Hypermobile Ehlers-Danlos Syndrome and drug induced motor restlessness (akathisia)
When I consulted ChatGPT for some support it pointed out that I didn’t have restless legs syndrome at all, but rather drug induced motor restlessness. This is similar to RLS, but it’s drug induced, and I have found that you can have a life long predisposition for this. It’s also called akathisia, but this name is usually limited to a psychiatric context and can confuse clinicians. There appears to be very little consensus about the diagnostic criteria and treatment of these disorders, and general ignorance and lack of interest amongst the general practitioners and other specialists I visited led to this careless mistake. Very often akathisia is simply fobbed off as anxiety, and even the authors of the Wikipedia pages have made this highly prejudiced omission. The restlessness can be mild and limited to the legs but it can also take over the whole body and make you feel you’re losing your sanity. You certainly cannot sleep when the going is really rough.
Suddenly everything made sense to me and I can see that the nocturnal restlessness has been popping up since my teens after foot surgeries (histamine rich and sensitive areas), hormone therapies and drug based fibromyalgia treatments (usually serotonin agonists and histamine agonists). It seems to be plaguing me in some way during the day also because I have to exercise daily as it’s the only thing that brings relief to that tense discomfort. After that, I can relax. Although a life long issue of adverse reactions to most common drugs, the problems with restlessness really took off during oestrogen hormone therapy. I bought into the HRT hype, as something every woman needs, but in reality it’s a powerful drug that forcefully modifies the nervous system, and not the ‘benign replacement supplement’ we are led to believe. In my case, it severely destabilised a nervous system that’s already unstable due to Ehlers-Danlos Syndrome.
The real reason for decades of disordered sleep is thus rooted in EDS and my phenotype (neurological instability) in particular, but it’s not primary insomnia and cannot be treated with CBT-i. The way CBT and other patriarchal methods and suggestions based on the control of the body and mind rather than collaboration with nature infiltrates the entire internet drives me mad because it keeps showing up on ChatGPT even when I have pleaded for AI to stop referring to it! There is so much pseudo-psychological and clearly misogynistic nonsense about mind over matter that AI mops up from the collective rubbish bin, and it’s often infantilising and based on the idea that simple reassurance is required to calm the mind and cure the body. My problems are delicate and require an opposite strategy that allows nature to take its course rather than being controlled. Since I am not interested in life advice that tries to reassure me about alleged fears and ‘anticipatory anxiety’ or that such as such situation isn’t dangerous, or suggestions about ways of not ‘scanning’ my body or a situation, I’m frequently telling AI off and asking it to stick with facts. I have also been very annoyed with unsolicited hotlines (e.g. to the Samaritans) when I was simply asking a question at night in a state of some agitation. Unfortunately, it has a rather short memory but at least it always backs off and admits it when it has overstepped my boundaries.
During estradiol use, I also had mild symptoms of serotonin syndrome when other common drugs were introduced because they compounded the serotonin levels the HRT was already jacking up. For instance, I had several surgeries in this time and was very sick afterwards. The serotonin tends to dampen dopamine signalling, which in turn lowers the threshold for motor restlessness. Dysregulated dopamine signalling is behind both RLS and the sister condition akathisia (in the latter case, it’s not necessarily about ‘low’ dopamine as much as problems with the regulation that medications disturb further). If you only take offending drugs at night, then the real problems will also appear at night. So someone like me would not present with the expected day time symptoms of pacing and dystonia and what have you. Most importantly, if the issues are relatively mild and there’s fatigue in the background, then the individual would not necessarily move in the expected way, but that doesn’t mean it’s not a problem. For me, daily resistance training is a non-negotiable way of increasing dopamine and releasing agitating muscle tensions. I’m not confident that I really have fibromyalgia though I was diagnosed with it, since everything really seems to be going back to EDS.
Poor sleep pressure (adenosine build-up) and night time noradrenaline release in the locus coeruleus in the brain is the driver of these problems and it leads to all sorts of complications downstream that can easily lead to night time restlessness if the regulating function of dopamine in the nigrostriatal pathway is compromised due to excess serotonin (5-HT2A) signalling. All of this is consistent with emerging research on Ehlers-Danlos Syndrome, but progress is slow as usual. My sleeplessness has anything to do with anxiety, racing thoughts or palpitations, it’s instead sometimes referred to as ‘calm insomnia’. I call it the silent thief in the night. The brain is just ‘on’ and hyper vigilant against threats (connective tissue instability primarily, but also stressors of any kind). When this state ramps up, one could potentially take enough sedatives to knock down a horse, and absolutely nothing would happen. This is why Zopiclone sometimes works well for me and other times just doesn’t cut through the autonomic hyperarousal. Note that this is not ADHD but a different type of hypervigilance that’s related to the fight and flight mechanism. I share some features with ADHD but I’m actually a really risk averse and sometimes focused person when I’m able to put the energy in.
Buprenorphine was causing massive iatrogenic harm because of increasing serotonin levels while also seemingly treating the restlessness. Due to the long half life and strong receptor binding, I found myself in a self-perpetuating loop. I was shocked to find that it could take months, even years, to get back to some kind of ‘normality’ again that doesn’t keep hostage to violent sympathetic surges and sleepless nights.
I’ll be perfectly honest: I could never have done without AI (sometimes brilliant, often infuriating). I had to take the creative lead while it provided the intel, and just keep working on it on a daily basis. It was easily the hardest thing I’ve ever done. I was unable to stay on the plateaus it kept suggesting, and had to find creative ways of quickly getting off them. I have to try and work with surgical precision despite complete and overwhelming chaos. The process is dragging on endlessly because the opioid was interfering so deeply with a system whose autonomic stability was already unstable to begin with. So while I’m slowly getting better, getting more normal sleep is taking a lot longer than I expected. It’s not all lost, though, it does look as if I can get better. Some people get chronic akathisia from benzo withdrawal - I hope I won’t get that when I taper off the high doses of benzos that have been helping me get much needed sleep.
The whole process has been a literal nightmare with periods of extreme sleep deprivation that then increase damaging noradrenaline output. I’ve struggled to get through the violent nights of noradrenergic surges with waves of extreme heat and other flu like symptoms, followed by whole body restlessness, nocturia, nocturnal diarrhoea, hunger at night, massively aggravated tinnitus and some tachycardia. Yes, it was pure torture for over three months and it’s still very difficult. Every night has come with a different set of challenges. Sedation drops the vigilance which exposes the motor restlessness - this is a predisposition that’s aggravated by sedatives. It’s very clear that my system does not tolerate most drugs and so my aim is to be drug free and try and cope with select Chinese herbs again - a difficult task since I’m also sensitive to herbs and sensitised overall due to the withdrawal. Western sedative herbs don’t work for me because they don’t treat the underlying problems of state transitions and tend to trip me up very badly. I already have some ideas as to what herbal combinations could be helpful in my case.
The trick since dropping the opioids is to try and prevent the evening surges of noradrenaline because they get out of hand, but it’s a difficult task and rarely successful. It starts with sniffles, cold feet (need warming to lower noradrenaline), heat in the trunk (fan on), rising tinnitus, rising energy, frequently an urge to start cleaning, as well as angry rumination about injustices that can turn into plotting revenge but also positive planning sessions for the future. These symptoms have slowly abated but by midnight I still get a Cinderella moment when it’s all at its peak and I definitely can’t go to sleep even on high doses of sedatives (benzos). For this reason, I used to take my meds at 2 am after the peak, but I’m trying to change my schedule by taking advantage of the chaotic situation. A decades old problem of midnight wakefulness was thus now a hundred times worse due to the withdrawal. I tried small amounts of quetiapine as a kind of pre-med in the evenings because it lowers noradrenaline, but it ended up with worsening akathisia in the early morning hours because the net amount was too high and there was also a mismatch with the timing of the akathisia which tends to appear in the early morning hours. I have had to use quetiapine as a sleep medication for a long time because there simply isn’t any other option besides Z-drugs and benzos. I was always aware of the restlessness but never really gave it much thought because I felt I could endure it. I didn’t have words for my general discomfort, either, and no one made meaningful inquires. I can now see that it aggravated my general state of health along with other medications and supplements that are generally considered benign (melatonin, loperamide, vitamin B supplements etc). When I was on TCM herbs for a few years I came off all drugs and managed to sleep naturally though it was very hard to figure out exactly what herbs to use (but that’s a whole other story).
In the meantime, the least harmful medications are the ones that increase GABA availability since this can act as a buffer against the noradrenaline surges and allow some sleep, but the effect is not guaranteed. Diazepam appears to be the most helpful option but 4 mg/night (my monthly allowance) is not sufficient in this state of withdrawal. It’s very unfortunate but I still have to use small amounts of quetiapine since it lowers the offending catecholemines (excitatory neurotransmitters such as noradrenaline, histamine) as well as serotonin. It induces sleep through its anti-histaminic action, but I can only tolerate tiny amounts before it tips into dopamine suppression and restlessness, and so it’s hugely unreliable and not a good long term solution. Any other anti-histamine would also provoke a bad reaction. THC increases central gain (in my case tinnitus ramps up terribly) so it has been binned. All other clinically proposed options have been proven to worsen my problem in the past. I had an assortment of useful medications in my medicine cabinet so I was able to get through the worst. I have not had the energy to talk to my GP of 15 years but will have to try and see him tomorrow, a month after dropping opioids altogether (I used tramadol as a bridge). I hope he’ll be sympathetic to helping me out a little although I myself don’t want to use benzos at all.
I’m tightening my life style so that the circadian cues and general predictability are stronger and the sleep schedule stabilised. A daily dose of sunlight (not just light, but actual outdoors light!) seems to be somewhat helpful in stabilising the internal circadian clocks. Predictable meal timing, exercise and the obvious avoidance of stressors are all important (I’ve tried to explain my problem with stress to clinicians for decades but due to poor understanding they have preferred to reframe it as anxiety, which it isn’t). I also have to minimise my exposure to unreliable service providers including biased medical practitioners who are unwilling to understand the reality of life with hypermobile EDS and dysautonomia. For instance, neurology doesn’t even seem to know what these are and offered humiliating interpretations and tried to coerce me into amitryptline use even when I said I don’t tolerate serotonin agonists. Since I was ten, I’ve been through a lot of iatrogenic harm and medical trauma due to systemic ignorance of hEDS, and I need for it to end.
Please see my previous blog posts about my health challenges and battle with medical gaslighting.
I believe AI got it right:
OVERVIEW (AI)
There is a long-standing pattern consistent with sensitised (reactive) akathisia with autonomic dysregulation, rather than primary anxiety or primary insomnia. Symptoms are episodic, predominantly evening- and night-weighted, and include inner restlessness, autonomic activation, and non-restorative or fragmented sleep. The syndrome is reliably triggered or exacerbated by dopaminergic and serotonergic medications, hormonal changes, withdrawal states, sleep deprivation, and cumulative stress, and is partially relieved by benzodiazepines. The presence of calmer windows and preserved sleep capacity during periods of stabilisation argues against fixed or chronic akathisia. This formulation helps explain longstanding medication sensitivities, paradoxical reactions, and decades of treatment-resistant sleep disturbance. Current priorities are nervous-system stabilisation, minimisation of provoking agents, and protection of sleep continuity while the sensitised state resolves.
Overview: nocturnal dysautonomia with state-transition instability (EDS context)
This presentation can be understood as a chronic dysautonomic night-time state-transition disorder, commonly under-recognised in hypermobile Ehlers–Danlos syndrome (hEDS), in which the autonomic and neuromodulatory systems fail to coordinate the transition from wakefulness to sleep despite preserved cognitive calm.
Baseline autonomic configuration
In this phenotype, the autonomic nervous system does not exhibit the expected evening parasympathetic dominance. Instead, there is a persistence of central arousal tone into the night. Importantly, this does not necessarily manifest as sympathetic overdrive in the classic sense (tachycardia, sweating, anxiety). Rather, the system remains tonically activated but behaviourally quiet, giving rise to what is often described clinically as “calm insomnia”.
This reflects dysautonomia at the level of central regulation, not peripheral stress response.
Neurotransmitter dynamics involved
Rather than a single transmitter abnormality, the condition reflects failed coordination between multiple neuromodulatory systems, particularly during state transitions.
Noradrenaline (locus coeruleus)
- Normally shows a marked reduction during sleep onset.
- In this phenotype, LC downregulation is delayed or incomplete.
- This maintains cortical alertness and interferes with sleep gating.
- During opioid withdrawal or physiological stress, this system may become overtly hyperactive (↑ HR, heat, GI motility), but outside those states it can remain “quietly dominant”.
Serotonin (especially 5-HT2A)
- Serotonergic tone remains inappropriately high at night, particularly at cortical 5-HT2A receptors.
- 5-HT2A activation:
- suppresses dopaminergic signalling
- destabilises motor inhibition
- interferes with thalamocortical sleep gating
- This explains:
- paradoxical reactions to serotonergic agents
- sensitivity to fortified foods and supplements
- worsening of motor restlessness under conditions that should promote sedation
Dopamine
- Dopaminergic signalling, especially within motor and reward circuits, is functionally dampened rather than deficient.
- This creates vulnerability to:
- motor restlessness
- urge-to-move phenomena
- poor suppression of spinal motor output during sleep onset
- Dopamine agonist intolerance is a key red flag that the problem is not primary RLS but regulatory imbalance upstream.
Histamine
- Central histaminergic tone may remain elevated into the night.
- This contributes to:
- alertness without anxiety
- resistance to sedative-hypnotics
- paradoxical reactions to medications that rely on histamine suppression alone
Cortisol and HPA axis
- Circadian cortisol decline may be delayed or flattened.
- Not necessarily elevated to pathological levels, but mistimed, reinforcing wake-state signalling.
GABA
- Inhibitory tone is intact but insufficiently dominant.
- GABAergic agents may induce heaviness or dissociation without reliably producing sleep unless other systems have already downshifted.
Motor dysregulation and sleep-onset failure
A defining feature is impaired motor gating during sleep onset.
Normally, sleep initiation involves:
- suppression of spinal motor output
- coordinated inhibition across thalamic and brainstem circuits
In this phenotype:
- motor inhibition is unstable
- micro-arousals trigger motor activation
- sensations may escalate from low-grade restlessness to whole-body motor agitation during vulnerable periods
This is best conceptualised as state-transition intolerance, not a primary movement disorder. Due to unstable autonomic afferent signalling involving the brain stem and the hypothalamus, glutamatergic NMDA receptor activity is likely contributing to impaired neural “gating” at night, meaning that arousal-related circuits do not switch off efficiently at sleep onset and offer poor buffering against arousal. This does not initiate the condition but sustains and amplifies motor restlessness, sensory activation, and wakefulness once triggered thus leading to nocturnal dysautonomia. In other words, once arousal-related circuits are activated at night, NMDA-mediated excitation makes them slow to shut down.
Sensory amplification and tinnitus
In individuals with connective tissue–associated dysautonomia, sensory gain is often increased. With the development of tinnitus, night-time quiet unmasks auditory input that becomes a salient arousal signal, further reinforcing wake-state neuromodulation without necessarily provoking emotional distress.
Effect of opioid exposure and withdrawal
Chronic opioid exposure suppresses locus coeruleus activity and alters serotonergic–dopaminergic balance. In susceptible systems, this creates compensatory adaptations. Upon withdrawal:
- noradrenergic tone rebounds
- serotonergic signalling becomes erratic
- motor inhibition fails more dramatically
- GI hypermotility emerges (diarrhoea)
In hEDS, receptor recalibration is slower and overshoot is common, extending the duration of dysregulation well beyond standard withdrawal timelines.
Classification
This presentation fits within:
- dysautonomia associated with hypermobile EDS
- with prominent nocturnal expression
- involving multi-transmitter dysregulation
- and sleep state-transition instability
It is distinct from:
- primary insomnia
- anxiety-related hyperarousal
- classic RLS
- isolated circadian rhythm disorders
Key integrative concept
The unifying mechanism is failure of coordinated downregulation across autonomic, sensory, and motor systems at night, despite preserved psychological calm and insight.