Milnacipran for the Treatment of Fibromyalgia

Gupta, Harshit; Girma, Brook; Jenkins, Jack S.; Kaufman, Sarah E.; Lee, Christopher A.; Kaye, Alan D.

doi:10.52965/001c.25532

Cited by 12 publications

(11 citation statements)

References 43 publications

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“…Milnacipran, at doses of 100-200 mg/day, is a serotonin-norepinephrine reuptake inhibitor and is one of only a handful of agents expressly developed to treat fibromyalgia [ 41 ]. While it reduces pain and fatigue, its benefits may be modest and side effects include sleep-related disturbances and depression [ 42 , 43 ].…”

Section: Reviewmentioning

confidence: 99%

Is Fibromyalgia a Fashionable Diagnosis or a Medical Mystery?

Varrassi,

Rekatsina,

Perrot

et al. 2023

Cureus

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Despite its prevalence, there is no clear-cut diagnostic path or treatment paradigm for fibromyalgia; this can lead to a multiplicity of symptoms and comorbid conditions that complicate care. "Overlapping symptoms" describe conditions that can occur concomitantly with fibromyalgia and include migraine, irritable bowel syndrome, obesity, and pelvic pain syndromes. A variety of pharmacologic and nonpharmacologic treatments are available for fibromyalgia, but treatment is best personalized for an individual and recognizes potential comorbidities. Opioids are not the recommended front-line treatment, cannabinoids hold promise but with limitations and nonpharmacologic options, such as aerobic or resistance exercise and cognitive behavior therapy, can play a very important but often underestimated role. Amitriptyline appears to be safe and effective in treating six of the main fibromyalgia domains: pain, disturbed sleep, fatigue, affective symptoms, functional limitations, and impaired cognition ("fibro fog"). Very low-dose naltrexone (2.5-4.5 mg) may offer analgesic and anti-inflammatory benefits to fibromyalgia patients, but further studies are needed. Fibromyalgia can be a devastating and debilitating condition for patients, and clinicians are challenged with its diagnosis and treatment as well. Further research as well as compassionate approaches to offering personalized care to those with fibromyalgia are required.

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Section: Reviewmentioning

confidence: 99%

Is Fibromyalgia a Fashionable Diagnosis or a Medical Mystery?

Varrassi,

Rekatsina,

Perrot

et al. 2023

Cureus

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“…Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain and comorbid symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder [1][2][3][4][5]. In the first definition of FM by the American College of Rheumatology (ACR) in 1990, patients must state 'painful' and not 'tender' to ≥11 of 18 tender points upon an approximate force of 4 kg [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…But pregabalin can have some side effects, including drowsiness, dizziness, peripheral edema, and dry mouth [23,24]. Duloxetine and milnacipran, which are known to inhibit norepinephrine and serotonin re-uptake mechanisms, also help to improve pain and promote an overall feeling of improvement in patients with fibromyalgia [4,[25][26][27]. As these neurotransmitters are linked to emotion and mood, these medicines can have some side effects, including nausea, dry mouth, constipation, decreased appetite, drowsiness, increased sweating, and agitation [22,[28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Fibromyalgia Animal Models Using Intermittent Cold and Psychological Stress

Ueda,

Neyama

2023

Biomedicines

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Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions. Both models show long-lasting and generalized pain and female-predominant sex differences after gonadectomy. Like many other neuropathic pain models, ICGP and IPGP were abolished in lysophosphatidic acid receptor 1 (LPAR1) knock-out mice or by LPAR1 antagonist treatments, although deciding the clinical importance of this mechanism depends on waiting for the development of a clinically available LPAR1 antagonist. On the other hand, the nonsteroidal anti-inflammatory drug diclofenac with morphine did not suppress hyperalgesia in these models, and this is consistent with the clinical findings. Pharmacological studies suggest that the lack of morphine analgesia is associated with opioid tolerance upon the stress-induced release of endorphins and subsequent counterbalance through anti-opioid NMDA receptor mechanisms. Regarding pharmacotherapy, hyperalgesia in both models was suppressed by pregabalin and duloxetine, which have been approved for FM treatment in clinic. Notably, repeated treatments with mirtazapine, an α2 adrenergic receptor antagonist-type antidepressant, and donepezil, a drug for treating Alzheimer’s disease, showed potent therapeutic actions in these models. However, the pharmacotherapeutic treatment should be carried out 3 months after stress, which is stated in the FM guideline, and many preclinical studies, such as those analyzing molecular and cellular mechanisms, as well as additional evidence using different animal models, are required. Thus, the ICGP and IPGP models have the potential to help discover and characterize new therapeutic medicines that might be used for the radical treatment of FM, although there are several limitations to be overcome.

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“…For example, uptake inhibition (K i value) of [ 3 H]-norepinephrine by the human transporter overexpressed in HEK cells was reported to be 68 nM for milnacipran, whereas that of [ 3 H]-serotonin uptake was reported to be 151 nM [ 3 ]. This unique characteristic distinguishes milnacipran from other SNRIs that exhibit a greater affinity for serotonin reuptake [ 4 , 5 ], although, in vivo, milnacipran shows comparable affinity for both serotonin and norepinephrine transporters [ 6 ]. Notably, levomilnacipran, which is an enantiomer of milnacipran ((1S,2R)-milnacipran) and is deemed to be more active than the racemic mixture, is available in the market as an extended-release capsule formulation and is approved by the FDA for MDD but not fibromyalgia [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Systemic and Brain Pharmacokinetics of Milnacipran in Mice: Comparison of Intraperitoneal and Intravenous Administration

Bagchi,

Nozohouri,

Ahn

et al. 2023

Pharmaceutics

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Milnacipran is a dual serotonin and norepinephrine reuptake inhibitor, clinically used for the treatment of major depression or fibromyalgia. Currently, there are no studies reporting the pharmacokinetics (PK) of milnacipran after intraperitoneal (IP) injection, despite this being the primary administration route in numerous experimental studies using the drug. Therefore, the present study was designed to investigate the PK profile of IP-administered milnacipran in mice and compare it to the intravenous (IV) route. First a liquid chromatography–mass spectrometry (LC-MS/MS) method was developed and validated to accurately quantify milnacipran in biological samples. The method was used to quantify milnacipran in blood and brain samples collected at various time-points post-administration. Non-compartmental and PK analyses were employed to determine key PK parameters. The maximum concentration (Cmax) of the drug in plasma was at 5 min after IP administration, whereas in the brain, it was at 60 min for both routes of administration. Curiously, the majority of PK parameters were similar irrespective of the administration route, and the bioavailability was 92.5% after the IP injection. These findings provide insight into milnacipran’s absorption, distribution, and elimination characteristics in mice after IP administration for the first time and should be valuable for future pharmacological studies.

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Milnacipran for the Treatment of Fibromyalgia

Cited by 12 publications

References 43 publications

Is Fibromyalgia a Fashionable Diagnosis or a Medical Mystery?

Is Fibromyalgia a Fashionable Diagnosis or a Medical Mystery?

Fibromyalgia Animal Models Using Intermittent Cold and Psychological Stress

Systemic and Brain Pharmacokinetics of Milnacipran in Mice: Comparison of Intraperitoneal and Intravenous Administration

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