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Home , Fibromyalgia, Milnacipran, Tranylcypromine, Visceral pain

Drug Evaluation

Milnacipran, a and inhibitor: a novel treatment for

Milnacipran hydrochloride is a serotonin (5-HT) and norepinephrine (NE) that was recently approved by the US FDA for the treatment of fibromyalgia (FM). Evidence has accumulated suggesting that, in animal models, milnacipran may exert -mitigating influences involving norepinephrine- and serotonin-related processes at supraspinal, spinal and peripheral levels in pain transmission. Milnacipran has demonstrated efficacy for the reduction of pain as well as improvements in global assessments of well-being and functional capacity among treated FM patients. Its role in addressing associated with FM, including visceral pain and migraine, has, as yet, to be investigated. Milnacipran may be of special interest for use in patients for whom hepatic dysfunction precludes the use of other agents, for example, . It has a negligible influence on cytochrome , and therefore may be of particular benefit in patients requiring multiple concurrently prescribed . Milnacipran may comprise a reasonable option in the armamentarium of treatments available to manage FM.

KEYWORDS: n n fibromyalgian milnacipran n serotonin Raphael J Leo and norepinephrine reuptake inhibitor Department of , School of Medicine and Fibromyalgia (FM) is a syndrome characterized Several pharmacological approaches have Biomedical Sciences, by chronic, widespread musculoskeletal pain and been advocated for the treatment of FM. State University of New York at tenderness. The prevalence of FM in the general Because of their impact on these presump- Buffalo, Erie County Medical population is estimated to be 2–4%; it tends to tive pathophysiologic processes, antidepres- Center, 462 Grider Street, show a female predilection, and increases with sants have frequently been advocated for Buffalo, NY 14215, USA age [1,2]. Criteria established by the American use in the management of pain associated Tel.: +1 716 898 4857 College of (ACR) dictates that with FM. Among these, antidepres- Fax: +1 716 898 3986 the pain must be present for at least 3 months, sants (TCAs) and their analogs have been [email protected] be associated with elicitation of 11 of 18 possible the drugs of choice [10–12]; their efficacy has tender points and be present above and below the been established in prior meta-analyses [13,14]. waist and on the right and left sides of the body Unfortunately, limit the tolerability [3]. In addition to pain, patients with FM experi- to, and consequently the utility of, the TCAs. ence other incapacitating symptoms, including The development of antidepressants such as the disturbances, and impair- serotonin–norepinephrine reuptake inhibitors ments. There are a number of significant comor- (SNRIs), for example, duloxetine (Cymbalta®, bidities associated with FM, including irritable , IN, USA) and mil- bowel syndrome, pelvic pain, temporomandibu- nacipran (SavellaTM, Forest Pharmaceuticals, lar joint pain and migraine [4]. Among the com- Inc., MO, USA), has made it possible to still mon psychiatric comorbidities, and derive benefit while avoiding many of appear to be most prevalent [5–7]. the adverse effects typically associated with the The exact pathophysiology underlying FM TCAs [15,16]. remains unclear. It is suggested that the symp- Naturally, given the high co-occurrence toms of FM arise from dysfunction within the rates, antidepressants may benefit FM patients CNS, allowing for augmented pain processing. experiencing distress from comorbid depression Disruptions in somatosensory processing from and/or anxiety. However, evidence has accumu- the periphery, amplification of peripheral sensory lated suggesting that antidepressants produce information at supraspinal levels and disruptions analgesic effects independent of the effects on in descending spinal tracts that normally serve a mood. Specifically, the analgesic effects of anti­ pain modulatory role of information relayed from depressants can be achieved earlier than the part of the periphery (or a confluence of such factors) have effects can be appreciated, are been implicated in the pathophysiology of FM [8,9]. often obtained at doses far lower than those

10.2217/IJR.09.39 © 2009 Future Medicine Ltd Int. J. Clin. Rheumatol. (2009) 4(5), 507–517 ISSN 1758-4280 507 Drug Evaluation Leo Milnacipran, a serotonin & norepinephrine reuptake inhibitor Drug Evaluation

required to achieve antidepressant effects and affinity for the NE transporter[22] . Nonetheless, have been demonstrated in patients with chronic its high affinity for both transporters suggests pain who are not depressed [17–19]. Therefore, that it acts more like TCAs, for example, imipra- anti­depressants may be appropriately utilized for mine, but without the side-effect profile. In con- patients with FM, regardless of whether or not trast, duloxetine has a slightly higher affinity for the patient is depressed. the 5-HT transporter. Unlike duloxetine, mil- The European League Against Rheumatism nacipran does not have affinity for the guidelines [20] suggest that antidepressants, transporter. In addition, reportedly milnacipran including TCAs, duloxetine and milnacipran, does not have affinity for a-adrenergic, acetyl- as well as and among other choline , peripheral 5-HT, N-methyl- agents, offer the strongest evidence of efficacy in d-aspartate or receptors at therapeutic the management of FM. To date, the anticonvul- doses [23]. In vitro, it was demonstrated that sant pregabalin, functioning as an a2-d modula- milnacipran influenced 5-HT3, N-methyl-d- tor, and two SNRIs, duloxetine and milnacip- aspartate and acetylcholine receptors, but only ran, have been approved by the US FDA for the at very high concentrations, in considerable treatment of FM. excess of plasma concentration ranges achieved through customary therapeutic uses [24]. Chemistry, pharmacodynamics Milnacipran is rapidly and extensively & absorbed from the gastrointestinal tract; The chemical name of milnacipran (Savella) its absolute exceeds 85%. is (±)-(1R[S],2S[R])-2-(aminomethyl)-N,N- Absorption is unaffected by food intake. It has diethyl-1-phenylcyclopropanecarboxamide a low affinity for protein binding and a large hydrochloride. Like duloxetine, its functions volume of distribution [25,26]. are ascribed to the inhibition of the reuptake Milnacipran is metabolized by glucuronic acid of synaptic serotonin (5-HT) and norepineph- conjugation and N-dealkylation [22]; its metabo- rine (NE). A comparative ana­lysis of human lites are clinically inactive. Unlike duloxetine, monoamine reuptake, as well as monoamine which undergoes cytochrome P450 metabolism, transporter binding affinities comparing mil- milnacipran does not have significant cyto- nacipran, duloxetine and TCAs chrome P450 interactions, and the metabolism and , revealed that the binding of coadministered medications does not appear and reuptake inhibition profile observed with to be affected by concomitant milnacipran milnacipran more closely resembled that of treatment [27–29]. Conversely, coadministration the TCAs than that of duloxetine [21]. Some of of can slightly reduce, whereas the pharmacokinetic and pharmacodynamic and lorazepam may slightly increase, features of milnacipran are compared with plasma levels of milnacipran, but the effects are ­duloxetine in Table 1. not clinically significant [26]. With regard to influence on the 5-HT and The elimination half-life of milnacipran NE transporters, milnacipran is the most bal- is estimated to be 8–10 h; twice-daily dos- anced of the SNRIs, but still has a slightly higher ing is recommended. Steady state plasma

Table 1. Comparisons of features of the SNRIs duloxetine and milnacipran*. Duloxetine Milnacipran Influence on the 5-HT/NE transporters 5-HT > NE NE > 5-HT Half-life (h) 12 8 Dosing 40–60 mg/day 50–100 mg b.i.d. Metabolism CYP1A2 and CYP2D6 Conjugation Active metabolites No No Drug–drug interactions Inhibits CYP2D6- and Minimal interaction with CYP CYP1A2-dependent agents P450-dependent agents Modifications required Hepatic insufficiency No dose adjustments necessary Avoid use

Renal insufficiency Reduce dose in mild cases but avoid in ESRD Reduce dose *Data from [22,27,53,68]. 5-HT: Serotonin; CYP: Cytochrome; b.i.d.: Twice-daily; ESRD: End-stage renal disease; NE: Norepinephrine; SNRI: Serotonin–norepinephrine reuptake inhibitors.

508 Int. J. Clin. Rheumatol. (2009) 4(5) future science group Drug Evaluation Leo Milnacipran, a serotonin & norepinephrine reuptake inhibitor Drug Evaluation

concentrations are achieved within 2 days and Finally, in an animal model of peripheral milnacipran is cleared from the body within inflammatory pain (formalin-induced noci- 3 days of cessation. A total of 90% milnacip- ception), systemically administered milnacip- ran can be recovered in the compared ran (intraperitoneal) produced antiallodynic with less than 5% in the . Since clearance responses. This effect was blocked by prazosin of its metabolites is largely dependent on renal (an a-1 antagonist) and (a 5-HT2 activity, dose adjustment in cases of severe renal antagonist) [38]. insufficiency should be considered [30]. As for acute visceral pain, intravenous and intrathecal milnacipran failed to demonstrate Analgesic mechanisms antinociceptive effectiveness in animal models, underlying milnacipran for example, colorectal or uterine cervical disten- The mechanisms that underlie the analgesic tion [39]. Although the effectiveness of milnacip- effects of milnacipran are thought to involve ran in acute visceral pain appears to be limited, supraspinal, spinal and peripheral pain process- its utility in chronic visceral pain, for example, ing sites. Milnacipran, like other antidepres- irritable bowel and chronic pelvic pain, requires sants, may produce pain relief by influencing further exploration. NE and 5-HT neurotransmission of the supra- Additional investigations are required to spinal modulatory systems [31,32]. NE and 5-HT, elucidate the analgesic mechanisms of mil- the two neurotransmitters implicated in depres- nacipran. Given the complexities of chronic sion, are likewise implicated in the monoamine pain encountered in FM, it is likely that mul- hypothesis of pain modulation. This model pro- tiple pathophysiologic mechanisms, including poses that two supraspinal nuclei, one emerging peripheral, spinal and supraspinal processes, from the raphe nucleus magnus () are involved in its genesis and perpetuation. An and the other from the locus coeruleus (nor- analgesic agent that can impact pain processing adrenergic), have axons that extend down the and transmission on each of these levels would spinal column terminating in, and modulating, be particularly advantageous. pain transmission entering the spinal dorsal horn via peripheral nerves containing pain- Clinical efficacy relaying A-d and C-fibers [33]. Antidepressants Several measures are advocated for assessing augmenting monoamine neurotransmission the efficacy and clinical outcomes of treatment from the supraspinal nuclei would be expected interventions employed in FM. These measures to enhance the inhibition of pain relayed from include pre- and post-intervention measures the periphery. of pain intensity. Pain intensity is commonly Animal studies employing microdialy- assessed using a standardized pain scale such as sis investigations confirm that milnacipran the visual analog scale (VAS), recorded with pen increases 5-HT and NE neurotransmitter lev- and paper and/or electronic diaries. Generally, an els within the CNS [34,35]. Electrophysiological improvement of 30% in a standard pain assess- assessments in animal models likewise support ment rating is considered to be the threshold for that the increased synaptic monoamine levels determining clinical efficacy[40] . influence autoreceptors, which in turn alter the In addition, functional status measures, such as firing rates of the locus coeruleus and raphe assessments of physical and emotional function- nucleus [36]. ing, are increasingly employed in FM research. In addition, some evidence has emerged Functional status is often assessed using scales suggesting that milnacipran may exert its such as the fibromyalgia impact questionnaire anti­nociceptive effects at the spinal level. In (FIQ) [41,42] and subscales of the 36-item short- animal models of , that is liga- form health survey (SF-36) [43]. The SF-36 con- tion of the lumbar (L)5 and L6 spinal nerves, tains both a physical and mental component, intrathecal, but not systemic (intraperitoneal), which provide valid and reliable measures of milnacipran produced reduction in pain behav- physical and emotional function, respectively, iors. The analgesic effects of intrathecal mil- along with information regarding quality of life nacipran were blocked by coadministration of in patients with musculoskeletal disorders [44]. (an a-2 antagonist) and methyser- A change in the total score of 20% or more has gide (a 5-HT antagonist), suggesting that the been suggested to be clinically significant in such NE and 5-HT reuptake inhibition influences functional assessments [41]. The patient’s subjec- of milnacipran in the mediate its tive assessment of degree of perceived change in analgesic effects [37]. the severity of FM symptoms overall are often

future science group www.futuremedicine.com 509 Drug Evaluation Leo Milnacipran, a serotonin & norepinephrine reuptake inhibitor Drug Evaluation

quantified using the Patient Global Impression respectively, whereas that for patients receiving of Change (PGIC) scale. This scale is rated on a placebo was 3.6%. Drop-outs from the study 7-point Likert scale ranging from 1 (being very were predominantly attributed to intolerable much improved) to 7 (meaning very much worse). side effects. The clinical meaningfulness of an investiga- The antidepressant effects of milnacipran tion is called into question if it demonstrates an demonstrated a trend towards improvement improvement in one measure, for example, sub- compared with placebo in patients with FM, jective pain assessments, without commensurate but it was not statistically significant. No sig- improvements in patient functioning. As such, nificant improvements were noted with mil- more recent investigations have employed com- nacipran treatment in ability to sustain work, posite responder assessments, requiring clinically depression or anxiety. In addition, sleep did not meaningful improvements in several domains appear to improve among FM patients given affected by FM. milnacipran, perhaps owing to its activating The clinical efficacy of milnacipran has been noradrenergic influences. However, no adverse tested in prospective, randomized, double-blind, sleep effects were attributed to, or reportedly placebo-controlled Phase II [45,46] and Phase III exacerbated by milnacipran. studies [47–50]. To date, there have been no Phase III studies comparing milnacipran with „„Phase III investigations alternative pharmacological treatments. Two Phase III investigations using milnacipran were conducted in the USA [49,50]. Both studies „„Phase II investigation employed a double-blind, randomized, placebo- In a 12-week double-blind, placebo-controlled controlled, fixed-dose trial enrolling FM patients Phase II trial enrolling 125 patients with FM ranging from 18–70 years of age. Milnacipran ranging from 18–70 years of age, milnacipran- was dosed at 50 or 100 mg b.i.d. treated patients reported overall improvements In both investigations, the primary end point in pain severity and fatigue [45,46]. Subjects were was the comparison of two composite response given either 200 mg milnacipran daily (q.d.), rates of milnacipran-treated and placebo- 100 mg milnacipran b.i.d. or placebo in a 3:3:2 administered patients. The first of these was the ratio. Improvements in reported pain, fatigue composite pain response. Patients were deemed and stiffness were noted among milnacipran- to be composite pain responders if they demon- treated patients. The proportions of patients strated at least a 30% reduction in baseline pain achieving 30 and 50% reductions in pain sever- ratings as measured by the VAS in addition to ity across the three conditions, using weekly conducting a self-assessment of the patient on electronic diary pain reports, are summarized the PGIC where they were revealed to be as in Table 2. ‘much’ or ‘very much’ improved compared with Pain ratings of patients receiving milnacip- baseline ratings. The second dependent variable, ran in two daily divided doses (100 mg b.i.d.) or rather the composite syndrome response, was were significantly improved compared with based upon demonstration of the above crite- those of patients receiving placebo; however, ria along with improvement in functioning as pain ratings did not improve significantly for reflected in at least a 30% improvement in the those receiving a single daily 200 mg dose FIQ physical function score from baseline, or compared with placebo. Attrition rates for mil- an improvement by 6 units from baseline rat- nacipran-treated patients were 13.7 and 21.7% ings on the physical component summary of for patients receiving b.i.d. and q.d. dosing, the SF-36.

Table 2. Proportion of fibromyalgia patients achieving pain reduction in a Phase II double-blind, randomized, placebo-controlled trial of milnacipran*­. 100 mg milnacipran b.i.d. 200 mg milnacipran q.d. Placebo Subjects n = 51 n = 46 n = 28 N (%) of subjects achieving pain reduction‡ ≥30% pain reduction 20 (39%)§ 13 (28%) 4 (14%) ≥50% pain reduction 19 (37%)§ 10 (22%) 4 (14%) *Data from [45]. ‡Based on average weekly electronic diary pain scores. §Significant difference when compared with placebo. b.i.d.: Twice-daily; q.d.: Daily.

510 Int. J. Clin. Rheumatol. (2009) 4(5) future science group Drug Evaluation Leo Milnacipran, a serotonin & norepinephrine reuptake inhibitor Drug Evaluation

An initial Phase III study enrolling demonstrated significant improvements in 888 patients in a study of milnacipran use in multiple domains [48], for example, pain, sleep, FM failed to reach statistical significance for fatigue and physical functioning (the latter improvement in one of the a priori established was assessed by the FIQ physical functioning co-primary end points [101]. Pursuant to the subscale and SF-36). It is noteworthy that only aforementioned negative results, the composite 77% of subjects completed the 3‑month trial; responder criteria were modified and the results the attrition rate for the milnacipran-treated were published in a subsequent report [50]. The group was 29.2% (127 out of 435), whereas attri- FIQ physical function criterion was eliminated tion for the placebo group was 17.6% (79 out of since it was deemed to be insufficiently respon- 449). Proportions of the composite responders sive to detect changes in functional status. A reflected a statistically significant improvement 6-point or greater improvement in the base- in favor of milnacipran-treatment over placebo line physical function component of the SF-36 (i.e., 75 out of 308 vs 54 out of 370; p < 0.0003). was utilized for the functional status criterion. Recently, results of another Phase III trial Both composite pain responder and composite completed in the USA assessing the durabil- syndrome responder rates revealed significant ity of milnacipran’s effects was reported [47]. improvements in favor of milnacipran as com- In this investigation, FM patients who were pared with placebo at the 3‑month assessment previously treated with 200 mg milnacipran/ interval, but not at the subsequent 6‑month day for a prior 6‑month study [49] were treated follow-up assessment interval. The proportion for an additional 6‑month period. In addi- of patients meeting the composite response cri- tion, patients previously receiving 100 mg mil- teria across conditions is summarized in Table 3. nacipran/day or placebo were re-randomized to The attrition rate for this study was 42% (patient receive milnacipran dosed at either 100 mg/day withdrawals were considered nonresponders in or 200 mg/day. The authors stated that mul- the table provided). Discontinuation from the tidimensional symptom improvements were study was predominantly due to adverse effects sustained for up to 1 year among patients con- in milnacipran-treated patients (10.3% in the tinuing 200 mg milnacipran per day. Patients placebo group; 27% in the 200 mg/day mil- previously receiving placebo who were re-ran- nacipran group; and 19.6% in the 100 mg/day domized to receive 200 mg/day of milnacipran milnacipran group), and therapeutic failure demonstrated a 40% reduction in pain sever- was the predominant factor influencing attri- ity and a 22% reduction in fatigue at the first tion among placebo-administered patients follow-up interval (8 weeks). However, impor- (15.2% in the placebo group; 11.2% in the tantly, the data presented lacked any statistical 200 mg/day milnacipran group; and 11.6% in comparisons, so the significance of the reported the 100 mg/day milnacipran group). effects cannot be determined. The results of A second Phase III investigation involving 1196 the patients re-randomized to 100 mg/day nondepressed FM patients reported more favor- were not presented. Attrition from the study able results from milnacipran treatment than the was 33%, but rates of withdrawal ascribable aforementioned Phase III study [49,102,103]. In this to adverse effects versus perceived treatment 15-week trial, milnacipran-treated patients were failure remain unreported. significantly more likely to demonstrate com- posite response rates compared with those tak- Depression as a ing placebo. Composite responder rates across co-variate accounting for conditions are summarized in Table 3. Significant multisymptom improvements improvements in pain were observed as early as Milnacipran (Ixel®, Pierre Fabre Medicaments, 1 week after treatment. Attrition rates were 34, Castres, ) is commercially available as a 35 and 28% for the 100 mg/day milnacipran, treatment for depression in and . 200 mg/day milnacipran and placebo condi- Naturally, questions arise as to whether the ben- tions, respectively. As in the aforementioned efits yielded from the aforementioned studies study, discontinuation from the study was pre- are attributable to an antidepressant effect, for dominantly due to adverse effects in milnacip- example, patients for whom depression is allevi- ran-treated patients and therapeutic failure in ated may be apt to rate their pain as less severe placebo-administered patients. or less incapacitating. If this were the case, a A large, multinational, European study greater response to milnacipran would con- enrolling 884 FM patients randomized to ceivably be achieved among FM patients with receive 200 mg milnacipran/day versus placebo comorbid depression.

future science group www.futuremedicine.com 511 Drug Evaluation Leo Milnacipran, a serotonin & norepinephrine reuptake inhibitor Drug Evaluation

Analyses conducted in the previously discussed Phase II trial revealed that 100 mg milnacip- ran b.i.d. did not produce different outcomes for depressed and nondepressed patients [45,46]. Milnacipran generated a 50% reduction in pain severity ratings (based upon weekly electronic diary reports) among 37 and 38% of nondepressed and depressed FM patients, respectively. In con- trast, for patients who were administered placebo, 33% of depressed patients and 5% of those that 27 (12%) 27 (19%) 43 (9%)35 66 (16%) Placebo 223 27 (12%) 27 39 (17%) 401 were not depressed demonstrated a comparable reduction in baseline pain ratings. Statistical comparisons of milnacipran-treated and placebo- administered nondepressed FM patients yielded significant differences (p < 0.001); however, no statistically significant differences were obtained between the two groups when depressed patients were compared, presumably owing to the greater placebo response rate among depressed patients.

§ These data suggest that the efficacy of milnacip- § § § ran in reducing pain is due to an analgesic effect mg milnacipran q.d. .

* rather than a potential antidepressant influence. Two other observations in the aforementioned 85 (19%) (14%) 55 98 (25%) 441 (19%) 118 73 (17%) 73 (17%) 104 396 studies are noteworthy, as these likewise suggest that milnacipran possesses a pain-mitigating influence independent of an indirect anti­ depressant effect. First, in an effort to avoid the potential confounding of antidepressant influ- ences, some investigations restricted enrollment of patients to those who were not depressed [48,49] and yet, were able to demonstrate improvement § * * in pain. For example, subjects were excluded if they scored beyond threshold on a standardized mg milnacipran q.d. 200

III trials employing milnacipran depression inventory, such as scoring 25 points 100 224 44 (20%) (27%) 61 58 (15%) (23%) 91 40 (18%) (24%) 53 399 or more on the Beck depression inventory [51]. Second, pain reductions in response to milnacip- ran began as early as 1 week after treatment ini- tiation [51]. Although maximal relief may not have been achieved until 9 weeks of continuous treatment, the expediential analgesic response still occurs before an antidepressant effect would

‡ be appreciated. ‡ ¶ Safety

¶ Milnacipran, like duloxetine, does not produce troublesome or a-adrenergic effects that are commonly associated with the TCAs. Milnacipran-related adverse effects encountered at least twice as often as those reported in placebo conditions included those that were noradrenergic, for example, dry mouth, 0.05. (2008)

l.

< sweating, increased heart rate, hyper­tension, hot

al. (2008) a

flashes and , and those that were sero- 3. Proportion of composite responders in two Phase tonergic, for example, , constipation and onth interval onth interval m m m m [51,52]. Nausea and headache were most ‑ ‑ ‑ ‑ ubjects (n) Significant p Greater than 30% improvement from baseline on diary pain assessments and Patient Global Impression Change of ratings ‘very of much’ or ‘much’ improved. Greater than 30% improvement from baseline on diary pain assessments. Data from [49,50,104]. Table Phase III trials Mease et S 3 onth interval 3 onth interval Drop-outs were considered to be nonresponders. ratingsChange of ‘very of Impression Global Patient much’ or ‘much’ improved and an above 6-point improvement on the 36-item short-form health survey. * ‡ § ¶ 6 6 composite of n (%) pain responders n (%) of composite syndrome responders n (%) of composite pain responders Clauw et Subjects (n) n (%) of composite of n (%) syndrome responders commonly reported. Milnacipran may exhibit

512 Int. J. Clin. Rheumatol. (2009) 4(5) future science group Drug Evaluation Leo Milnacipran, a serotonin & norepinephrine reuptake inhibitor Drug Evaluation

slightly more noradrenergic-related and slightly sequelae [60]. To date, one fatality has been less serotonergic side effects than duloxetine [27,53], reported in association with a milnacipran over- given its neurotransmitter transporter affinities. dose (at 40-times the customary serum treatment However, no direct head-to-head comparison of concentration) [61]. these agents has been conducted in this regard. Effects of milnacipran on fetal development are Although adverse effects were mild-to-mod- unknown; it has been assigned FDA pregnancy erate in severity, attrition rates owing to adverse category C. Patients should be advised to notify effects among milnacipran-treated patients were their physician if they become pregnant or intend approximately twice that associated with placebo to become pregnant during milnacipran therapy. conditions across studies [51]. Adverse effects were reversible with drug discontinuation. The dosing „„Drug interactions regimen and peak serum drug levels may be deter- Coadministration of SNRIs such as milnacipran minants of severity of adverse effects, for exam- with seroronin selective reuptake inhibitors – for ple, the 100 mg b.i.d regimen tended to be better example, and among others, tolerated than a single 200 mg q.d. dose [45,46]. and inhibitors (MAOI’s), Side-effect tolerability may also be influenced by for example, (Marplan®, Oxford the rate of milnacipran dose escalation. It is rec- Pharmaceutical Services, Inc, NJ, USA), phen- ommended that milnacipran is administered in elzine (NardilTM, , Inc, NY, USA), rasagi- two divided doses q.d., beginning at 12.5 mg q.d. line (AzilectTM, Teva Pharmaceutical Industries and increased gradually to 50 mg b.i.d. at 7 days. Ltd, Petah Tikva, Israel), (EldeprylTM, Although the recommended dose is 50 mg b.i.d., Somerset Pharmaceuticals Inc, FL, USA and further dose increases to 100 mg b.i.d. may be EmsamTM, Bristol-Myers Squibb, NY, USA) or required if treatment response is suboptimal and (ParnateTM, GlaxoSmithKline side effects are not prohibitive [54]. plc, London, UK) – is contraindicated due to Milnacipran does not influence voltage-depen- concerns about . Similar dent calcium, potassium or sodium ion channels in concerns are raised regarding concomitant excitable tissues. As such, it is unlikely to influence administration with serotonergic pain medica- cardiac functioning [55]. In animal studies compar- tion, for example, tramadol (used in cases of ing milnacipran with the TCAs, mild mild pain) or (used in migraine treat- was observed with milnacipran administration, ment). No cases of serotonin syndrome have whereas cardiac arrhythmias and subsequent death been reported in trials of milnacipran to date. were noted among TCA-administered animals. To avoid such potentially hazardous outcomes, Milnacipran is associated with minimal blood a sufficient washout period must be pressure effects. In a study of 4000 patients given adhered to before initiating milnacipran treat- milnacipran, the mean increase was ment, for example, only beginning milnacipran less than 1 mm Hg. Minimal increases in heart 14 days after stopping an MAOI. Conversely, rate and slight changes in the QT interval cor- after patients stop taking milnacipran, they must rected for (QTc) have been associated wait at least 5 days before taking an MAOI or with milnacipran [49,50,56]. other serotonergic agent. Because milnacipran does not require oxida- Sedation can result from concurrent use of mil- tive metabolism and its pharmacokinetics are nacipran with over-the-counter cold and allergy not altered by hepatic disease, no dose adjust- medication, muscle relaxants, sedative hypnot- ments appear to be required for milnacipran in ics, and narcotic . Because hepatic illness [57]. However, in a small propor- milnacipran interferes with serotonin reuptake, tion of patients, there may be slight alterations there is the potential for an increase in the risk of in function tests with use. Duloxetine has abnormal bleeding; patients should be cautioned been associated with hepatitis and cholestatic about its use in conjunction with NSAIDs, , and its use in patients with pre-existing or other drugs affecting coagulation. liver disease is a concern [58]. In a small percentage of patients, abrupt Clinical applicability discontinuation of milnacipran has been asso- Available treatments for FM have not been ciated with anxiety, and rarely, nausea and particularly effective in reducing pain and [59]. Gradual dose reductions may be disability or sustaining treatment compli- required to circumvent withdrawal reactions. ance [62,63]. The recent FDA approval and avail- Cases of human overdose of up to 2.8 g of ability of milnacipran offers a new option in the milnacipran have demonstrated no significant ­treatment arsenal.

future science group www.futuremedicine.com 513 Drug Evaluation Leo Milnacipran, a serotonin & norepinephrine reuptake inhibitor Drug Evaluation

Milnacipran is administered orally twice- comparisons have been made comparing milnacip- daily; the recommended antidepressant dosing ran against existing treatments for pain and other regimen is 50 mg b.i.d. The dosages employed FM symptoms, for example, TCAs, duloxetine in investigations assessing milnacipran’s utility or other agents. As such, the ability to delineate in FM have ranged from 100–200 mg q.d.. Dose ­comparative efficacies and tolerabilities are limited. reductions may be necessary for patients with Third, direct comparisons between the dosing renal dysfunction. In addition, lower doses may regimens for milnacipran were notably absent be required if intolerable side effects supervene. in the investigations reported herein. Rather, It was noteworthy that only the 100 mg b.i.d. each milnacipran dosing regimen was compared regimen, but not the 200 mg q.d. regimen, with placebo. Without direct comparisons of yielded significant benefits when compared with dosing levels, the minimal and optimal doses for placebo [45,46]. Although the two dosing regi- ­therapeutic efficacy remain a mystery. mens were not statistically compared directly, Fourth, most studies controlled for co- these data suggest that milnacipran adminis- administered medications. However, patients tered in divided doses may be more effective were often allowed to make use of analgesic than a single q.d. dose. The divided dose allows rescue medication during the course of the for sustained serum drug levels and thus, sus- trial [45,46,49,50]. Unfortunately, the influence tained analgesic benefit that may not otherwise of rescue medications on the study outcomes is be maintained with a single q.d. dose. not clear, for example, influencing either desired As previously mentioned, attrition rates during clinical benefits or untoward effects. The impact clinical investigations were quite high – mostly of milnacipran on the amount of rescue medica- attributable to adverse effects. It appears that most tion required during the course of past investiga- of these tended to occur during initial phases of the tions has been unreported. Other aspects of the investigations when dose escalations were under- potential benefits of milnacipran on pain, for taken [45,46,49]. A majority of adverse effects were example, the influence of milnacipran on the transient, resolving within 1-to-2 weeks [49,50]. It number of tender points upon which the ACR is unclear from available reports whether more diagnostic criteria are based, were not reported. gradual dose increases may be better tolerated. Finally, the restrictive patient inclusion/exclu- Milnacipran may be of special interest for sion criteria employed in previous studies of use in patients for whom hepatic dysfunction milnacipran make it impossible to speculate on precludes the use of other agents, for example, the generalizability of its effectiveness in several duloxetine. In addition, patients requiring con- patient populations, for example, in those who are currently prescribed medications that rely on nonwhite, male and in those with distinct comor- CYP450 metabolism may benefit from milnacip- bidities such as irritable bowel, migraine and so ran use since it is unlikely to induce or interfere on, or requiring multiple concurrently-prescribed with cytochrome metabolism [64]. medications [61]. As such, there is insufficient evi- dence for the effectiveness of milnacipran in less Shortcomings of existing research well-controlled clinical populations. on milnacipran There are several limitations to the research focus- Conclusion ing on milnacipran in the treatment of pain and Fibromyalgia is a chronic, severe and disabling comorbidities associated with FM. First, in gen- condition. Many patients can manage the disease eral, brief investigations prevent adequate state- with a combination of medications, exercise and ments regarding long-term efficacy from being other treatments [63]. There are a number of agents made. For example, the effects on illness dura- that have been employed to address the symptoms tion and course, and tolerability; very few studies of FM. To date, agents that have received FDA described herein incorporated assessment intervals approval for the treatment of pain and related of 6 months or longer [65]. This is concerning as symptoms associated with FM include duloxetine, FM is a lifelong disorder requiring long-term treat- pregabalin and most recently, milnacipran [10]. ment. Given the relatively short-term follow-up in Milnacipran provides another alternative for pain the extant body of research, the optimal duration and symptom relief in some FM patients. of treatment with milnacipran is, as yet, unknown. Milnacipran is well-tolerated, and has minimal Second, customarily, Phase III investigations adverse effects compared with TCAs. It is safe in are long duration trials in which one agent is overdose and has a negligible influence on cyto- compared against a standard, or at least a rea- chrome . These features make it sonable alternative, treatment. To date, no direct particularly suitable for use in FM.

514 Int. J. Clin. Rheumatol. (2009) 4(5) future science group Drug Evaluation Leo Milnacipran, a serotonin & norepinephrine reuptake inhibitor Drug Evaluation

Evidence suggests that milnacipran may have a It must be kept in mind that the vast major- role in reducing pain, fatigue and impediments to ity of studies investigated a population that functioning associated with FM. However, its role did not include nonwhite and male patients. in addressing common comorbidities associated Further evidence of milnacipran’s efficacy in with FM, for example, irritable bowel, pelvic pain such subgroups is required. and migraine, warrants further investigation. Future investigations attempting to iden- tify positive and negative outcome predictors Future perspective or FM subgroups would be helpful to better Several investigations have advocated the use of select medication and other treatment options a number of pharmacological therapies for the for individual patients. Genetic studies may treatment of pain and comorbidities in FM. Direct help to guide rational treatment approaches to comparison of milnacipran with other pharmaco- FM, and may help to clarify whether there are logical therapies will be necessary to determine its subgroups of FM patients who are more likely role compared with other treatment options for to yield benefits from milnacipran as com- FM symptoms. There is a need for studies of lon- pared with other currently available treatment ger duration to investigate the long-term efficacy options [15,66,67]. and side effects of treatment with milnacipran in FM. In this context, it would also be important to Financial & competing interests disclosure assess the influence of the medication on patients’ The author has no relevant affiliations or financial involve- quality of life and on how many patients return ment with any organization or entity with a financial to normal q.d. life and work while receiving mil- interest in or financial conflict with the subject matter or nacipran treatment. Furthermore, trials analyzing materials discussed in the manuscript. This includes the cost–effectiveness of milnacipran treatment employment, consultancies, honoraria, stock ownership or should be performed. From an economic point options, expert ­testimony, grants or patents received or of view, it would also be of interest to know if pending, or royalties. ­milnacipran reduces FM-related healthcare No writing assistance was utilized in the production of costs [65]. this manuscript.

Executive summary Mechanisms of action ƒƒ Milnacipran is a serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor. ƒƒ The exact mechanisms underlying its analgesic effects have, as yet, to be elucidated. Animal studies suggest that analgesic effects are mediated by its influences on 5-HT and NE at supraspinal, spinal and peripheral levels. Pharmacokinetic properties ƒƒ Milnacipran has a high bioavailability, exceeding 85%. ƒƒ Absorbtion is minimally influenced by food intake. ƒƒ Milnacipran is metabolized in the liver by glucuronic acid conjugation and N-dealkylation and excreted as inactive metabolites by the kidneys. ƒƒ It has negligible influences on the CYP450 metabolism of other medications. ƒƒ Mild-to-moderate liver function impairment has not been shown to significantly influence the metabolism of milnacipran. ƒƒ Dose reductions are recommended for patients with moderate-to-severe renal dysfunction. Clinical efficacy ƒƒ Significantly greater composite response rates (encompassing 30% reductions in pain ratings, improvement in self-rated patient global status and improvements in functional status) have been demonstrated among milnacipran-treated as compared with placebo-administered fibromyalgia patients. ƒƒ Data from long-term extension studies are lacking, but one study suggested that benefits in pain and functional status parameters are sustained at 1 year. ƒƒ There were no direct comparisons of milnacipran with other treatments for pain and symptoms of fibromyalgia. Safety & tolerability ƒƒ Milnacipran is associated with a number of serotonergic (e.g., nausea) and noradrenergic (e.g., headache, sweating and palpitations) side effects. ƒƒ There are no significant safety concerns regarding its influences on cardiac functioning, blood pressure or hepatic function. Drug interactions ƒƒ Milnacipran should not be coadministered with monoamine oxidase inhibitors due to concerns regarding precipitating of a serotonin syndrome. ƒƒ Because of its effects on serotonin and the potential increased risk of bleeding, caution is required when milnacipran is coadministered with NSAIDs, aspirin or other drugs affecting coagulation.

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