Drug Treatment of Fibromyalgia

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Introduction[edit]

In the opinion of the author, the assumption that fibromyalgia can be cured by drugs is suspect. The reason for this that it involves so many different parts of the brain. Based on his own unpublished detailed review of imaging studies of fibromyalgia the author found that in one study or another almost every gyrus or lobule of the entire cerebral cortex of the brain has been implicated. Furthermore, if one considers the dozens of biochemical abnormalities mentioned in the literature and the fact that the associated sleep deprivation can have numerous chemical effects on the body, it is hard to imagine how any single drug could be effective overall, even if it can have a positive effect on one or a few biochemical or neurochemical abnormalities.

Furthermore, there is a downside of drug treatment which plays out repeatedly in clinical medicine. It is the endless “musical chairs” of swapping drugs as patients fail on one drug only to be shifted to another. Years go by as patients shift from drug to drug. Generally, in the present state of affairs precious time is lost as the search for the elusive drug treatment misdirects the patient’s energies and attention when they could have been working on controlling their mind to reduce the central sensitization and on finding ways to rebuild their sleep.

Calandre et al. 2015 recommendations for drugs of choice[edit]

Here is the expert opinion based on Calandre et al. 2015) “According to the available evidence, pregabalin, duloxetine and milnacipran should be the drugs of choice for the treatment of this disease, followed by amitriptyline and cyclobenzaprine. Other drugs with at least one positive clinical trial include some selective serotonin reuptake inhibitors, moclobemide, pirlindole, gabapentin, tramadol, tropisetron, sodium oxybate and nabilone. None of the currently available drugs are fully effective against the whole spectrum of fibromyalgia symptoms, namely pain, fatigue, sleep disturbances and depression, among the most relevant symptoms. Combination therapy is an option that needs to be more thoroughly investigated in clinical trials.” (An update on pharmaco-therapy for the treatment of fibromyalgia. Calandre EP1, Rico-Villademoros F, Slim M. Expert Opin Pharmacother. 2015 Jun;16(9):1347-68.)

Häuser et al.’s 2014 disappointing review of FDA approved drugs[edit]

Häuser et al. wrote: “The pain-reducing benefits of pregabalin, duloxetine, and milnacipran are minimally outweighed by side effects (Table 1). In that only a minority of patients will experience substantial relief [17,19,20], vigilance regarding adverse effects is required (Table 2). Most commonly, tolerability is limited by troublesome, but generally not serious, side effects, such as drowsiness, weight gain or peripheral edema for pregabalin…” (Review of pharmacological therapies in fibromyalgia syndrome. Winfried Häuser, 1,2 Brian Walitt,3 Mary-Ann Fitzcharles,4 and Claudia Sommer5Arthritis Res Ther. 2014; 16(1): 201, available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979124/. Italics added after the fact.)

Hauser et al. went on to say”: “Drug therapy is not mandatory for the management of FMS. Pregabalin, duloxetine, milnacipran, and amitriptyline are the current first-line prescribed agents but have had a mostly modest effect. With only a minority of patients expected to experience substantial benefit, most will discontinue therapy because of either a lack of efficacy or tolerability problems.” (Review of pharmacological therapies in fibromyalgia syndrome. Häuser W, Walitt B, Fitzcharles MA, Sommer C. Arthritis Res Ther. 2014 Jan 17;16(1):201. Italics added after the fact.)

Hauser et al. concluded their major review of drugs for fibromyalgia with the following statement: “Drug therapy as the sole strategy for the management of patients with FMS should be discouraged. Taking into consideration the modest effect of currently available drugs, high prevalence of adverse effects, and poor record of continued use, the health-care community must be vigilant in adhering to responsible prescribing practices and carefully monitor patients for both efficacy and side effects.”

[In the experience of the author in working with severe fibromyalgia patients, a large percentage had to stop some or all of these drugs due to side effects. Some said they were getting good benefit, but typically many still had a multitude of symptoms.]

Hauser et al stated: “The centrally acting agents (pregabalin, gabapentin, duloxetine, and milnacipran) received approval during the observation period of the study. Use rates increased from 10% to 39% over the 11 years, but mean pain, fatigue, and disability measurements did not change in this study population. For patients treated with duloxetine or milnacipran, or pregabalin, pain scores were reduced significantly - by 0.17 (0.03, 0.30) units, an improvement of 2.8% - following the start of these drugs but with no significant improvements in fatigue or function. These results question whether the changes attributable to use of these agents are truly clinically meaningful. However, a patient’s choice to continue a treatment implies some level of satisfaction. The estimated 25th and 50th percentiles of time to discontinuation for centrally acting agents were 1 and 2.5 years, respectively [24]. In a German fibromyalgia consumer reports study, patients did not identify any medication in the top 10 effective therapies. Rather, medication therapy was only perceived as harmful, with pregabalin identified as the 3rd, duloxetine the 6th, and amitriptyline the 7th most harmful therapies [10]. Taking all these factors and, especially, real-world clinical observation into consideration, we contend that the overall benefit of these agents remains limited for most patients.” (Review of pharmacological therapies in fibromyalgia syndrome. Winfried Häuser, 1,2 Brian Walitt,3 Mary-Ann Fitzcharles,4 and Claudia Sommer5,Arthritis Res Ther. 2014; 16(1): 201, available in full online at: \http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979124/ through a Creative Commons license: http://creativecommons.org/licenses/by/2.0)

“Both duloxetine and milnacipran were superior to pregabalin for improvement in depressed mood, whereas pregabalin was superior to milnacipran for improvement in sleep disturbance. Amitriptyline was similar to duloxetine, milnacipran, and pregabalin on outcomes of pain and fatigue, and data on the other outcomes were insufficient. Although there were differences in specific adverse events, they did not produce any differences in overall withdrawals, adverse events, or withdrawals due to adverse events [50].” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979124/

Häuser et al. stated: “Drug therapy is not a panacea for the care of patients with symptoms of FMS. For many, who may have been through various treatment trials, the final compromise may be the limited use of prescription medications, on demand over-the-counter agents, and focus toward non-pharmacologic strategies. In those continuing drug treatments, many will use a combination of drugs, generally in lower doses than may be recommended by manufacturers. There is, however, no current evidence that patients benefit from drug combinations, despite widespread use.” (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979124/ Italics added after the fact by the author of this wiki.)

Amitriptyline[edit]

A review by Rico-Villademoros (2015) argues that amitriptyline (10-75mg per day) should be a first line treatment for fibromyalgia. (Amitriptyline for the treatment of fibromyalgia: a comprehensive review. F1, Slim M1, Calandre EP. Expert Rev Neurother. 2015 Sep 22:1-28.)

NSAIDS[edit]

Bellato et al. state that in fibromyalgia: “most nonsteroidal anti-inflammatory drugs… have limited benefit”. (Fibromyalgia Syndrome: Etiology, Pathogenesis, Diagno-sis, and Treatment Enrico Bellato, 1 , Eleonora Marini, 1 Filippo Castoldi, 1 Nicola Barbasetti, 1 Lorenzo Mattei, 1Davide Edoardo Bonasia, 2 and Davide Blonna 1 Pain Res Treat. 2012; 2012:426130 available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503476/.)

Opiods[edit]

Bellato et al. 2012 state that in fibromyalgia: “opioids have limited benefit”. A Cochrane review in 2014 by Gaskell et al. stated: “No convincing, unbiased evidence suggests that oxycodone (as oxycodone CR) is of value in treating people with painful diabetic neuropathy or postherpetic neuralgia. There is no evidence at all for other neuro-pathic pain conditions, or for fibromyalgia. Adverse events typical of opioids appear to be common. (Oxycodone for neuropathic pain and fibromyalgia in adults. Gaskell H1, Moore RA, Derry S, Stannard C. Cochrane Database Syst Rev. 2014 Jun 23;6:CD010692.”)

[Author’s opinion: No single journal article should trump clinical judgment. For example if an analgesic before bed helps control pain just enough to sleep better, and if that sleep substantially improves symptoms, then it seems reasonable.]

Tramadol[edit]

Tramadol is a novel, synthetic opioid receptor agonist. It has serotonin-norepinephrine reuptake inhibitor properties. A review by Aline Pereira da Rocha et al. concluded that the literature says “there is a fair evidence base to support its use as a second-line treatment for more resistant cases.” (Tramadol for the treatment of fibromyalgia, Ashley J B MacLean 1, Thomas L Schwartz, Expert Rev Neurother. 2015 May;15(5):469-75, doi: 10.1586/14737175.2015.1034693. Epub 2015 Apr 20, DOI: 10.1586/14737175.2015.1034693.)

A review by Mizzaci et al. in 2020 found a dearth of clinical trials on tramadol in patients with fibromyalgia. They noted that: “Although the combination of monoamine and opioid mechanism of tramadol has shown positive effects for fibromyalgia, the available evidence is not sufficient to support or refute the use of tramadol in clinical practice for pain or symptom management.” Tramadol for management of fibromyalgia pain and symptoms: Systematic review, 1 2, Carolina Christianini Mizzaci 1 2, Ana Carolina Pereira Nunes Pinto 1 2 3 4, Alexia Gabriela da Silva Vieira 1 2, Vinicius Civile 1 2, Virgínia Fernandes Moça Trevisani 1 2DOI: 10.1111/ijcp.13455, Int J Clin Pract . 2020 Mar;74(3):e13455, https://onlinelibrary.wiley.com/doi/abs/10.1111/ijcp.13455.

Neuromodulating antiepileptics[edit]

Bellato et al. 2012 state they have an “important role”. Others disagreed.

SSRIs[edit]

A Cochrane review done in 2015 found: “There is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia, namely pain, fatigue and sleep problems. SSRIs might be considered for treating depression in people with fibromyalgia.” (Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Walitt B1, Urrútia G, Nishishinya MB, Cantrell SE, Häuser W. Cochrane Database Syst Rev. 2015 Jun 5;6:CD011735.)

SSRIs use needs to be monitored for adverse effects by checking the manufacturers product monographs especially looking for common adverse events.

SNRIs[edit]

A 2018 Cochrane Library study by Welsch et al reaffirmed the major findings of the previous review. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Patrick Welsch 1, Nurcan Üçeyler, Petra Klose, Brian Walitt, Winfried Häuser Cochrane Database Syst Rev. 2018 Feb 28;2(2):CD010292, DOI: 10.1002/14651858.CD010292.pub2, available in full online at: Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia - Welsch, P - 2018 | Cochrane Library.)

They stated that their conclusions were based on low- to very low-quality evidence. The findings were that “SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in the frequency of pain relief of 50% or greater”. However, they did find that the “patient's global impression to be much or very much improved and in the frequency of pain relief of 30% or greater there was a clinically relevant benefit.”

Another disappointing find was that “duloxetine and milnacipran provided no clinically relevant benefit over placebo in improving health-related quality of life and in reducing fatigue.” Nor did they significantly differ from placebo in lowering sleep problems.” In their opinion “On average, the potential benefits of duloxetine and milnacipran in fibromyalgia were outweighed by their potential harms. However, a minority of people with fibromyalgia might experience substantial symptom relief without clinically relevant adverse events with duloxetine or milnacipran.”

Gabapentin[edit]

A Cochrane Review done in 2014 of gabapentin in fibromyalgia found: “There was no top tier evidence that was unequivocally unbiased. Second tier evidence, with potentially important residual biases, showed that gabapentin at doses of 1200 mg or more was effective for some people with some painful neuropathic pain conditions.” (Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Moore RA1, Wiffen PJ, Derry S, Toelle T, Rice AS. Cochrane Database Syst Rev. 2014 Apr 27;4:CD007938.)

Cyclobenzaprine[edit]

A 2004 review on the use of cyclobenzaprine in fibromyalgia concluded that it was helpful. (For details see: Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Tofferi JK1, Jackson JL, O'Malley PG. Arthritis Rheum. 2004 Feb 15;51(1):9-13.)

Nabilone[edit]

A study by Walitt et al. stated: “We found no convincing, unbiased, high quality evidence suggesting that na¬bilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia.” (Cannabinoids for fibromyalgia. Walitt B1, Klose P, Fitzcharles MA, Phillips T, Häuser W. Cochrane Database Syst Rev. 2016 Jul 18;7:CD011694.)

Prior to this study there had been a 2008 Canadian study that suggested some benefit. (See the WebMD article entitled Fibromyalgia and Medical Marijuana: What the experts have to say about the use of marijuana for treating fibromyalgia available online at:http://www.webmd.com/fibromyalgia/guide/fibromyalgia-and-medical-marijuana?page=4)

[Author’s comment: Marijuana is not the same as nabilone, but this study suggests that any cannabinoid in marijuana is not likely to help fibromyalgia patients. There are individuals that swear by marijuana for fibromyalgia. The remaining question is this: Is it due to placebo or to a mystery ingredient.”]

Naltrexone[edit]

Naltrexone is an opioid receptor antagonist. Its active metabolite is 6-β-naltrexol which is a competitive antagonists at μ- and κ-opioid receptors. To some degree it is also at δ-opioid receptor antagnonist. A study by Younger et al. found that low dose naltrexone at 4.5 mg/day reduces fibromyalgia severity and increases general life satisfaction and mood. It was compared to placebo. The placebo effect was substantial at 18%, but the drug reduced pain even more. The drug did not improve sleep or fatigue. (The article was published under the auspices of the American College of Rheumatolgy which as been a leading body in setting diagnostic criteria for fibromylagia.) The abstract concludes with the following statement. “The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.” (Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Younger J, Arthritis Rheum. 2013 Feb;65(2):529-38 available in full online at: http://onlinelibrary.wiley.com/doi/10.1002/art.37734/epdf.)

Suvorexant[edit]

A study by Roehrs et al. of 20 mgs of suvorexant versus placebo found that it “increased total sleep time (7.2 versus 6.7 hours, P < .05) and reduced wake after sleep onset (37 versus 67 minutes, P < .04) with no night effects or interaction.”

“FWL on both am and pm tests varied as a function of intensity (P < .001). Average FWL (over 5 intensities and both days) was increased relative to placebo on both the am (13.9 versus 13.1 seconds) and pm tests (15.8 versus 14.1 seconds, P < .03) following suvorexant the previous night.” The concluded that the drug “improved sleep time and reduced next-day pain sensitivity on assessments of FWL to a radiant heat stimulus.” Sleep and pain in humans with fibromyalgia and comorbid insomnia: double-blind, crossover study of suvorexant 20 mg versus placebo. Timothy Roehrs 1 2, Dana Withrow 1, Gail Koshorek 1, Jelena Verkler 1, Luisa Bazan 1, Thomas Roth 1 2 J Clin Sleep Med. . 2020 Mar 15;16(3):415-421, DOI: 10.5664/jcsm.8220.

[Author’s opinion: The patient group seems to be make up of vary mild cases who did not have psychiatric disorders and who were sleeping 6.7 hours which is an unusually large number compared to what is seen in fibromyalgia specialty clinics.]

Cannabis[edit]

A 2011 study by Fiz et al. found some pain relief as well as stiffness, enhancement of relaxation, and an increase in somnolence and feeling of well being after two hours. (Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life. Jimena Fiz 1, Marta Durán, Dolors Capellà, Jordi Carbonell, Magí Farré , PLoS One. 2011 Apr 21;6(4):e18440, DOI: 10.1371/journal.pone.0018440.

A small study by De Donk et al. showed modest beneficial effects on pain, after a single inhalation.

An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Tine van de Donk 1, Marieke Niesters 1, Mikael A Kowal 2, Erik Olofsen 1, Albert Dahan 1, Monique van Velzen 1 Pain. 2019 Apr;160(4):860-869.DOI: 10.1097/j.pain.0000000000001464, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430597/.)

A randomized study for 8 weeks in a poor area of a city in Brazil using THC-rich cannabis oil showed benefits on the FIQ score. (Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Carolina Chaves 1, Paulo Cesar T Bittencourt 2, Andreia Pelegrini 3 Pain Med. 2020 Oct 1;21(10):2212-2218, DOI: 10.1093/pm/pnaa303) A study by Sagy et al done 2019 claimed that it was safe and effective. (Safety and Efficacy of Medical Cannabis in Fibromyalgia. Iftach Sagy,1,2,† Lihi Bar-Lev Schleider,2,3,† Mahmoud Abu-Shakra,4 and Victor Novack2,* J Clin Med. 2019 Jun; 8(6): 807, 10.3390/jcm8060807.)

A survey by Boehnke suggested cannabinol is commonly used in fibromyalgia and seems to be effective. (Cannabidiol Use for Fibromyalgia: Prevalence of Use and Perceptions of Effectiveness in a Large Online Survey. Kevin F Boehnke 1, Joel J Gagnier 2, Lynne Matallana 3, David A Williams 4 J Pain 2021 May;22(5):556-566, DOI: 10.1016/j.jpain.2020.12.001.)

[Author’s comments: While studies on cannabis treatment are generally encouraging, the enthusiasm is best tempered because there is a lot of bias in the system and hug sale organization pressing for cannabis. Cannabis became a very big legal business in recent years. There has been a lot of hype and some companies even leave the impression that they have a cure all. All cure alls should be viewed is due suspicion. See the entry for Cure Alls for further details.

There are theoretical reasons to suspect that marijuana is effective. The chemical changes in the brain of FM due to the pain and typical terrible sleep suggest there are far to man abnormalities for any one drug to bee able address.]

FDA approved drugs for fibromyalgia[edit]

Introduction[edit]

According to the FDA web site as of June 2017: “People with fibromyalgia are typically treated with pain medicines, antidepressants, muscle relaxants, and sleep medicines. In June 2007, Lyrica (pregabalin) became the first FDA-approved drug for specifically treating fibromyalgia; a year later, in June 2008, Cymbalta (duloxetine hydrochloride) became the second; and in January 2009, Savella (milnacipran HCI) became the third…Lyrica and Cymbalta are approved for use in adults 18 years and older.” (Living with Fibromyalgia, Drugs Approved to Manage Pain, January 31, 2014, https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm107802.htm.) A study by stated that as of 2020, the emerging data was showing a positive effect. (Cannabis and cannabidiol (CBD) for the treatment of fibromyalgia. Amnon A Berger 1, Joseph Keefe 2, Ariel Winnick 2, Elasaf Gilbert 2, Jonathan P Eskander 3, Cyrus Yazdi 4, Alan D Kaye 5, Omar Viswanath 6, Ivan Urits 4(Best Pract Res Clin Anaesthesiol. 2020 Sep;34(3):617-631. Epub 2020 Aug 15, DOI: 10.1016/j.bpa.2020.08.010.)

Duloxetine/Cymbalta[edit]

“Duloxetine is a SNRI that has been approved for use by the FDA for maintenance and management of acute major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic peripheral neuropathic pain (DPNP) and fibromyalgia (FM) (Duloxetine for the treatment of fibromyalgia, Cheryl L Wright,†,1 Scott D Mist,1 Rebecca L Ross,1 and Kim D Jones1Expert Rev Clin Immunol. 2010 Sep; 6(5): 745–756, available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056054/.)

Pregabalin/Lyrica[edit]

Results on efficacy are quite mixed. Häuser et al.’s review found “Thirty percent pain reduction rates in randomized controlled trials with antidepressants and pregabalin in patients with fibromyalgia syndrome.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979124/ A trial in Japan “demonstrated that pregabalin, at doses of up to 450 mg/day, was effective for the symptomatic relief of pain in Japanese patients with fibromyalgia.” (A randomized, double-blind, multicenter, placebo-controlled phase III trial to evaluate the efficacy and safety of pregabalin in Japanese patients with fibromyalgia, Hiroyoshi Ohta,1 Hiroshi Oka,2 Chie Usui,3 Masayuki Ohkura,1 Makoto Suzuki,1 and Kusuki Nishioka , Arthritis Res Ther. 2012; 14(5): R217, available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580529/.)

Milnacipran[edit]

A review was conducted on the effect of milnacipran for neuropathic pain and fibromyalgia in adults by Derry et al. in 2012. (Milnacipran for neuropathic pain and fibromyalgia in adults. Sheena Derry,1 Dipender Gill,1 Tudor Phillips,1 and R Andrew Moore1, Cochrane Database Syst Rev. 2012; 3: CD008244, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164830/.)

They looked at over 4000 participants for 8-24 weeks at the target dose. Results were: “Milnacipran in either 100 mg or 200 mg doses provides at least a 30% reduction in pain intensity, to 10% more participants than placebo.” They also noted: “Adverse events were reported by the majority of participants in all groups, but were more common with milnacipran than placebo, with nausea and constipation showing the greatest differences. Serious adverse events were uncommon (less than 2%)…. Withdrawals due to adverse events were also more common with milnacipran than placebo, and were more common with 200 mg than 100 mg, while withdrawals due to lack of efficacy were less common with milnacipran, with no difference between doses.”

Ormseth et al. claim that “Milnacipran may be particularly beneficial for FMS patients with significant symptoms of Fatigue, Fibrofog and/or depression.” (Milnacipran for the management of fibromyalgia syndrome. Ormseth MJ1, Eyler AE, Hammonds CL, Boomershine CS. J Pain Res. 2010 Mar 1;3:15-24 available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004654/)

This drug is an NSRI. It “has a three-fold greater efficacy for inhibiting norepine-phrine reuptake compared to serotonin, which differentiates it from the SNRIs which are more serotonin active”. (Ormseth et al. 2010)

The approved dose is 100 or 200 mg divided twice daily. Side effects may include gastrointestinal complaints, headache, hyper-hidrosis, hypertension and palpitations. “Milnacipran use has been linked to elevations in liver function tests and severe liver injury. We [Ormseth et al. 2010] recommend regular lab monitoring and avoiding milnacipran use in patients with chronic liver disease or concomitantly with hepatotoxic substances.” The authors further stated: “Unlike duloxetine, milnacipran can be used in patients with severe renal disease at 50% of the indicated dose.”

“Milnacipran tolerability can be maximized by gradual uptitration and by taking milnacipran with food.” (Ormseth et al. 2010) A study of the use of mirtazapine in Japanese patients with fibromyalgia (FM). “The primary endpoint was change in mean numerical rating scale (NRS) pain score from baseline to endpoint (week 12 or early discontinuation).” Results showed: “At the study endpoint, mirtazapine caused a significantly greater reduction in the mean NRS pain score compared with placebo (difference, 0.44; 95% confidence interval, -0.72 to -0.17; P = 0.0018). The reduction by mirtazapine remained significantly greater compared with placebo from week 6 onward. More patients treated with mirtazapine had their NRS pain score reduced by ≥30% from baseline (45.5% vs 30.8%). Mirtazapine also improved pain-related quality of life assessed by the Japanese version of the Fibromyalgia Impact Questionnaire and the Short-Form 36 Questionnaire.” (Efficacy of mirtazapine for the treatment of fibromyalgia without concomitant depression: a randomized, double-blind, placebo-controlled phase IIa study in Japan. Miki K1, Murakami M, Oka H, Onozawa K, Yoshida S, Osada K. Pain. 2016 Sep;157(9):2089-96.)

Further information on drug treatments of fibromyalgia[edit]

Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis. Häuser W, Bernardy K, Uçeyler N, Sommer C. JAMA. 2009;301(2):198–209.

Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Häuser W, Petzke F, Üçeyler N, Sommer C. Rheumatology (Oxford). 2011;50(3):532–543.

Pharmacotherapy of fibromyalgia. Traynor LM, Thiessen CN, Traynor AP Am J Health Syst Pharm. 2011;68(14):1307–1319.

Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Tofferi JK, Jackson JL, O'Malley PG. Arthritis Rheum. 2004;51(1):9–13.