Fibromyalgia – which drug for which symptom?

23rd May 2022, Dr Chee L Khoo


We all know that the term fibromyalgia is a wishy-washy term used to cover something rather imprecise. Don’t get me wrong. I am not doubting the syndrome but just the name used to refer to the constellation of symptoms of widespread chronic pain, easy physical exhaustion, cognitive difficulties, depressed mood, sleep problems and digestive problems. We used to bundled all these into chronic fatigue syndrome but no, no, no, it is not cool to use this term because there are connotations of naturopathy or complementary medicine when you use the term. When you have a diagnosis which is imprecise, then it is difficult to undertake any scientific study to test the efficacy of any treatment. Nonetheless, we have a recent analysis comparing the various agents we may use in fibromyalgia.

What is fibromyalgia?
Fibromyalgia syndrome (FMS) is a chronic illness characterised by widespread pain (meaning multiple sites) and other clinical and emotional symptoms. The lack of objective markers of the illness has been a persistent problem in FMS research, clinical management, and social recognition of the disease. The prevalence of FMS is estimated at 2%–4% in the general population, being more frequent in women than in men [2]. The prevalence of FMS varies between countries probably because of different diagnostic criteria and different sociocultural beliefs.

The American College of Rheumatology (ACR) first proposed diagnostic criteria back in 1990. It necessitated a demonstration of multiple tender spots (which can be subjective depending on how hard you press) but did not include consideration of sleep and fatigue symptoms. The criteria were revised in 2010 and were based on 2 scales – the Widespread Pain Index (WPI) and the Symptom Severity (SS) Scale. The WPI comprises of a list of 19 painful areas. Patients report whether each point hurts her/him. The need for physical examination is removed. The SS includes two parts: Part SS2a evaluates the severity of fatigue, waking unrefreshed, and cognitive symptoms. Part SS2b consists of a checklist of 41 symptoms (irritable bowel syndrome, fatigue/tiredness, muscle weakness, Raynaud’s, ringing in ears, etc.). To diagnose FMS, one of these two conditions must be fulfilled: a WPI ≥ 7 and SS ≥ 5, or a WPI between 3 and 6 and SS ≥ 9. The symptoms have to be present for more than 3 months. There have been attempts in revising the diagnostic criteria but the 2010 “standards” remain.

Three drugs have been approved by the US FDA for fibromyalgia – pregabalin (2007), duloxetine (2008) and milnacipran (2009). Milnacipran is a serotonin and noradrenaline re-uptake inhibitor (SNRI) not widely used in Australia. Amitryptiline is widely used here and in the US to treat fibromyalgia but it is used off label. These agents are used to treat the symptoms of fibromyalgia – pain relief, fatigue, sleep disturbances, depression and somehow may translate into improving the quality of life of these patients. Because the syndrome is subjective and imprecise, it is difficult to compare the efficacy of each agent. It is even more difficult to compare one agent versus another as there are no head-to-head comparison trials.

Hussein M Farag et al. recently performed a systematic review and network meta-analysis of 36 randomized clinical trials (11 930 patients with fibromyalgia) (1). They first conducted a literature review of MEDLINE/PubMed, Embase, Cochrane Library, and databases using search terms for fibromyalgia, pregabalin, duloxetine, milnacipran, and amitriptyline. Double-blind randomised controlled trials (RCTs) comparing the off-label use of amitriptyline and FDA-approved doses of pregabalin, duloxetine, or milnacipran head-to-head or with placebo in adults (aged ≥18 years) with fibromyalgia were included, according to the post– and pre–ACR criteria for diagnosing fibromyalgia.



Compared with placebo, duloxetine 120 mg was associated with the highest pain reduction, followed by pregabalin 450 mg. Milnacipran 100 mg was associated with the lowest reduction in pain. Duloxetine 120 mg and pregabalin 450 mg were associated with the highest probability of effectiveness for fibromyalgia pain.


Although all the treatments, except milnacipran 200 mg, were associated with reduced sleep problems, amitriptyline was associated with the highest improvement compared with, and followed by pregabalin 600 mg. Duloxetine 60 mg was associated with the least improvement. Amitriptyline and pregabalin 600 mg were associated with the highest probability of effectiveness on sleep.


Compared with placebo, duloxetine 120 mg, duloxetine 60 mg, pregabalin 600 mg, pregabalin 300 mg, pregabalin 450 mg, milnacipran 100 mg, milnacipran 200 mg, and pregabalin 150 mg were associated with improved depression. Amitriptyline was not significantly different from placebo. Duloxetine 120 mg, duloxetine 60 mg, and pregabalin 600 mg were associated with the highest probability of effectiveness on depression.


All treatments were associated with improved fatigue; amitriptyline was associated with the greatest improvement, followed by pregabalin 150 mg, and pregabalin 600 mg. Milnacipran 100 mg and duloxetine 120 mg were associated with the least improvement in fatigue. Amitriptyline and pregabalin 150 mg were associated with the highest probability of effectiveness on fatigue.

Quality of life

Compared with placebo, amitriptyline, duloxetine 120 mg, duloxetine 60 mg, pregabalin 450 mg, pregabalin 300 mg, and pregabalin 150 mg were associated with improved QoL. Pregabalin 600 mg, milnacipran 100 mg, and milnacipran 200 mg were not associated with improved QoL. Amitriptyline and duloxetine 120 mg were associated with the highest probability of effectiveness on QoL


There were 26 trials that evaluated discontinuations associated with adverse drug reactions. Amitriptyline did not differ from placebo while all the other treatments were associated with lower acceptability. Amitriptyline (93.2%) was associated with the highest probability of being the most acceptable.


Remember, this is not a back-to-back comparison trial but a meta-analysis of RCTs. This is the next best thing we have in comparing the different agents treating different populations with all sorts of symptoms over a wide variety of time frames. Nonetheless, it appears that different agents target different subsets of the array of symptoms of FMS.

If the patient’s symptom is primarily pain and depression, then duloxetine 120mg appears most efficacious. If the patient’s symptom are primarily sleep and fatigue, amitryptiline appears most efficacious. Amitryptiline and duloxetine seem to be most efficacious for quality of life improvement. Amitryptiline is also least likely to be discontinued.

While the other agents have different doses mentioned, there was no mention of the amitryptiline doses used. There is also no mention of the efficacy of the combination of agents.


Farag HM, Yunusa I, Goswami H, Sultan I, Doucette JA, Eguale T. Comparison of Amitriptyline and US Food and Drug Administration–Approved Treatments for Fibromyalgia: A Systematic Review and Network Meta-analysis. JAMA Netw Open. 2022;5(5):e2212939. doi:10.1001/jamanetworkopen.2022.12939