's called Tonmya, a bedtime under-the-tongue form of an old muscle relaxant, cyclobenzaprine, reformulated to target the non-restorative sleep that drives so much of the central sensitisation we talked about last week. In its trials it produced statistically significant reductions in daily pain. One important caveat for us specifically: this is currently a US approval and US launch. It is not yet available on prescription in the UK, and whether or when it reaches us through licensing or private routes is still unfolding. I'm telling you it exists so you understand the direction of travel and can ask an informed question when the time comes, not because you can get it here tomorrow.
Pain neuroscience education has surprisingly strong evidence, and I'm careful here because the concept gets misused constantly. It is not being told your pain is psychological and to think positively. It is detailed, structured teaching about what central sensitisation actually is, exactly what these last few newsletters have been doing. When people genuinely grasp that the danger signal is a processing error rather than a tissue problem, the brain re-reads the signal and the output changes. Measurable pain reductions in the trials. Neuroscience, not attitude.
Graded activity and genuine pacing work for the same reason. A sensitised nervous system has learned that movement equals threat. Careful, consistent, within-tolerance activity slowly builds counter evidence. It is slow, and it asks for a patience the condition itself makes very hard. But it works at the right level, which most things don't.
Low-dose naltrexone, worth knowing about
This comes up constantly in chronic illness circles and I want to give you the honest version, not the hyped one.
Naltrexone is an old, cheap drug. At low doses, far below its normal use, the proposed mechanism is exactly the one we covered last week: calming activated microglia and reducing the neuroinflammation lowering your pain threshold from the inside. On paper it targets the biology beautifully.
The evidence is genuinely mixed and I won't pretend otherwise. Several reviews through 2025 found it modestly reduces pain versus placebo with a favourable safety profile, the most common side effect being vivid dreams. But some larger recent trials have not confirmed clear benefit, and most reviewers still rate the overall strength of evidence as low. It isn't licensed for fibromyalgia, so it's prescribed off-label, usually via a compounding pharmacy, and you will often have to advocate for it. My honest read: low-risk, low-cost, mechanistically sensible, worth a properly monitored trial for the right person, but not the miracle some corners of the internet present. Some people get substantial relief. Others get nothing. That unpredictability is itself a clue, and I'll come back to it.
Mestinon, a more specialist consideration
Some of you reading this don't have fibromyalgia in isolation. You have the fatigue-dominant, autonomic-heavy picture, the kind that overlaps with ME/CFS and dysautonomia, where standing up is its own daily battle.
In that specific subgroup, a medication called Mestinon, the brand name for pyridostigmine, is sometimes used by specialists. It works on a different mechanism to everything else here, supporting signalling in the autonomic nervous system, and the interest in it is mainly for people whose picture is dominated by orthostatic symptoms and post-exertional crashes rather than pain alone.
I want to be careful and clear about this one. It is firmly an off-label, specialist-initiated treatment. It is not a fibromyalgia drug, the evidence base is limited and largely in the autonomic and ME/CFS space, and it is absolutely not something to source or trial independently. It needs a clinician who knows your full picture, can assess whether the autonomic component justifies it, and can monitor you properly. I include it here only so that if your picture is the autonomic-dominant kind, you know it exists as a conversation to have with the right specialist, not as something to pursue alone.
GLP-1 medications, genuinely new and genuinely preliminary
You've heard of these for weight loss and diabetes. They're appearing in chronic pain conversations because the same anti-inflammatory and microglial mechanisms keep surfacing.
Here's what actually exists. Large real-world database analyses through 2025 and early 2026 found fibromyalgia patients on GLP-1 medications had lower recorded pain, less fatigue, and notably reduced opioid use compared with matched patients who weren't. Animal work with semaglutide showed reduced pain and the same shift from inflammatory to anti-inflammatory microglial activity we keep returning to.
I want to be very clear what this is and isn't. These are observational and preclinical signals, not randomised controlled trials. The improvements may partly reflect weight, blood sugar, or other factors rather than a direct effect on pain processing. No GLP-1 is approved for fibromyalgia, and I'm not suggesting anyone pursue one for this reason. I include it because you deserve to know what's genuinely on the horizon, and because when your GP eventually hears about this, you'll understand the mechanism better than the headline does.
Why the same treatment helps one person and does nothing for another
This is the part almost nobody says plainly. Fibromyalgia is not one thing. It's a shared endpoint people reach through different routes, different histories, different nervous systems. Someone whose picture is driven mainly by wrecked sleep needs a different emphasis than someone whose picture is dominated by mast cell activity, or autonomic dysfunction, or an old threat the nervous system never stood down from. That is exactly why one person thrives on amitriptyline and another gets nothing, why LDN transforms one life and does nothing for the next, why the autonomic subgroup needs a completely different conversation.
A generic protocol treats the label as though it tells you everything. It doesn't. The label tells you there's central sensitisation. It doesn't tell you what's feeding it in your specific case, and that is the question that actually decides what works for you.
Next week I'll start pulling that apart: how to work out what's likely driving your particular picture, and how to build an approach around your biology rather than someone else's average.
As always, if you'd rather not do that detective work alone, that's exactly what the Mend Chronic Illness Roadmap Service is built for. Full details here.
Next week I will also be sending out a email about what condition/condition’s you would like more info on. This will allow me to send you more personal newsletters.
Stay Well
Dr Ahmed
Disclaimer
This newsletter is for general information and education only. It is not medical advice, and it does not replace a consultation with a qualified healthcare professional who knows your individual history.
Nothing here is a recommendation to start, stop, or change any medication. Treatments are discussed to help you understand the landscape and have better-informed conversations with your own doctors, not to guide self-treatment. Medications mentioned, including those used off-label, carry risks and are only appropriate for some people. Decisions about them must be made with a prescriber who can assess your full clinical picture.
Some treatments discussed may not be licensed or available in your country, and regulatory status varies by region and over time. Mention of a medication does not imply it is suitable, available, or recommended for you.
Never start or stop a prescribed medication without medical supervision. Stopping some medications abruptly can be harmful.
If you have urgent or serious symptoms, contact your GP, NHS 111, or emergency services rather than waiting for newsletter content or any service response.
