Review

An update on pharmacotherapy for the treatment of fibromyalgia Elena P Calandre†, Fernando Rico-Villademoros & Mahmoud Slim †

Universidad de Granada, Instituto de Neurociencias, Granada, Spain

1.

Introduction

2.

Drugs approved for use in fibromyalgia or recommended

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by clinical practice guidelines 3.

Investigational drugs

4.

Expert opinion

Introduction: Fibromyalgia is a syndrome characterized by chronic generalized pain in addition to different symptoms such as fatigue, sleep disturbances, stiffness, cognitive impairment, and psychological distress. Multidisciplinary treatment combining pharmacological and nonpharmacological therapies is advised. Areas covered: Publications describing randomized controlled trials and longterm extension studies evaluating drug treatment for fibromyalgia were searched in PubMed and Scopus and included in this review. Expert opinion: Different drugs are recommended for the treatment of fibromyalgia by different published guidelines, although only three of them have been approved for this indication by the US FDA, and none have been approved by the European Medicines Agency. 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. Keywords: drug efficacy, drug tolerability, drug treatment, fibromyalgia, review Expert Opin. Pharmacother. (2015) 16(9):1347-1368

1.

Introduction

Fibromyalgia, a common musculoskeletal pain disorder, is characterized by chronic generalized pain accompanied by a broad spectrum of associated somatic and psychological manifestations, including fatigue, sleep disturbances, stiffness, anxiety and cognitive dysfunction [1]. The pain seems to be neurogenic in origin and both hyperalgesia (increased response to painful stimuli) and allodynia (pain resulting from stimuli not normally painful) are usually found [2]. It has an estimated global prevalence of 2.7% and a 3:1 female-to-male ratio [3]. An incidence of 6.88 new cases of fibromyalgia per 1000 person-years has been documented for males, and the incidence is 11.28 new cases per 1000 person-years for females [4]. A considerable proportion of patients with fibromyalgia exhibit one or more comorbid conditions, including a mood disorder, anxiety disorder, migraine, tension-type headaches, irritable bowel syndrome, chronic fatigue syndrome, temporomandibular disorder and multiple chemical sensitivities [5,6]. The broad symptomatologic profile of patients with fibromyalgia along with the high rate of comorbidity render fibromyalgia a highly disabling syndrome that is linked to increased health-care costs and has a detrimental impact on quality of life [7]. Complex syndromes such as this are not easy to treat. Thus, a combination of pharmacological with nonpharmacological treatments is usually recommended [8]. In addition, a combination of two or more nonpharmacological therapies 10.1517/14656566.2015.1047343 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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. .

Pharmacological treatment for fibromyalgia provides only partial relief for pain, fatigue, sleep disturbances and psychological distress. Only pregabalin, duloxetine and milnacipran have been approved by some of the medicine agencies for the treatment of fibromyalgia, and must be considered firstchoice drugs. Amitriptyline, although not licensed for the treatment of fibromyalgia, has shown to improve fibromyalgia symptomatology and must be also considered as a drug of choice. The combination of two or more drugs in patients with only partial response is an option to be considered. The treatment of fibromyalgia should combine pharmacological and nonpharmacological measures in most of the cases.

This box summarizes key points contained in the article.

(a so-called multicomponent treatment) is also recommended by most evidence-based guidelines for the management of fibromyalgia [9,10]. The purpose of the present review is to provide an updated perspective of the pharmacological alternatives available for the treatment of fibromyalgia. Only data from short-term randomized clinical trials and long-term extension studies (‡ 6 months) published as full-length articles written in English, Spanish, Italian or French and available in PubMed or Scopus were included in this review. Among the relevant measurements of efficacy, we considered the following parameters: pain, depression, sleep quality, fatigue, Fibromyalgia Impact Questionnaire (FIQ) total scores and health-related quality of life (HRQL). In addition, tolerability was evaluated, considering the percentage of patient dropouts due to adverse events.

2. Drugs approved for use in fibromyalgia or recommended by clinical practice guidelines

Only three drugs, pregabalin, duloxetine and milnacipran, have been approved for use in the treatment of fibromyalgia by the US FDA, and no drug has been approved for this indication by the European Medicines Agency. Health Canada has approved pregabalin and duloxetine. Thus, patients with fibromyalgia frequently need to be treated on an off-label basis. However, different drugs, both old and new, have been studied in randomized clinical trials and are recommended by different clinical practice guidelines [10-14]. The next sections evaluate the available data for all of these drugs. Table 1 (short-term studies) and Table 2 (long-term studies) summarize the methodological characteristics of the trials included in this review. 1348

Antidepressants Antidepressants are commonly used for the treatment of different types of chronic pain, including fibromyalgia, although their degrees of efficacy vary depending of the type and mechanisms of action of the drug and the specific condition being treated [15]. 2.1

Article highlights.

Tricyclic antidepressants Although different tricyclic antidepressants (TCAs) have been used in the treatment of chronic pain, amitriptyline has been the most thoroughly studied for the treatment of fibromyalgia, and it is recommended by all published clinical practice guidelines [10-14]. Only one study has evaluated nortriptyline [16], and only one other study has evaluated dothiepin [17]. We found a total of 17 clinical trials that evaluated amitriptyline either as an investigational drug or as a comparator in relation to other drugs or therapeutic techniques [16,18-33]. One additional study comparing fluvoxamine with amitriptyline using a crossover design was retrieved, but it was in Turkish and the information provided in the abstract was limited; therefore, we have not included information on it [34]. Eleven trials had double-blind designs, one was single-blinded and the remainder were open-label. Ten studies included a placebo arm. Samples sizes were small. The administered daily doses were generally low (10 -- 50 mg). Only two studies, which both used flexible dosages, reached a maximum daily dosage of 75 mg [31,33], and one used a 100 mg/day fixed dosage. Only one long-term trial was identified [19]. Most clinical trials evaluating amitriptyline were performed > 15 years ago; therefore, the methodological qualities of many of them were low according to current standards. Overall, amitriptyline was well tolerated. A total of 11 short-term studies reported numbers of patient dropouts due to adverse events ranging from 0 to 18% [16,18,21-23,26-28,31,33]. The small sample sizes evaluated in these trials makes difficult to evaluate the efficacy of amitriptyline due to the risk of Type II error (i.e., not rejecting the null hypothesis when in fact the alternate hypothesis is true. In a superiority trial, stating that there is no difference compared to the control group when the truth is that there is a difference). Of nine placebo-controlled short-term trials [16,18,20-23,25,26,28], seven reported comparative efficacy results on pain [18,20-22,25,26,28], five of which showed positive results for amitriptyline (i.e., the superiority of amitriptyline compared with placebo). In addition, seven reported sleep disturbance results [18,20-23,26,28], six of which showed significant improvement, and seven reported results on fatigue [20-23,25,26,28], four of which reported that amitriptyline was superior compared with placebo. The effects of amitriptyline on depressive symptoms have been scarcely investigated in placebo-controlled trials, including two negative trials: a short-term [22] and long-term trial [19]. With regard to the overall impact of amitriptyline on fibromyalgia symptoms, importantly, three of the five trials reporting FIQ results [16,22,30,31,33] showed reductions from baseline to end 2.1.1

Expert Opin. Pharmacother. (2015) 16(9)

An update on pharmacotherapy for the treatment of fibromyalgia

Table 1. Short-term studies characteristics. Author (year)

Design

Comparator groups (n)

Drug dose

Duration (weeks)

Key selection criteria

Amitriptyline Carette et al. (1986) [18]

Double-blind, parallel

AMT (n = 34) versus placebo (n = 36) n = 62 equally distributed to: AMT/NP, NP, AMT and placebo AMT versus placebo (n = 36)

AMT: 10 -- 50 mg HS

9

- Primary fibrositis (Smythe criteria)

AMT: 25 mg HS NP: 500 mg BID

6

- FMS (Modified Yunus et al. criteria)

AMT: 10 mg HS (wk 1); 25 mg HS (wk 2) followed by 50 mg HS AMT: 25 mg HS

4 each phase

- Fibrositis syndrome (Smythe and Moldofsky criteria)

15

- PFS (Yunus et al. and Wolfe et al. criteria) - Able to participate in the heavy physical training

8

- PFS (Yunus et al.) - Without severe psychiatric comorbidity

- Age‡ 18 - FMS (ACR 1990) - Score of ‡ 4 on at least 1 of 2 selfadministered 10-cm VAS (1 evaluating pain and 1 evaluating global fibromyalgia symptoms) - PFS (ACR 1990)

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Goldenberg et al. Double-blind, (1986) [21] parallel

Scudds et al. (1989) [23]

Double-blind, crossover

Isomeri et al. (1993) [24]

Open-label, parallel

Kempenaers et al. Double-blind, parallel (1994) [25]

AMT (n = 16) versus CFT (n = 15) versus AMT/CFT (n = 14) SER282 (n = 12) AMT: 50 mg/day versus AMT SER282: 20 mg/ml (n = 12) versus 3 times/wk placebo (n = 12)

Carette et al. (1995) [20]

Double-blind, crossover

AMT versus placebo (n = 22)

AMT: 10 -- 25 mg HS

8 each phase

Ginsberg et al. (1996) [26]

Double-blind, parallel

AMT SR (n = 26) versus placebo (n = 25) AMT versus FLX versus AMT/FLX versus placebo (n = 31) AMT (n = 34) versus PRX (n = 34) AMT (n = 42) versus MOC (n = 43) versus placebo (n = 45)

AMT SR: 25 mg/ day

8

AMT: 25 mg HS FLX: 20 mg/day

6 each phase

AMT: 100 mg HS PRX: 20 mg/day

6

AMT: 25 -- 37.5 mg HS MOC: 450 -- 600 mg/day

12

Goldenberg et al. Double-blind, crossover (1996) [22]

Ataog˘lu et al. (1997) [27]

Open-label, parallel

Hannonen et al. (1998) [28]

Double-blind, parallel

- Aged 18 -- 60 - FMS (ACR 1990) - Pain (VAS 0 -- 100) ‡ 30 - HDRS £ 18 - Women - FMS (ACR 1990) - Without previous diagnosis of depression - Women aged 18 -- 65 - FMS (ACR 1990) - A minimum baseline score of 4 (moderate) on at least 3 of 4 10-point VAS (general health, pain, sleep and fatigue) - Without depression or psychosis

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American college of rheumatology; ACU: Acupuncture; AER: Aerobic exercise; AMT: Amitriptyline; APAP: Acetaminophen; BDI-II: Beck depression inventory-II; BID: Twice daily; BMI: Body mass index; BPI-s: Brief pain inventory-severity; CBT: Cognitive-behavioral therapy; CFT: Cardiovascular fitness training; cm: Centimeters; CPM: Citalopram; CR: Controlled-release; CYB: Cyclobenzaprine; DLX: Duloxetine; DSN: Dolasetron; DTP: Dothiepin; ECPM: Escitalopram; EEG: Electroencephalographic; FIQ: Fibromyalgia impact questionnaire; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; Ga-As: Galliuem-arsenide; GAD: Generalized anxiety disorder; GBT: Gabapentin; HDRS: Hamilton depression rating scale; HS: Once nightly; IBU: Ibuprofen; IV: Intravenous; J/cm2: Joules per square centimeter; kg: Kilogram; m2: Meters squared; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; MOC: Moclobomide; NBN: Nabilone; NFB: Neurofeedback receiving sensory motor rhythm treatment; NP: Naproxen; NRS: Numeric rating scale; NTP: Nortriptyline; PFS: Primary fibromyalgia syndrome; PGB: Pregabalin; PHY: Physiotherapy; PRL: Pirlindole; PRX: Paroxetine; PSG: Polysomnographic; PXL: Pramipexole; QD: Once daily; RBX: Reboxetine; REM: Rapid eye movement; SER282: Antidiencephalon immune serum; SF-MPQ: Short form McGill pain questionnaire; SR: Sustained-release; SXB: Sodium oxybate; TENS: Transcutaneous nerve stimulation; TID: Three times per day; TML: Tramadol; TPN: Tropisetron; TST: Total sleep time; VAS: Visual analogue scale; WASO: Wake after sleep onset; wk: Week; wkly: Weekly; XR: Extended release. Expert Opin. Pharmacother. (2015) 16(9)

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Table 1. Short-term studies characteristics (continued). Author (year)

Design

Comparator groups (n)

Drug dose

Duration (weeks)

Key selection criteria

Heymann et al. (2001) [16]

Double-blind, parallel

AMT: 25 mg/day NTP: 25 mg/day

8

- Women ‡ 18 - FMS (ACR 1990)

C¸apaci et al. (2002) [29]

Rater-blind, parallel

AMT: 20 mg/day PRX: 40 mg/day

8

- FMS (ACR 1990)

Gu¨r et al. (2002) [30]

Single-blind, parallel

AMT: 10 mg HS Ga-As laser: 2 j/ cm2 for 3 min at each tender point

AMT: 8 Laser: 2

- FMS (ACR 1990) - Without recent or past history of psychiatric comorbidity

Konuk et al. (2010) [31]

Open-label, parallel

- FMS (ACR 1990) - Without major depression

Double-blind, parallel

AMT: 25 -- 75 mg/ day RBX: 4 -- 8 mg/day AMT: 25 mg/day Lidocaine: 240 mg IV once per wk

8

Vlainich et al. (2011) [32]

4

- Women aged 18 to 60 - FMS (ACR 1990) - Without psychiatric comorbidity

Calandre et al. (2014) [33]

Open-label, parallel

AMT (n = 40) versus NTP (n = 38) versus placebo (n = 40) AMT (n = 20) versus PRX (n = 20) AMT (n = 25) versus Ga-As laser (n = 25) versus placebo laser (n = 25) AMT (n = 11) versus RBX (n = 10) AMT (n = 15) versus AMT/ lidocaine (n = 15) AMT (n = 45) versus quetiapine XR (n = 45)

AMT: 10 -- 75 mg/ day Quetiapine XR: 50 -- 300 mg/day

16

- Adults 18 -- 70 years - FMS (ACR 1990) - FIQ ‡ 40 - BPI-s ‡ 4 - Without psychiatric comorbidity except MDD - Without severe depression (BDI-II < 30)

Dothiepin Caruso et al. (1987) [17]

Double-blind, parallel

DTP (n = 30) versus placebo (n = 30)

DTP: 75 mg/day

8

- Aged 25 -- 65 - PFS (Campbell et al. questionnaire)

Duloxetine Arnold et al. (2004) [37]

Double-blind, parallel

DLX (n = 104) versus placebo (n = 103)

DLX: 60 mg BID

12

Arnold et al. (2005) [38]

Double-blind, parallel

12

Arnold et al. (2012) [41]

Double-blind, parallel

DLX 60 mg QD DLX: 60 mg QD (n = 118) versus DLX: 60 mg BID DLX 60 mg BID (n = 116) versus placebo (n = 120) DLX (n = 155) DLX: 30 mg/day versus placebo (n = 153)

- Age ‡ 18 - FMS (ACR 1990) - Pain (FIQ sub-item) ‡ 4 - Without psychiatric comorbidity except MDD - Women ‡ 18 - FMS (ACR 1990) - BPI-s ‡ 4 - Without psychiatric comorbidity except MDD

12

- Age ‡ 18 - FMS (ACR 1990) - BPI-s ‡ 4 - Without psychiatric comorbidity except MDD or GAD

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American college of rheumatology; ACU: Acupuncture; AER: Aerobic exercise; AMT: Amitriptyline; APAP: Acetaminophen; BDI-II: Beck depression inventory-II; BID: Twice daily; BMI: Body mass index; BPI-s: Brief pain inventory-severity; CBT: Cognitive-behavioral therapy; CFT: Cardiovascular fitness training; cm: Centimeters; CPM: Citalopram; CR: Controlled-release; CYB: Cyclobenzaprine; DLX: Duloxetine; DSN: Dolasetron; DTP: Dothiepin; ECPM: Escitalopram; EEG: Electroencephalographic; FIQ: Fibromyalgia impact questionnaire; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; Ga-As: Galliuem-arsenide; GAD: Generalized anxiety disorder; GBT: Gabapentin; HDRS: Hamilton depression rating scale; HS: Once nightly; IBU: Ibuprofen; IV: Intravenous; J/cm2: Joules per square centimeter; kg: Kilogram; m2: Meters squared; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; MOC: Moclobomide; NBN: Nabilone; NFB: Neurofeedback receiving sensory motor rhythm treatment; NP: Naproxen; NRS: Numeric rating scale; NTP: Nortriptyline; PFS: Primary fibromyalgia syndrome; PGB: Pregabalin; PHY: Physiotherapy; PRL: Pirlindole; PRX: Paroxetine; PSG: Polysomnographic; PXL: Pramipexole; QD: Once daily; RBX: Reboxetine; REM: Rapid eye movement; SER282: Antidiencephalon immune serum; SF-MPQ: Short form McGill pain questionnaire; SR: Sustained-release; SXB: Sodium oxybate; TENS: Transcutaneous nerve stimulation; TID: Three times per day; TML: Tramadol; TPN: Tropisetron; TST: Total sleep time; VAS: Visual analogue scale; WASO: Wake after sleep onset; wk: Week; wkly: Weekly; XR: Extended release.

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Table 1. Short-term studies characteristics (continued). Author (year)

Design

Comparator groups (n)

Drug dose

Duration (weeks)

Key selection criteria

Milnacipran Gendreau et al. (2005) [45]

Double-blind, parallel

MLN: Dose escalation up to 200 mg/day

12

-

Clauw et al. (2008) [46]

Double-blind, parallel

MLN: 100 mg/day MLN: 200 mg/day

15

Arnold et al. (2010) [48]

Double-blind, parallel

MLN QD (n = 46) versus MLN BID (n = 51) versus placebo (n = 28) MLN 100 mg/ day (n = 401) versus MLN 200 mg/day (n = 401) versus placebo (n = 405) MLN (n = 516) versus placebo (n = 509)

MLN: 100 mg/day

4 -- 6 (dose escalation) 12 (stable dose)

Branco et al. (2010) [51]

Double-blind, parallel

MLN (n = 435) versus placebo (n = 449)

MLN: 200 mg/day

16

Matthey et al. (2013) [53]

Double-blind, parallel

MLN (n = 39) versus placebo (n = 40)

MLN: 100 -- 200 mg/day

7

Bateman et al. (2013) [54]

Double-blind, parallel

MLN (n = 86) versus placebo (n = 21)

MLN: 100 -- 200 mg/day

10

- Aged 18 -- 70 - FMS (ACR 1990) - FIQ physical function component ‡ 4 - Pain (VAS 0 -- 100) ‡ 40 - Without severe psychiatric illness or current major depressive episode - BDI £ 25 - Aged 18 -- 70 - FMS (ACR 1990) - FIQ physical function component ‡ 4 - Pain (VAS 0 -- 100) ‡ 40 and £ 90 - Without current major depressive episode - BDI-II £ 25 - Aged 18 -- 70 - FMS (ACR 1990) - FIQ physical function component ‡ 3 - Pain (VAS 0 -- 100) ‡ 40 and £ 90 - Without severe psychiatric illness including GAD or current major depressive episode - BDI-II £ 25 - Women > 18 years - FMS (ACR 1990) - Pain (VAS 0 -- 100) > 40 - Without severe psychiatric illness or current major depressive episode - BDI-II £ 25 - Aged 18 -- 70 - FMS (non-specified criteria) - Pain (VAS 0 -- 100) ‡ 40 and £ 90 - Without adequate response to DLX (Pain VAS maintained ‡ 40 following 2-wk run-in period with DLX 60 mg/day)

Citalopram Nørregaard et al. (1995) [56]

Double-blind, parallel

CPM: 20 -- 40 mg/ day

8

Anderberg et al. (2000) [57]

Double-blind, parallel

CPM (n = 22) versus placebo (n = 21) CPM (n = 21) versus placebo (n = 19)

CPM: 20 -- 40 mg/ day

16

Aged 18 -- 70 FMS (ACR 1990) Pain (20-point logarithmic scale) ‡ 10 Without severe psychiatric illness

- FMS (ACR 1990) - Without diagnosis of endogenous depression - Women with FMS (ACR 1990) - Not seriously depressed

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American college of rheumatology; ACU: Acupuncture; AER: Aerobic exercise; AMT: Amitriptyline; APAP: Acetaminophen; BDI-II: Beck depression inventory-II; BID: Twice daily; BMI: Body mass index; BPI-s: Brief pain inventory-severity; CBT: Cognitive-behavioral therapy; CFT: Cardiovascular fitness training; cm: Centimeters; CPM: Citalopram; CR: Controlled-release; CYB: Cyclobenzaprine; DLX: Duloxetine; DSN: Dolasetron; DTP: Dothiepin; ECPM: Escitalopram; EEG: Electroencephalographic; FIQ: Fibromyalgia impact questionnaire; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; Ga-As: Galliuem-arsenide; GAD: Generalized anxiety disorder; GBT: Gabapentin; HDRS: Hamilton depression rating scale; HS: Once nightly; IBU: Ibuprofen; IV: Intravenous; J/cm2: Joules per square centimeter; kg: Kilogram; m2: Meters squared; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; MOC: Moclobomide; NBN: Nabilone; NFB: Neurofeedback receiving sensory motor rhythm treatment; NP: Naproxen; NRS: Numeric rating scale; NTP: Nortriptyline; PFS: Primary fibromyalgia syndrome; PGB: Pregabalin; PHY: Physiotherapy; PRL: Pirlindole; PRX: Paroxetine; PSG: Polysomnographic; PXL: Pramipexole; QD: Once daily; RBX: Reboxetine; REM: Rapid eye movement; SER282: Antidiencephalon immune serum; SF-MPQ: Short form McGill pain questionnaire; SR: Sustained-release; SXB: Sodium oxybate; TENS: Transcutaneous nerve stimulation; TID: Three times per day; TML: Tramadol; TPN: Tropisetron; TST: Total sleep time; VAS: Visual analogue scale; WASO: Wake after sleep onset; wk: Week; wkly: Weekly; XR: Extended release.

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Table 1. Short-term studies characteristics (continued). Author (year)

Design

Comparator groups (n)

Drug dose

Duration (weeks)

Key selection criteria

Escitalopram Kayıran et al. (2010) [58]

Rater-blind, parallel

ECPM (n = 18) versus NFB (n = 18)

ECPM: 10 mg/day

ECPM: 8 NFB: 4 Evaluation: 24

- Women aged 16 -- 49 - FMS (ACR 1990)

Fluoxetine Wolfe et al. (1994) [59]

Double-blind, parallel

FLX: 20 mg/day

6

Arnold et al. (2002) [62]

Double-blind, parallel

FLX: 10 -- 80 mg/ day

12

Hadianfard et al. (2012) [63]

Rater-blind, parallel

FLX (n = 21) versus placebo (n = 21) FLX (n = 30) versus placebo (n = 30) FLX (n = 15) versus ACU (n = 15)

-

Paroxetine Giordano et al. (1999) [64]

Single-blind, parallel

PRX: 20 mg/day

12

- FMS (ACR 1990)

Sencan et al. (2004) [65]

Open-label, parallel

PRX: 20 mg/day AER: 3 times/wk TENS: 3 times/wk

Double-blind, parallel

6 Follow-up evaluation: 24 12

- Women aged 18 -- 50 - FMS (ACR 1990)

Patkar et al. (2007) [66]

PRX (n = 20) versus placebo (n = 20) PRX (n = 20) versus AER (n = 20) versus TENS (n = 20) PRX CR (n = 58) versus placebo (n = 58)

Moclobemide Yavuzer et al. (1998) [69]

Single-blind, parallel

MOC (n = 30) versus placebo (n = 30)

MOC: 150 mg BID

6

- FMS (ACR 1990)

Pirlindole Ginsberg et al. (1998) [70]

Double-blind, parallel

PRL (n = 50) versus placebo (n = 50)

PRL: 75 mg BID

4

-Aged 18 -- 75 - FMS (ACR 1990)

Pregabalin Crofford et al. (2005) [71]

Double-blind, parallel

PGB 150 mg/ PGB: 150 mg/day day (n = 132) PGB: 300 mg/day versus PGB PGB: 450 mg/day 300 mg/day (n = 134) versus PGB 450 mg/ day (n = 132) versus placebo (n = 131)

8

- Age ‡ 18 - FMS (ACR 1990) - SF-MPQ (VAS 0 -- 100) ‡ 40 - Pain rating scale (0 -- 10) ‡ 4 in at least 4 daily pain diary entries, during the wk before randomization

FLX: 20 mg/day FLX: 8 ACU: 3 sessions/wk ACU: 2 Evaluation: 52

PRX CR: 12.5 -- 62.5 mg/ day

Women aged 21 -- 70 FMS (criteria set by the authors) Pain (VAS 0 -- 3) > 1 Age ‡ 18 FMS (ACR 1990) HDRS < 10 FMS (ACR 1990) Pain (VAS 0 -- 10) > 4 Without severe psychiatric comorbidity

- Aged 18 -- 65 - FMS (ACR 1990) - Pain (VAS 0 -- 10) ‡ 5 - BDI-II £ 23 - Without psychotic disorders, current depressive or anxiety disorders

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American college of rheumatology; ACU: Acupuncture; AER: Aerobic exercise; AMT: Amitriptyline; APAP: Acetaminophen; BDI-II: Beck depression inventory-II; BID: Twice daily; BMI: Body mass index; BPI-s: Brief pain inventory-severity; CBT: Cognitive-behavioral therapy; CFT: Cardiovascular fitness training; cm: Centimeters; CPM: Citalopram; CR: Controlled-release; CYB: Cyclobenzaprine; DLX: Duloxetine; DSN: Dolasetron; DTP: Dothiepin; ECPM: Escitalopram; EEG: Electroencephalographic; FIQ: Fibromyalgia impact questionnaire; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; Ga-As: Galliuem-arsenide; GAD: Generalized anxiety disorder; GBT: Gabapentin; HDRS: Hamilton depression rating scale; HS: Once nightly; IBU: Ibuprofen; IV: Intravenous; J/cm2: Joules per square centimeter; kg: Kilogram; m2: Meters squared; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; MOC: Moclobomide; NBN: Nabilone; NFB: Neurofeedback receiving sensory motor rhythm treatment; NP: Naproxen; NRS: Numeric rating scale; NTP: Nortriptyline; PFS: Primary fibromyalgia syndrome; PGB: Pregabalin; PHY: Physiotherapy; PRL: Pirlindole; PRX: Paroxetine; PSG: Polysomnographic; PXL: Pramipexole; QD: Once daily; RBX: Reboxetine; REM: Rapid eye movement; SER282: Antidiencephalon immune serum; SF-MPQ: Short form McGill pain questionnaire; SR: Sustained-release; SXB: Sodium oxybate; TENS: Transcutaneous nerve stimulation; TID: Three times per day; TML: Tramadol; TPN: Tropisetron; TST: Total sleep time; VAS: Visual analogue scale; WASO: Wake after sleep onset; wk: Week; wkly: Weekly; XR: Extended release.

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Table 1. Short-term studies characteristics (continued). Author (year)

Design

Comparator groups (n)

Drug dose

Duration (weeks)

Key selection criteria

Mease et al. (2008) [73]

Double-blind, parallel

PGB: 300 mg/day PGB: 450 mg/day PGB: 600 mg/day

13

-

Age ‡ 18 FMS (ACR 1990) Pain (NRS 0 -- 10) ‡ 4 SF-MPQ (VAS 0 -- 100) ‡ 40

Arnold et al. (2008) [76]

Double-blind, parallel

PGB: 300 mg/day PGB: 450 mg/day PGB: 600 mg/day

14

-

Age ‡ 18 FMS (ACR 1990) Pain (VAS 0 -- 100) ‡ 40 Pain wkly average (NRS 0 -- 10) ‡ 4

Pauer et al. (2011) [77]

Double-blind, parallel

PGB: 300 mg/day PGB: 450 mg/day PGB: 600 mg/day

14

- Age ‡ 18 - FMS (ACR 1990) - SF-MPQ (VAS 0 -- 100) ‡ 40 - Pain (NRS 0 -- 10) ‡ 4 - Without high placebo response ( ‡ 30% decrease on the VAS following the placebo run-in period)

Roth et al. (2012) [78]

Double-blind, crossover

PGB 300 mg/ day (n = 185) versus PGB 450 mg/day (n = 183) versus PGB 600 mg/ day (n = 190) versus placebo (n = 190) PGB 300 mg/ day (n = 183) versus PGB 450 mg/day (n = 190) versus PGB 600 mg/ day (n = 188) versus placebo (n = 184) PGB 300 mg/ day (n = 184) versus PGB 450 mg/day (n = 182) versus PGB 600 mg/ day (n = 186) versus placebo (n = 184) PGB versus placebo (n = 119)

PGB: 300 -- 450 mg/day

4 each phase

Ohta et al. (2012) [79]

Double-blind, parallel

PGB (n = 250) versus placebo (n = 248)

PGB: 300 -- 450 mg/day

15

- Age ‡ 18 - FMS (ACR 1990) - Difficulty in maintaining sleep for ‡ 3 nights/wk for ‡ 1 month - Subjective TST £ 6 h and subjective WASO ‡ 60 min for ‡ 3 nights/wk - PSG: average of 2 PSG nights of WASO > 45 min and TST of 3.0 -- 6.5 h - Without psychiatric comorbidity - Age ‡ 18 - FMS (ACR 1990) - Pain (VAS 0 -- 100) ‡ 40 - Weekly average of pain daily dairy (NRS 0 -- 10) ‡ 4 - Without high placebo response (‡ 30% decrease on the VAS following the placebo run-in period)

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American college of rheumatology; ACU: Acupuncture; AER: Aerobic exercise; AMT: Amitriptyline; APAP: Acetaminophen; BDI-II: Beck depression inventory-II; BID: Twice daily; BMI: Body mass index; BPI-s: Brief pain inventory-severity; CBT: Cognitive-behavioral therapy; CFT: Cardiovascular fitness training; cm: Centimeters; CPM: Citalopram; CR: Controlled-release; CYB: Cyclobenzaprine; DLX: Duloxetine; DSN: Dolasetron; DTP: Dothiepin; ECPM: Escitalopram; EEG: Electroencephalographic; FIQ: Fibromyalgia impact questionnaire; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; Ga-As: Galliuem-arsenide; GAD: Generalized anxiety disorder; GBT: Gabapentin; HDRS: Hamilton depression rating scale; HS: Once nightly; IBU: Ibuprofen; IV: Intravenous; J/cm2: Joules per square centimeter; kg: Kilogram; m2: Meters squared; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; MOC: Moclobomide; NBN: Nabilone; NFB: Neurofeedback receiving sensory motor rhythm treatment; NP: Naproxen; NRS: Numeric rating scale; NTP: Nortriptyline; PFS: Primary fibromyalgia syndrome; PGB: Pregabalin; PHY: Physiotherapy; PRL: Pirlindole; PRX: Paroxetine; PSG: Polysomnographic; PXL: Pramipexole; QD: Once daily; RBX: Reboxetine; REM: Rapid eye movement; SER282: Antidiencephalon immune serum; SF-MPQ: Short form McGill pain questionnaire; SR: Sustained-release; SXB: Sodium oxybate; TENS: Transcutaneous nerve stimulation; TID: Three times per day; TML: Tramadol; TPN: Tropisetron; TST: Total sleep time; VAS: Visual analogue scale; WASO: Wake after sleep onset; wk: Week; wkly: Weekly; XR: Extended release.

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Table 1. Short-term studies characteristics (continued). Author (year)

Design

Comparator groups (n)

Mease et al. (2013) [74]

Open-label, parallel

Nasser et al. (2014) [81]

Drug dose

Duration (weeks)

Key selection criteria

PGB (n = 180) PGB: versus PGB/MLN 300 -- 450 mg/day (n = 184) MLN: 100 mg/day

11

Double-blind, parallel

PGB (n = PGB (n =

BID 88) versus HS 89)

PGB: 150 mg BID PGB: 300 mg HS

8

- Aged 18 -- 70 - FMS (ACR 1990) - Pain wkly average (VAS 0 -- 100) ‡ 40 - Incomplete responders to pregabalin after 4 -- 12 weeks run-in period - BMI < 40 kg/m2 - Without severe psychiatric comorbidity - Women ‡ 18 - FMS (ACR 1990) - Pain (NRS 0 -- 10) ‡ 4

Gabapentin Arnold et al. (2007) [75]

Double-blind, parallel

GBT (n = 75) versus placebo (n = 75)

GBT: 1200 -- 2400 mg/ day

12

-

Cyclobenzaprine Bennett et al. (1988) [83]

Double-blind, parallel

CYB: 10 -- 40 mg HS

12

- Fibrositis syndrome (criteria set by the authors)

Quimby et al. (1989) [84]

Double-blind, parallel

- FMS (criteria set by the authors)

Double-blind, crossover

CYB: 10 mg in the morning; 30 mg HS CYB: 20 -- 40 mg/ day

6

Reynolds et al. (1991) [85]

4 each phase

- FMS (criteria set by Bennett et al., 1988)

Fossaluzza et al. (1992) [86]

Open-label, parallel

CYB: 10 mg HS IBU: 600 mg HS

10 days

- PFS (Yunus et al. criteria)

Santandrea et al. (1993) [87]

Double-blind, crossover

CYB10: 10 mg HS CYB30: 10 mg TID

2 each phase

- Age 18 -- 65 - FMS (Yunus et al. Criteria) - Without depression

Cantini et al. (1994) [60]

Open-label, parallel

CYB: 10 mg HS FLX: 20 mg/day

12

- Women - FMS (ACR 1990)

Garcı´a et al. (2006) [88]

Open-label, parallel

CYB (n = 62) versus placebo (n = 58) CYB (n = 23) versus placebo (n = 22) CYB versus placebo (n = 12) CYB (n = 15) versus CYB/IBU (n = 17) CYB 10 mg/day versus CYB 30 mg/day (n = 40) CYB/FLX (n = 11) versus CYB (n = 10) CBT (n =7) versus CYB (n = 7) versus CBT/CYB (n = 7) versus non-treatment (n = 7)

CYB: 10 mg/day CBT: one time/wk

9

- FMS (ACR 1990)

Age ‡ 18 FMS (ACR 1990) BPI-s ‡ 4 Without psychiatric comorbidity

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American college of rheumatology; ACU: Acupuncture; AER: Aerobic exercise; AMT: Amitriptyline; APAP: Acetaminophen; BDI-II: Beck depression inventory-II; BID: Twice daily; BMI: Body mass index; BPI-s: Brief pain inventory-severity; CBT: Cognitive-behavioral therapy; CFT: Cardiovascular fitness training; cm: Centimeters; CPM: Citalopram; CR: Controlled-release; CYB: Cyclobenzaprine; DLX: Duloxetine; DSN: Dolasetron; DTP: Dothiepin; ECPM: Escitalopram; EEG: Electroencephalographic; FIQ: Fibromyalgia impact questionnaire; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; Ga-As: Galliuem-arsenide; GAD: Generalized anxiety disorder; GBT: Gabapentin; HDRS: Hamilton depression rating scale; HS: Once nightly; IBU: Ibuprofen; IV: Intravenous; J/cm2: Joules per square centimeter; kg: Kilogram; m2: Meters squared; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; MOC: Moclobomide; NBN: Nabilone; NFB: Neurofeedback receiving sensory motor rhythm treatment; NP: Naproxen; NRS: Numeric rating scale; NTP: Nortriptyline; PFS: Primary fibromyalgia syndrome; PGB: Pregabalin; PHY: Physiotherapy; PRL: Pirlindole; PRX: Paroxetine; PSG: Polysomnographic; PXL: Pramipexole; QD: Once daily; RBX: Reboxetine; REM: Rapid eye movement; SER282: Antidiencephalon immune serum; SF-MPQ: Short form McGill pain questionnaire; SR: Sustained-release; SXB: Sodium oxybate; TENS: Transcutaneous nerve stimulation; TID: Three times per day; TML: Tramadol; TPN: Tropisetron; TST: Total sleep time; VAS: Visual analogue scale; WASO: Wake after sleep onset; wk: Week; wkly: Weekly; XR: Extended release.

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Table 1. Short-term studies characteristics (continued). Author (year)

Design

Comparator groups (n)

Drug dose

Duration (weeks)

Key selection criteria

Moldofsky et al. (2011) [89]

Double-blind, parallel

CYB (n = 18) versus placebo (n = 18)

CYB: 1 -- 4 mg HS

8

- Aged 18 -- 65 - FMS (ACR 1990) - Documented sleep disturbance (Nonrestful nights for at least 3 months) - a-non-REM EEG sleep anomaly - Without primary psychiatric disorder

Tramadol Russell et al. (2000) [92]

Double-blind, parallel

TML (n = 35) versus placebo (n = 34)

TML: 50 -- 400 mg/ 6 day

Bennett et al. (2003) [93]

Double-blind, parallel

TML/APAP (n = 158) versus placebo (n = 157)

TML/APAP combination tablet (37.5 mg/325 mg): 1 -- 2 tablets 4 times/day

13

Tropisetron Fa¨rber et al. (2000) [94]

Double-blind, parallel

TPN: 5 mg/day TPN: 10 mg/day TPN: 15 mg/day

10 days

- Aged 18 -- 65 - FMS (ACR 1990) - Pain (VAS 0 -- 100) ‡ 30

Spa¨th et al. (2004) [96]

Double-blind, parallel

TPN 5 mg/day (n = 107) versus TPN 10 mg/day (n = 103) versus TPN 15 mg/day (n = 102) versus placebo (n = 106) TPN (n = 9) versus placebo (n = 12)

TPN: 5 mg/day IV bolus

5 days

Seidel et al. (2007) [95]

Open-label, parallel

TPN/PHY (n = 36) versus PHY (n = 36)

TPN: 5 mg/day IV bolus

5 days

-

Aged 18 -- 65 FMS (ACR 1990) Pain (VAS 0 -- 100) ‡ 40 BDI-II < 20 FMS (ACR 1990) Pain (VAS 0 -- 100) ‡ 50

DSN (n = 29) versus placebo (n = 31)

DSN: 12.5 mg/day IV 4 days/month

12

-

Aged 18 -- 75 FMS (ACR 1990) Pain (VAS 0 -- 100) ‡ 40 Non-responders of standard therapy

PXL (n = 39) versus placebo (n = 21)

PXL: 0.25 mg HS (wk 1) increased gradually to reach 4.5 mg (wk 12)

14

-

Aged 22 -- 67 FMS (ACR 1990) Pain (VAS 0 -- 10) ‡ 5 Tender point score (0 -- 54) > 10

Dolasetron Double-blind, VergneSalle et al. (2011) parallel [97]

Pramipexole Holman et al. (2005) [98]

Double-blind, parallel

- Aged 18 -- 75 - FMS (ACR 1990) - Responders to TML during 3-week lead-in phase - Without MDD - Aged 18 -- 75 - FMS (ACR 1990) - Pain (VAS 0 -- 100) ‡ 40

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American college of rheumatology; ACU: Acupuncture; AER: Aerobic exercise; AMT: Amitriptyline; APAP: Acetaminophen; BDI-II: Beck depression inventory-II; BID: Twice daily; BMI: Body mass index; BPI-s: Brief pain inventory-severity; CBT: Cognitive-behavioral therapy; CFT: Cardiovascular fitness training; cm: Centimeters; CPM: Citalopram; CR: Controlled-release; CYB: Cyclobenzaprine; DLX: Duloxetine; DSN: Dolasetron; DTP: Dothiepin; ECPM: Escitalopram; EEG: Electroencephalographic; FIQ: Fibromyalgia impact questionnaire; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; Ga-As: Galliuem-arsenide; GAD: Generalized anxiety disorder; GBT: Gabapentin; HDRS: Hamilton depression rating scale; HS: Once nightly; IBU: Ibuprofen; IV: Intravenous; J/cm2: Joules per square centimeter; kg: Kilogram; m2: Meters squared; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; MOC: Moclobomide; NBN: Nabilone; NFB: Neurofeedback receiving sensory motor rhythm treatment; NP: Naproxen; NRS: Numeric rating scale; NTP: Nortriptyline; PFS: Primary fibromyalgia syndrome; PGB: Pregabalin; PHY: Physiotherapy; PRL: Pirlindole; PRX: Paroxetine; PSG: Polysomnographic; PXL: Pramipexole; QD: Once daily; RBX: Reboxetine; REM: Rapid eye movement; SER282: Antidiencephalon immune serum; SF-MPQ: Short form McGill pain questionnaire; SR: Sustained-release; SXB: Sodium oxybate; TENS: Transcutaneous nerve stimulation; TID: Three times per day; TML: Tramadol; TPN: Tropisetron; TST: Total sleep time; VAS: Visual analogue scale; WASO: Wake after sleep onset; wk: Week; wkly: Weekly; XR: Extended release.

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Table 1. Short-term studies characteristics (continued). Author (year)

Design

Comparator groups (n)

Drug dose

Duration (weeks)

Nabilone Skrabek et al. (2008) [106]

Double-blind, parallel

NBN (n = 20) versus placebo (n = 20)

Ware et al. (2010) [107]

Double-blind, crossover

NBN versus AMT (n = 32)

NBN: 0.5 mg HS 4 (wk 1); 0.5 mg BID (wk 2); 0.5 mg in the morning and 1 mg HS (wk 3); 1 mg BID (wk 4) NBN: 0.5 -- 1 mg 2 each HS phase AMT: 10 -- 20 mg HS

Sodium oxybate Scharf et al. (2003) [101]

Double-blind, crossover

Russell et al. (2009) [102]

Double-blind, parallel

Russell et al. (2011) [103]

Double-blind, parallel

Spaeth et al. (2012) [104]

Double-blind, parallel

SXB versus placebo (n = 24) SXB 4.5 g/day (n = 58) versus SXB 6 g/day (n = 66) versus placebo (n = 64) SXB 4.5 g/day (n = 182) versus SXB 6 g/day (n = 183) versus placebo (n = 183) SXB 4.5 g/day (n = 195) versus SXB 6 g/day (n = 190) versus placebo (n = 188)

Key selection criteria

- Aged 18 -- 70 - FMS (ACR 1990)

- Aged ‡ 18 - FMS (ACR 1990) - Self-reported chronic insomnia (disturbed sleep every night or every other night for the past 6 months)

SXB: 6 g HS

4 each phase

- FMS (ACR 1990) - a-intrusion in at least 30% of non-REM on 2 of 3 nights - Age ‡ 18 - FMS (ACR 1990) - Pain (VAS 0 -- 100) > 40 - Without depression

SXB: 4.5 g HS SXB: 6 g HS

8

SXB: 4.5 g HS SXB: 6 g HS

14

-

Age ‡ 18 FMS (ACR 1990) BMI < 40 kg/m2 Pain (VAS 0 -- 100) ‡ 50 Without MDD or GAD

SXB: 4.5 g HS SXB: 6 g HS

14

-

Age ‡ 18 FMS (ACR 1990) BMI < 40 kg/m2 Pain (VAS 0 -- 100) ‡ 50 Without MDD or GAD

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American college of rheumatology; ACU: Acupuncture; AER: Aerobic exercise; AMT: Amitriptyline; APAP: Acetaminophen; BDI-II: Beck depression inventoryII; BID: Twice daily; BMI: Body mass index; BPI-s: Brief pain inventory-severity; CBT: Cognitive-behavioral therapy; CFT: Cardiovascular fitness training; cm: Centimeters; CPM: Citalopram; CR: Controlled-release; CYB: Cyclobenzaprine; DLX: Duloxetine; DSN: Dolasetron; DTP: Dothiepin; ECPM: Escitalopram; EEG: Electroencephalographic; FIQ: Fibromyalgia impact questionnaire; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; Ga-As: Galliuem-arsenide; GAD: Generalized anxiety disorder; GBT: Gabapentin; HDRS: Hamilton depression rating scale; HS: Once nightly; IBU: Ibuprofen; IV: Intravenous; J/cm2: Joules per square centimeter; kg: Kilogram; m2: Meters squared; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; MOC: Moclobomide; NBN: Nabilone; NFB: Neurofeedback receiving sensory motor rhythm treatment; NP: Naproxen; NRS: Numeric rating scale; NTP: Nortriptyline; PFS: Primary fibromyalgia syndrome; PGB: Pregabalin; PHY: Physiotherapy; PRL: Pirlindole; PRX: Paroxetine; PSG: Polysomnographic; PXL: Pramipexole; QD: Once daily; RBX: Reboxetine; REM: Rapid eye movement; SER282: Antidiencephalon immune serum; SF-MPQ: Short form McGill pain questionnaire; SR: Sustained-release; SXB: Sodium oxybate; TENS: Transcutaneous nerve stimulation; TID: Three times per day; TML: Tramadol; TPN: Tropisetron; TST: Total sleep time; VAS: Visual analogue scale; WASO: Wake after sleep onset; wk: Week; wkly: Weekly; XR: Extended release.

point in the score of this questionnaire by over 30%, although only one [22] of the two placebo-controlled trials showed positive results for this outcome, while the other [16] showed a statistical trend. Data from these 16 short-term trials did not reveal any dose-related patterns for the efficacy or tolerability outcomes. Amitriptyline has been studied as part of a combination therapy in two trials [21,22]. One of them, which evaluated its combination with naproxen, did not find greater improvement in the combination group compared with the group 1356

administered amitriptyline alone [21]. The other trial, which compared amitriptyline, fluoxetine and the combination of these two drugs, found that the combination group performed better than both monotherapy groups [22]. In a systematic review that evaluated the efficacy and acceptability of amitriptyline (10 studies), duloxetine (4 studies) and milnacipran (5 studies), amitriptyline has been found to improve pain, fatigue, sleep and HRQL with small-tomoderate effect sizes and has been found to be superior to duloxetine and milnacipran for all of these outcomes;

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Table 2. Long-term studies characteristics. Author (year)

Design

Comparator groups (n)

Drug dose

Duration (weeks)

Key selection criteria

Amitriptyline Carette et al. (1994) [19]

Double-blind, parallel

AMT (n = 84) versus CYB (n =82) versus placebo (n =42)

AMT: 25 mg HS (wks 2 -- 12); 50 mg HS (wks 12 -- 24) CYB: 20 mg HS (wks 2 -- 12); 10 mg in the morning and 20 mg HS (wks 12 -- 24)

24

- Age ‡ 18 - FMS (ACR 1990) - Score of ‡ 4 on at least 1 of 2 self-administered 10-cm VAS (1 evaluating pain and 1 evaluating global fibromyalgia symptoms)

Duloxetine Russell et al. (2008) [42]

Double-blind, parallel

Chappell et al. (2008) [43]

Double-blind, parallel

DLX 20/60 mg/day (n = 79) versus DLX 60 mg/day (n = 150) versus DLX 120 mg/day (n = 147) versus placebo (n = 144) DLX (n = 162) versus placebo (n = 168)

DLX: 20 mg/day 28 dosage increase to 60 mg/day after 3 months DLX: 60 mg/day DLX: 120 mg/day DLX: 60 -- 120 mg/day 27

Chappell et al. (2009) [44]

Lead-in: openlabel phase Phase II: Double-blind, parallel Acute phase: double-blind, parallel Phase II: extension, double-blind

Lead-in: DLX (n = 350) Phase II: DLX 60 mg/day (n = 104) versus DLX 120 mg/day (n = 203)

Double-blind, parallel

MLN 100 mg/day (n = 224) versus MLN 200 mg/day (n = 441) versus placebo (n = 223)

MLN: 100 mg/day MLN: 200 mg/day

Placebo/MLN100 (n = 29) versus placebo/ MLN200 (n = 100) versus MLN100/ MLN100 (n = 19) versus MLN100/ MLN200 (n = 92) versus MLN200/ MLN200 (n = 209) Placebo/MLN100 (n = 91) versus placebo/ MLN150 (n = 92) versus placebo/MLN200 (n = 87)

MLN: 100 mg/day MLN: 200 mg/day

Arnold et al. (2010, 2011) [39,40]

Milnacipran Mease et al. (2009) [47]

Goldenbergetal. Double-blind, parallel (2010) [50]

Branco et al. (2011) [52]

Double-blind, parallel

Acute phase: DLX (n = 263) versus placebo (n = 267) Phase II: DLX/DLX (n = 176) versus placebo/ DLX (n = 187)2

- Age ‡ 18 - FMS (ACR 1990) - BPI-s ‡ 4 - Without psychiatric comorbidity except MDD

- Age ‡ 18 - FMS (ACR 1990) - Without psychiatric comorbidity except MDD Lead-in: DLX 60 mg/ Lead-in: 8 - Age ‡ 18 day Phase II: 52 - FMS (ACR 1990) Phase II: DLX: 60 mg - BPI-s ‡ 4 or 120 mg/day - Without psychiatric comorbidity DLX: 60 -- 120 mg/day Acute phase: Acute phase: 12 - Age ‡ 18 Phase II: 12 - FMS (ACR 1990) - BPI-s ‡ 4 - Without psychiatric comorbidity except MDD or GAD Phase II: - Completers of the acute phase (12 wks) [39]

MLN: 100 mg/day MLN: 150 mg/day MLN: 200 mg/day

- Aged 18 -- 70 - FMS (ACR 1990) - Pain (VAS 0 -- 100) ‡ 50 - Without severe psychiatric illness or current major depressive episode 28 (extension - Completers of the lead-in phase) study [47] 27 (lead-in phase)

52

- Completers of the lead-in study [51]

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American College of Rheumatology; AMT: Amitriptyline; BDI-II: Beck Depression Inventory-II; BPI-s: Brief pain inventory-severity; cm: Centimeters; CYB: Cyclobenzaprine; DLX: Duloxetine; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; HS: Once nightly; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; PGB: Pregabalin; PGIC: Patient global impression of change; PHY: Physiotherapy;SRT: Sertraline; SXB: Sodium oxybate; ULS: Ultrasonography; VAS: Visual analogue scale; wk: Week.

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Table 2. Long-term studies characteristics (continued). Author (year)

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Arnold et al. (2013) [49]

Sertraline Gonza´lezViejo et al. (2005) [67] Pregabalin Crofford et al. (2008) [72]

Ohta et al. (2013) [80]

Design

Open-label, flexible-dose

Comparator groups (n) versus MLN200/ MLN200 (n = 198) n = 1227

Drug dose

Duration (weeks)

Key selection criteria

MLN: 50 -- 200 mg/ day

3.25 years

- Aged 18-- 7 0 - FMS (ACR 1990) - Without significant psychiatric illness -- BDI £ 25

Open-label, parallel

SRT (n = 36) versus ULS/PHY (n = 34)

SRT: 50 mg/day ULS/PHY: 5 times/wk

SRT: 24 ULS/PT: 3

- Aged 42 -- 52 - FMS (ACR 1990)

Double-blind, parallel

PGB (n = 279) versus placebo (n = 287)

PGB: 300 -- 600 mg/ day

26

Open-label, extension

PGB (n = 106)

PGB: 300 -- 450 mg/ day

53

- Age ‡ 18 - FMS (ACR 1990) - Pain (VAS 0 -- 100) ‡ 40 - Responders to PGB after a 6-week lead-in phase: Defined as ‡ 50% reduction in pain VAS from lead-in baseline and self-rating improvement on the PGIC of “much improved” or “very much improved” - Without severe depression - Completers of the preceding double-blind phase [79]

CYB/FLX (n = 16) versus CYB (n = 18)

CYB: 10 mg HS FLX: 20 mg every other day

52

- Women - FMS (ACR 1990)

SXB (n = 560)

SXB: 4.5 -- 9 g HS

38

- Completers of the clinical studies conducted by Russell et al. [103] and Spaeth et al. [104]

Cyclobenzaprine Open-label, Cantini et al. parallel (1995) [61] Sodium oxybate Open-label, Spaeth et al. extension (2013) [105]

Drugs are ordered according to their mention in the text and studies listed by year of publication. ACR: American College of Rheumatology; AMT: Amitriptyline; BDI-II: Beck Depression Inventory-II; BPI-s: Brief pain inventory-severity; cm: Centimeters; CYB: Cyclobenzaprine; DLX: Duloxetine; FLX: Fluoxetine; FMS: Fibromyalgia syndrome; g: Grams; HS: Once nightly; MDD: Major depressive disorder; mg: Milligrams; MLN: Milnacipran; PGB: Pregabalin; PGIC: Patient global impression of change; PHY: Physiotherapy;SRT: Sertraline; SXB: Sodium oxybate; ULS: Ultrasonography; VAS: Visual analogue scale; wk: Week.

however, the authors concluded that amitriptyline could not be considered as a gold standard due to the methodological limitations of the trials [35]. Another meta-analysis has shown that amitriptyline has similar effects as duloxetine, milnacipran and pregabalin on improving pain and fatigue and is not different from these drugs in terms of the proportion of overall withdrawals [36]. Serotonin and noradrenaline reuptake inhibitors Two serotonin and noradrenaline reuptake inhibitors (SNRIs), namely duloxetine and milnacipran, have been approved by the FDA for use in the treatment of fibromyalgia and are currently recommended for this indication by all published clinical practice guidelines [10-14]. 2.1.2

1358

Eight clinical trials have been published evaluating duloxetine, all of which had double-blind designs, and six of which included a placebo arm [37-44]. The durations of these studies ranged from 12 to 52 weeks. One trial had a 24-week duration, but placebo was administered only during the first 12 weeks, and the following 12-week period was an extension phase that compared two different doses of duloxetine; as its results were analyzed and published separately for both treatment periods, we considered them to be two separate studies [39,40]. Duloxetine has been administered at dosages ranging from 30 to 120 mg/day. Dropouts due to adverse events have ranged from 9 to 23% in short-term studies and from 11.4 to 27.2% in long-term studies. Of the six placebo-controlled trials evaluating duloxetine, four showed

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Table 3. Investigational drugs. Drug name or code

Clinictrials. gov registration number

Clinicaltrials.gov registry link

Casopitant (GW679769)

NCT00264628

Cyclobenzaprine SL

NCT01903265

Desvenlafaxine

NCT00696787

Eplivanserin (SR6349B)

NCT00313885

Eslicarbazepine

NCT01820585

Ibutamoren (MK-0677)

NCT00116129

IMC-1

NCT01850420

Lacosamide

NCT00401830

Levetiracetam

NCT00254657

Mirogabalin (DS-5565)

NCT02187471

https://clinicaltrials.gov/ct2/ show/NCT00264628? term=NCT00264628&rank=1 https://clinicaltrials.gov/ct2/ show/NCT01903265? term=NCT01903265&rank=1 https://clinicaltrials.gov/ct2/ show/NCT00696787? term=NCT00696787&rank=1 https://clinicaltrials.gov/ct2/ show/NCT00313885? term=NCT00313885&rank=1 https://clinicaltrials.gov/ct2/ show/NCT01820585? term=NCT01820585&rank=1 https://clinicaltrials.gov/ct2/ show/NCT00116129? term=NCT00116129&rank=1 https://clinicaltrials.gov/ct2/ show/NCT01850420? term=NCT01850420&rank=1 https://clinicaltrials.gov/ct2/ show/NCT00401830? term=NCT00401830&rank=1 https://clinicaltrials.gov/ct2/ show/NCT00254657? term=NCT00254657&rank=1 https://clinicaltrials.gov/ct2/ show/NCT02187471? term=NCT02187471&rank=1 https://clinicaltrials.gov/ct2/ show/NCT02187159? term=NCT02187159&rank=1 https://clinicaltrials.gov/ct2/ show/NCT02146430? term=NCT02146430&rank=1 https://clinicaltrials.gov/ct2/ show/NCT02234583? term=NCT02234583&rank=1 https://clinicaltrials.gov/ct2/ show/NCT00366535? term=NCT00366535&rank=1 https://clinicaltrials.gov/ct2/ show/NCT00464737? term=NCT00464737&rank=1 https://clinicaltrials.gov/ct2/ show/NCT01693692? term=NCT01693692&rank=1

NCT02187159

NCT02146430

NCT02234583

Neurotropin

NCT00366535

Rotigotine

NCT00464737

TD-9855

NCT01693692

Investigational drugs are ordered in alphabetical order.

significant beneficial effects on pain (the dose of duloxetine in these trials was between 60 and 120 mg/day), one was negative in this respect but used a dosage of duloxetine of 30 mg/day [41], and one trial that investigated flexibly dosed duloxetine (60 -- 120 mg/day) showed a trend of greater improvement in this symptom [43]. Depressive symptoms

significantly improved compared with placebo in three of the five trials reporting this outcome [37-39,41,43] and showed a trend of greater improvement in the other two trials [37,43]. In contrast, the results suggest that duloxetine has no effect on fatigue because only one trial [39] out of the four reporting this outcome [37,39,42,43] showed superior results of duloxetine over placebo. In addition, its effect on sleep disturbance has been assessed only in one placebo-controlled trial [39], providing positive but inconclusive results due to the lack of information in this regard in the remaining five placebocontrolled trials. Overall, duloxetine has been shown to significantly improve the symptoms and impact of fibromyalgia, as evaluated with the FIQ (four out of six placebo-controlled trials) as well as the mental component of quality of life (five out of the six placebo-controlled trials), but not the physical component (one out of the six placebo-controlled trials). The results from the placebo-controlled trials suggest that the target dose should be 60 mg/day because a dosage of 120 mg/day does not produce a larger effect, and as indicated above, it seems to be associated with poorer tolerability. On the other hand, a dosage of 30 mg/day has no effect on pain. Ten clinical trials have been published evaluating milnacipran, nine of which had double-blind designs [45-54]. Seven of them included a placebo arm (one of which had no formal hypothesis testing), and the remaining three were long-term extension studies. Their durations ranged from 7 weeks to 3.25 years. Milnacipran was administered in dosages of 100 and 200 mg/day. The proportion of dropouts due to adverse events ranged from 13.7 to 28.2% in short-term studies and from 11 to 38% in long-term studies. Of the six placebo-controlled trials with hypothesis testing, milnacipran was found to significantly improve pain in six trials [45-48,51,53] in addition to fatigue in five trials [45-48,51]. When reported, results regarding depression were positive in two placebocontrolled trials [46,48] and negative in another two trials [51,53]. The five placebo-controlled trials reporting sleep outcomes showed negative results [45-47,51,53]. Significant improvement in overall symptomatology as evaluated with the FIQ was found in four placebo-controlled trials [46,48,51,53] and was not observed in two trials [45,47]. Of the four placebocontrolled trials reporting results of the two dimensions of quality of life [46,48,51,53], three found a positive effect of milnacipran on the physical component [46,48,51], and three revealed that it positively affected the mental component [48,51,53]. Doses of 200 mg of milnacipran were not associated with better efficacy outcomes than those of 100 mg/day and were associated with a higher rate of discontinuation due to adverse events. According to the results of a meta-analysis, duloxetine (five studies) and milnacipran (five studies) improve pain and patient-perceived clinical improvement, fatigue, depressed mood and HRQL. However, for both drugs, the effect sizes were small for pain and patient-perceived clinical improvement and nonsubstantial for fatigue, depressed mood and quality of life [55].

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2.1.3

Selective serotonin reuptake inhibitors

Among selective serotonin reuptake inhibitors (SSRIs), citalopram [56,57], escitalopram [58], fluoxetine [22,59-63], paroxetine [64-66] and sertraline [67] have been investigated for the treatment of fibromyalgia. In addition, one study evaluated the efficacy of fluvoxamine, but it could not be retrieved [34]. The use of SSRIs is recommended by all practice guidelines [10-14]. The results of the two placebo-controlled trials evaluating citalopram showed no significant effects of this drug on pain or fatigue [56,57]. The study of escitalopram was a randomized comparison with a type of neurofeedback. This neurofeedback was found to be superior to the comparator for the improvement of pain, depression and fatigue, but there were no significant differences between them in overall efficacy (FIQ) and quality of life [58]. Placebo-controlled trials showed the superiority of fluoxetine flexible dosed between 10 and 80 mg/day for improving pain, fatigue, depression and overall symptomatology [62]; however, a randomized study using a standard dosage of fluoxetine (20 mg/day) did not show differences relative to placebo in those outcomes [59]. Fluoxetine (20 mg/day) has been compared to acupuncture in one study, which has shown significantly greater improvements in fatigue and overall symptoms with acupuncture [63]. Regarding paroxetine, one placebo-controlled trial did not report comparative results [64], and another trial demonstrated the superiority of paroxetine over TENS in terms of reductions in pain and depression [65]. Finally, a placebo-controlled trial of the controlled-release formulation has shown that paroxetine is superior for reducing fatigue and overall symptomatology but that it does not significantly reduce pain [66]. A randomized comparison of sertraline with the combination of ultrasonography and physiotherapy showed significant reductions in pain and sleep disturbances with sertraline only but not with the combination treatment [67]. Dropouts due to adverse events associated with the use of SSRIs have been low (£ 15%). According to the results of meta-analysis, SSRIs (two studies of paroxetine, two of citalopram and three of fluoxetine) improve pain, depression, sleep and HRQL. However, the effect sizes have been small for pain, depression and HRQL and nonsubstantial for sleep [68]. In addition, we do not think that SSRIs are interchangeable; therefore, the utility of these pooled results is, in our view, questionable. Monoamine oxidase inhibitors Two monoamine oxidase inhibitors (MAOIs), both reversible and selective of the MAO-A subtype, namely moclobemide [28,69] and pirlindole [70], have been studied for the treatment of fibromyalgia. Moclobemide (150 mg b.i.d.) has been shown to improve depression, sleep disturbances and fatigue to a significantly greater extent than placebo, but its effects on pain do not differ from those of placebo [69]. Pirlindole (75 mg b.i.d.) has been reported to be superior to placebo

in the improvement of pain, but it does not improve psychological symptoms, fatigue or sleep disturbances [70]. MAOIs are not available in all countries and have been infrequently investigated. Their use is recommended only by the European League Against Rheumatism (EULAR) practice guidelines [11]. Gabapentinoids Pregabalin and gabapentin are drugs that bind to the alpha2delta subunit of voltage-gated calcium channels in the CNS. Although they are originally licensed as antiepileptics, they are currently mainly used for the treatment of chronic pain. Pregabalin has FDA approval for the treatment of fibromyalgia, and its use is recommended in all published guidelines [10-14]. Pregabalin has been extensively studied for the treatment of fibromyalgia, whereas gabapentin has only been investigated in one clinical trial [71-81]. Pregabalin has been consistently demonstrated to improve pain and sleep disturbances in six short-term placebo-controlled trials [71,73,76-79]. However, it has not been found to significantly differ from placebo in the improvement of fatigue in two of four trials [71,73,76,79], and results have been negative regarding the improvement of depressive symptoms in all four trials reporting this outcome [71,76,77,79]. It has been associated with a significantly greater reduction in the FIQ total score in three of five trials, but at a dosage of 450 mg/day or flexible dosages of 300 -- 450 mg/day [71,73,76,77,79]. Its effect on the mental component of quality of life has been shown to be positive in one trial that reported this outcome, but only at a 600 mg/day dosage [76]. The results of a long-term placebo-substitution study have shown the significantly longer maintenance of improvements in all outcomes, including quality of life [72]. Dropouts associated with adverse events have ranged from 7.5 to 32.6%. Interestingly, in a randomized study comparing pregabalin (300 -- 400 mg/day) with the combination of pregabalin (300 -- 450 mg/day) and milnacipran, the combination group showed significant and much larger improvements in weekly pain, fatigue and the physical and mental components of quality of life [74]. A meta-analysis has shown that pregabalin (five studies) and gabapentin (one study) improve pain, fatigue, sleep and HRQL but fail to improve depression; however, effect sizes have been small. In addition, significant improvements in fatigue and anxiety have been observed; however, effect sizes have been nonsubstantial [82]. 2.2

2.1.4

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Other drugs Cyclobenzaprine

2.3.1

Cyclobenzaprine is a drug as old as TCAs to which it is structurally related, but that is licensed as a muscle relaxant. The use of cyclobenzaprine is recommended by the EULAR and the German and Spanish practice guidelines [11-13]. A total of nine studies have evaluated the efficacy of cyclobenzaprine for the treatment of fibromyalgia [60,61,83-89]. This

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drug has been evaluated in dosages ranging from 10 to 40 mg/ day, with the exception of one trial that investigated its efficacy at very low dosages (1 -- 4 mg/day) [89]. Of the three trials that have reported comparative results versus placebo [83,84,89], two have revealed a significant improvement in sleep disturbances [83,84], and three have shown a greater improvement in pain [83,89]. In addition, all three have demonstrated a lack of effect on fatigue, and only one placebo-controlled trial has reported its effects on depressive symptoms, describing positive results of doubtful clinical relevance [89]. An additional placebo-controlled trial only reported within-group changes, which were significant for cyclobenzaprine for sleep disturbances and fatigue but not for pain [85]. Two dosages of cyclobenzaprine (10 and 30 mg/day) have been compared using a crossover design, revealing that the higher dosage does not differ from the lower dosage according to efficacy outcome but that it results in a higher incidence of adverse events [87]. The use of a combination of ibuprofen (600 mg/day) and cyclobenzaprine (10 mg/day) is not superior to cyclobenzaprine alone in the reduction of pain or sleep disturbances [86], while the combination of cyclobenzaprine (10 mg/day) with fluoxetine (20 mg/day) is associated with a significantly greater reduction in pain [60]. These latter results have been confirmed in a long-term randomized, placebo-controlled trial using the same dosages [61]. A randomized study comparing cognitive behavioral therapy, cyclobenzaprine (10 mg/ day) and their combination with a nontreatment group revealed that only the groups that received cognitive behavioral therapy with or without cyclobenzaprine showed a significant improvement in overall symptomatology, as evaluated with the FIQ [88]. Dropouts due to adverse events in these trials have ranged from 0 to 19%. In a meta-analysis of five trials of cyclobenzaprine [90], the authors concluded that this drug improves the global functioning of patients, with moderate improvement in sleep quality. A new sublingual formulation of low-dose (2.8 mg), slow-release cyclobenzaprine (TNX-102) is currently being investigated against placebo in a Phase IIb clinical trial (NCT1903265) that is still ongoing. Tramadol Tramadol is an atypical analgesic because it acts as a weak agonist of µ-opioid receptors and as an inhibitor of serotonin and noradrenaline reuptake. Single-dose intravenous tramadol has been shown to decrease pain in patients with fibromyalgia [91]. Oral tramadol has been evaluated for the treatment of fibromyalgia both as a monotherapy and in combination with paracetamol. In a short-term placebo-substitution study, tramadol has been shown to be associated with a significantly longer time to discontinuation because of inadequate pain relief compared with placebo [92]. When combined with paracetamol, it decreases pain and the total FIQ score and improves physical functioning [93]. Tramadol was associated with 19% dropout rates, due to adverse events, in both 2.3.2

studies. The use of tramadol for the treatment of fibromyalgia is recommended by the EULAR and the German, Spanish and Canadian practice guidelines [11-14]. 5-HT3 antagonists Among drugs that act as serotonin 5-HT3 receptors antagonists, oral and intravenous tropisetron and intravenous dolasetron have been studied for the treatment of fibromyalgia. Tropisetron has been investigated in three very short-term studies [94-96]. One of them has evaluated the efficacy and tolerability of this drug in oral dosages of 5, 10 and 15 mg/ day for 10 days, and the remaining two have evaluated its efficacy and tolerability in an intravenous dose of 5 mg for 5 days. Five mg intravenous tropisetron and 5 and 10 mg oral tropisetron have been determined to be more effective than placebo for the reduction of pain [94,95]. The combination of intravenous tropisetron (5 mg) with physiotherapy is more effective than physiotherapy alone for the reduction of pain [96]. Similarly, intravenous dolasetron has been associated with a significantly greater reduction in pain but no effects on depression, overall symptomatology or quality of life [97]. Dropouts due to adverse events were < 5% for the three oral tropisetron dosages assayed, and no dropouts were associated with the intravenous administration of the drug. The use of tropisetron is recommended by the EULAR and German practice guidelines [11,12]. 2.3.3

Dopaminergic agonists Data pertaining to dopamine agonists are conflicting. Pramipexole has been shown to improve pain, fatigue and overall symptoms as evaluated by the FIQ total score [98], whereas two clinical trials evaluating ropinirole have failed to demonstrate efficacy in this respect [99]. Rotigotine has been studied in a clinical trial with unpublished results (NCT00464737). Pramipexole is recommended for the treatment of fibromyalgia by the EULAR and Spanish practice guidelines [11,13]. 2.3.4

Sodium oxybate Sodium oxybate is the sodium salt of g-hydroxybutyrate, a metabolite of GABA. It is licensed for the treatment of narcolepsy and was submitted for approval for the treatment of fibromyalgia in the US. However, in 2010, the FDA rejected this request due to concerns regarding its potential for abuse [100]. This drug has been shown to improve fibromyalgia symptomatology in five clinical trials, four randomized trials and one long-term open-label extension study [101-105]. The evaluated dosages of sodium oxybate were 4.5 and 6 g/day. In the four placebo-controlled trials [101-104], sodium oxybate has been shown to consistently improve pain and fatigue. In addition, it has been demonstrated to ameliorate sleep disturbances in three of the four trials and overall symptoms in the three trials reporting this outcome [102-104]. It also has been shown to improve the physical component of the quality of life in two trials [103,104] but has not been demonstrated to improve depression. Dropouts due to adverse events ranged 2.3.5

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from 8.6 to 19% for the 4.5 g dose and from 18.2 to 23% for the 6 g dose. The use of sodium oxybate for the treatment of fibromyalgia is recommended by the Spanish practice guideline. However, sodium oxybate is not easy to use, as it must be administered twice nightly and its use is contraindicated in patients taking alcohol or benzodiazepines; in addition, its potential for abuse restricts its administration in many countries by imposing special conditions for its use. Cannabinoids Among synthetic cannabinoids, only nabilone has been evaluated for the treatment of fibromyalgia in two clinical trials, both with small patient sample sizes. One of these studies has found that nabilone improves pain, the total FIQ score and anxiety [106], and the other has found that it beneficially affects sleep but not pain, mood, or quality of life [107]. Nabilone was associated with dropout rates due to adverse events of 15 and 21%, respectively. Cannabinoids are considered to be potential pharmacological alternatives for patients with fibromyalgia, especially those with relevant sleep disturbances, by the Canadian practice guidelines [14].

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2.3.6

3.

Investigational drugs

In addition to drugs that have been approved or that are recommended for use in the treatment of fibromyalgia, other drugs are and/or have been tested in patients with this disease. This section briefly evaluates drugs that are licensed for other indications and have been assessed in at least one randomized trial of patients with fibromyalgia and new drugs that are currently being investigated for the treatment of this disease. Table 3 shows data concerning the locations of these new drugs on the US National Institutes of Health web page, which provides information about clinical studies (ClinicalTrials.gov). 3.1

Drugs licensed for other indications Antidepressants

3.1.1

Among antidepressants, esreboxetine, an active enantiomer of reboxetine and a selective noradrenaline reuptake inhibitor, has been studied in four clinical trials, two of which have been published, showing that it decreases pain and the FIQ total score [108,109]; however, Pfizer halted the development of this drug for fibromyalgia, and it is not currently available for the treatment of this disease. Mirtazapine, an antidepressant that acts as an antagonist of presynaptic a2 adrenergic receptors, has been studied in a pilot Phase II trial [110] at dosages of 15 and 30 mg/day. Although patients treated with mirtazapine have shown decreases in pain, the total FIQ score and sleep disturbances, no differences have been observed compared with placebo, presumably due to the small sample size evaluated. Desvenlafaxine, another SNRI licensed for the treatment of major depressive disorder, has been tested against placebo and pregabalin (NCT00696787); however, this trial was prematurely terminated by the sponsor. 1362

Anticonvulsants Three anticonvulsants with different mechanisms of action, namely lacosamide (NCT00401830), levetiracetam (NCT00254657) and eslicarbazepine (NCT01820585), have been investigated for the treatment of fibromyalgia. Although all three clinical trials have been completed, no published results are available; however, descriptive results of the lacosamide and eslicarbazepine trials are available on the ClinicalTrials.gov webpage. 3.1.2

Other drugs Melatonin, a pineal hormone that has been suggested to be deficient in patients with fibromyalgia, has been assessed at doses of 3 and 5 mg alone and in association with fluoxetine [111]. Although patients receiving melatonin (both alone and in combination) showed decreases in the total FIQ score as well as in the pain, sleep and depression subscores, the authors did not compare inter-group differences. A Phase II clinical trial has been recently published comparing melatonin (10 mg/day) alone and in combination with amitriptyline (25 mg/day). Patients treated with melatonin, either alone or in association with amitriptyline, have shown highly significant improvement in pain compared with those receiving amitriptyline alone [112]. Extended-release quetiapine, a second-generation antipsychotic, has been investigated for the treatment of fibromyalgia in four randomized clinical trials, although only the results in abstract form are available for one of the studies [113]. Quetiapine has been shown to improve comorbid major depression, anxiety and sleep disturbances, but its role in improving pain is unclear, and in two of the trials, its tolerability was poor. In addition, in one trial quetiapine failed to demonstrate the noninferiority of this drug to amitriptyline. Memantine, an NMDA receptor antagonist administered at a 20 mg daily dose, has been shown to decrease pain, depression, the total FIQ score and HRQL in a 6-month clinical trial, in which 6.5% of memantine-treated patients withdrew due to adverse events [114]. Neurotropin, a nonprotein extract from the inflamed skin of rabbits inoculated with vaccinia virus that is widely used in Japan for the treatment of chronic pain, is being investigated in a clinical trial that is currently in progress (NCT00366535). 3.1.3

New drugs Several new drugs have been studied for the treatment of fibromyalgia. However, clinical trials evaluating some of these drugs were completed years ago and never published. These drugs include, among others, casopitant (GW67969), a neurokinin-1 receptor antagonist, eplivanserin (SR6349B), a 5-HT2A/2C antagonist, and ibutamoren (MK-0677) a nonpeptide growth hormone secretagogue. The drugs that have been recently investigated are summarized below. 3.2

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IMC-1, described as a combination treatment designed to suppress tissue-resident herpes virus, which has been suspected to be casually related to fibromyalgia symptoms, has undergone a Phase II clinical trial against placebo (NCT01850420). This study is still ongoing. TD-9855, a new SNRI, has been studied against placebo in a Phase II clinical trial (NCT01693692). This study was completed in April 2014, but the results are still unavailable. Mirogabalin (DS-5565) is a new alpha2delta antagonist that is being investigated exclusively for the treatment of chronic pain, namely peripheral diabetic neuropathy (NCT01496365), post-herpetic neuralgia (NCT02318719) and fibromyalgia. Three Phase III trials comparing this drug with placebo and pregabalin are currently ongoing (NCT02187471, NCT02187159, NCT02146430), and a long-term 1-year extension open-label trial (NCT02234583) is planned after the completion of the first three trials. 4.

Expert opinion

Although many drugs have been studied and are currently recommended for the treatment of fibromyalgia, few of them have the support of two or more clinical trials for their efficacies in the treatment of this disease. Pregabalin, duloxetine and milnacipran have been evaluated in several high-quality, randomized, double-blind clinical trials in addition to long-term trials, which have shown that their efficacies are maintained over time. Therefore, these three drugs should be considered the first-line treatment for the pharmacological management of fibromyalgia. They have been shown to ameliorate pain but have somewhat different profiles for other symptoms. These findings may help prescribers to select the appropriate drug for individual patients depending on the predominant or more disturbing symptoms. Thus, in addition to their effects on pain, pregabalin has been consistently demonstrated to ameliorate sleep disturbances, duloxetine has been demonstrated to improve depressive symptoms, and milnacipran has been shown to improve fatigue (see comment below). The tolerability of these drugs seems to be dose-dependent, and the highest doses (i.e., 120 mg of duloxetine, 200 mg of milnacipran and 600 mg of pregabalin) are associated with higher rates of discontinuation due to adverse events without causing greater effects on any of the cardinal symptoms of fibromyalgia. The results from flexible dosage studies have shown that, generally speaking, these dosages are associated with lower rates of discontinuation due to adverse events relative to fixed dosages. This fact and the overall clinical experience of our group and others indicate that drugs for the treatment of fibromyalgia are better tolerated if each patient is started at a low dose and titrated slowly until reaching the effective dose. Amitriptyline is a special case. It has been extensively studied, but most trials have had small sample sizes and are considered to be of poor quality according to the current standards. Nevertheless, two meta-analyses have shown that amitriptyline at least does not differ from duloxetine, milnacipran and pregabalin

in the improvement of pain and fatigue [35,36]. The perception of some physicians that amitriptyline has poor tolerability is not supported by the results of these trials, which have reported discontinuation rates due to adverse events caused by amitriptyline of no higher than those reported for pregabalin, duloxetine and milnacipran. Interestingly, a recent randomized comparison of amitriptyline, duloxetine and pregabalin in patients with neuropathic pain has found no differences in the reduction of pain among these three drugs, although these findings cannot be directly extrapolated to patients with fibromyalgia [115]. In that trial, amitriptyline was not found to compromise cognitive function, tolerability or safety parameters and showed similar results as the comparators in terms of quality of life. Considering all of these data together, we suggest that amitriptyline should be considered as a first-line option for the treatment of fibromyalgia in the current cost-containing environment. We agree with Clauw [116], who has stated that all patients should have a trial of low doses of a tricyclic compound; however, we think that the tricyclic compound should be specifically amitriptyline (25 -- 75 mg/day). Overall, none of the first-line drugs for the treatment of fibromyalgia (namely, pregabalin, duloxetine, milnacipran, and, in our view, amitriptyline) have improved all of the cardinal symptoms of fibromyalgia (more specifically, pain, fatigue, depression and sleep disturbances) and in fact, with the exception of milnacipran, none have consistently improved the physical component of the quality of life. This latter finding is interesting because, together with sodium oxybate, milnacipran has been more consistently demonstrated to have a beneficial effect on fatigue. Therefore, it is possible that fatigue plays an especial role in the deterioration of the quality of life of these patients. This hypothesis is consistent with the finding that in patients with rheumatic diseases, fatigue is strongly associated with health status, health satisfaction and work dysfunction [117]. The differences among the different drugs used to treat fibromyalgia on symptoms other than pain can be partially explained by their different mechanisms of action and pharmacological effects. The treatment of depression requires drugs that potentiate serotonergic and/or noradrenergic neurotransmission; thus, it seems logical that drugs like pregabalin or sodium oxybate that do not interfere monamine neurotransmission are unable to improve depression in patients with fibromyalgia [82,102-104], whereas all of the antidepressants that are used to treat fibromyalgia are also associated with an improvement in concomitant depression [55,68]. Similarly, drugs that have been shown to facilitate restorative sleep by improving sleep continuity and/or increasing slow wave sleep such as pregabalin [78], sodium oxybate [118], amitriptyline [119] or cyclobenzaprine [89] have also demonstrated to ameliorate sleep disturbances associated to fibromyalgia, while antidepressants without sedative properties such as SNRIs and SSRI did not. The case of fatigue is somewhat different, as this symptom can be a consequence of depression and/or disturbed sleep but must be also independent of

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them; in this last case, it has been postulated that central mechanisms are involved in its pathophysiology and that low brain levels of monoamines are, at least partially, responsible for it [120]; at this respect, the beneficial effect on fatigue of drugs that potentiate monoamine neurotransmission such as SNRIs [40,121] and, to a lesser extent, SSRIs [62,63,66] is coherent with this hypothesis. The limited efficacies of first-line pharmacological treatments for fibromyalgia have several implications. First, the treatment of this disease requires an integrative approach, combining pharmacological and nonpharmacological (i.e., exercise and cognitive behavioral therapy) interventions. Second, more pharmacological agents with a wider spectrum of action are needed. Third, despite the limitations of polypharmacy, the combination of two or more drugs with different spectrum of action may play a role in the treatment of this condition. In clinical practice, combination therapy is the rule more than the exception [122-124]. However, clinical trials investigating the efficacy and tolerability of combination therapy are scarce, and most of them are old, including drugs that are currently not considered to be useful for the chronic treatment of fibromyalgia, such as nonsteroidal anti-inflammatory agents or benzodiazepines [125]. Only one trial [74] has evaluated the combination of the first-line drugs pregabalin and milnacipran in this disease, and only two trials have evaluated combination treatment with amitriptyline [125]. The available data suggest that a rational polytherapy, such as the combination of milnacipran with pregabalin or the combination of Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

Smith HS, Barkin RL. Fibromyalgia syndrome: a discussion of the syndrome and pharmacotherapy. Dis Mon 2011;57:248-85

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Clauw DJ, Arnold LM, McCarberg BH. The science of fibromyalgia. Mayo Clin Proc 2011;86:907-11 An interesting review about pain mechanisms in fibromyalgia.

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Declaration of interest This review has not received any financial support. F RicoVillademoros has served as freelance consultant for Almirall, AstraZeneca, Eli Lilly, GSK, Lundbeck, Pfizer, Roche and Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Complement Alternat Med 2013;2013:485272

conditions. Best Pract Res Clin Rheumatol 2003;17:563-74 6.

White LA, Birnbaum HG, Kaltenboeck A, et al. Employees with fibromyalgia: medical comorbidity, healthcare costs, and work loss. J Occup Environ Med 2008;50:13-24

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Skaer TL. Fibromyalgia: disease synopsis, medication cost effectiveness and economic burden. Pharmacoeconomics 2014;32:457-66

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Queiroz LP. Worldwide epidemiology of fibromyalgia. Curr Pain Headache Rep 2013;17:356 Weir PT, Harlan GA, Nkoy FL, et al. The incidence of fibromyalgia and its associated comorbidities: a populationbased retrospective cohort study based on International Classification of Diseases, 9th Revision codes. J Clin Rheumatol 2006;12:124-8

amitriptyline with fluoxetine, can be more effective than monotherapy. However, evidence is limited, and additional studies are needed to investigate the benefits and harm of combination treatments in the management of fibromyalgia. In summary, the pharmacotherapy available for the treatment of fibromyalgia is less than optimal. Only three drugs, namely pregabalin, duloxetine and milnacipran, have been adequately and extensively evaluated and are approved for use for this indication by some medicine regulatory agencies. In addition, in our view, amitriptyline should be considered as a first-line option for the treatment of fibromyalgia. Many of the remaining drugs recommended by different practice guidelines have only been studied in one or two randomized clinical trials. In addition, the mechanisms of action of these drugs are rather limited, and antidepressants acting on neurotransmitter reuptake and alpha2delta ligands are the most commonly used and recommended drugs.

Sarzi-Puttini P, Atzeni F, Salaffi F, et al. Multidisciplinary approach to fibromyalgia: what is the teaching? Best Pract Res Clin Rheumatol 2011;25:311-19

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Affiliation

Elena P Calandre†, Fernando Rico-Villademoros & Mahmoud Slim † Author for correspondence † Universidad de Granada, Instituto de Neurociencias, Granada, 18012, Spain Tel: +0034 958246291; Fax: +0034 958246187; E-mail: [email protected]

An update on pharmacotherapy for the treatment of fibromyalgia.

Fibromyalgia is a syndrome characterized by chronic generalized pain in addition to different symptoms such as fatigue, sleep disturbances, stiffness,...
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