Chapter 23 Duloxetine and Milnacipran

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Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American

Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.427736. Printed 5/10/2009 from

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Chapter 23. Duloxetine and Milnacipran

DULOXETINE AND MILNACIPRAN: INTRODUCTION

Duloxetine was first synthesized in the 1980s and subsequently patented in 1991. The U.S. Food

and Drug Administration (FDA) did not approve this drug for the treatment of major depressive

disorder and diabetic neuropathy, however, until the third quarter of 2004. This long delay occurred

because the drug was initially tested in depressed patients at low dosages of 5–20 mg/day, which

were not efficacious. Duloxetine has received approval in most countries worldwide since then but

became available in Canada only in 2008. It is also approved in the United States for generalized

anxiety disorder and fibromyalgia. Milnacipran was approved in France for the treatment of

depression in 1996 but only recently was approved for use in North America for patients with

fibromyalgia.

STRUCTURE–ACTIVITY RELATIONS

Duloxetine and milnacipran (Figure 23–1), along with venlafaxine, are antidepressant medications

that can act as serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine reuptake inhibitors.

Whereas selective serotonin reuptake inhibitors (SSRIs) target only the 5-HT transporter (5-HTT),

the dual-acting medications have the potential to inhibit both the 5-HTT and the norepinephrine

transporter (NET). Collectively, these three medications are referred to as

serotonin–norepinephrine reuptake inhibitors (SNRIs). Several lines of evidence have to be

considered, however, to determine at which concentrations SNRIs are indeed effective dual

reuptake inhibitors. This is of crucial importance in estimating their potency in clinical settings.

FIGURE 23–1. Chemical structures of duloxetine and milnacipran.Print: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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PHARMACOLOGICAL PROFILES

In Vitro Assessments

The first data to consider in determining the biochemical profile of reuptake inhibitors are their

affinity values for membranal carriers. These values can be calculated by determining the

concentration of a medication necessary to displace 50% of the specific binding of a standard ligand

for a given transporter subtype in a lyzed cell preparation (Ki). This technique generally provides

rough estimates of the potential for drugs to inhibit reuptake. A somewhat more indicative

approach consists of determining the concentrations of drugs necessary to inhibit the uptake of

transmitters in intact cells from either animal brains or human cell lines. These physiological results

are more reliable than mere binding data because of the integrity of the tissue. Indeed, recent data

indicate that the binding of some norepinephrine reuptake blockers varies markedly when they are

tested in membrane preparations versus intact cells, whereas with other agents, such as the

tricyclic antidepressants (TCAs), it does not (Mason et al. 2007). As can be seen in Table 23–1, not

only do the absolute potencies vary between the two preparations, their ratios vary as well.

TABLE 23–1. In vitro affinity and inhibition values for milnacipran and duloxetine for human

reuptake transporters

Serotonin

transporter

Norepinephrine

transporter

Dopamine

transporter

Affinity values, Ki (nM)

Milnacipran 8.4 22 ND

Duloxetine 0.1 1.2 230Print: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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Serotonin

transporter

Norepinephrine

transporter

Dopamine

transporter

Inhibition values, Ki

(nM)

Milnacipran 151 68 ND

Duloxetine 3.7 20 439

Note. ND = Not detectable; values for duloxetine for the dopamine transporter are not physiologically

significant.

Source. Adapted from Vaishnavi et al. 2004.

In Vivo Assessments

Ideally, the potency of reuptake inhibitors in animal experiments should be assessed in vivo with

the medications administered systemically. One common technique is to conduct microdialysis

studies whereby extracellular levels of neurotransmitters are estimated from the perfusion of an

artificial cerebrospinal fluid. Data generated with duloxetine in rats indicate that it first enhances

brain levels of 5-HT, and that with increasing doses it increases norepinephrine levels (Koch et al.

2003). In the case of milnacipran, the levels of 5-HT and norepinephrine are generally enhanced to

the same extent (in guinea pigs; Moret and Briley 1997), although pronounced regional differences

have been observed. For instance, milnacipran is six times more potent in the rat hypothalamus

than in the midbrain raphe nuclei and the frontal cortex (Bel and Artigas 1999). These results

suggest that milnacipran may not readily penetrate the blood–brain barrier.

Potency can also be assessed in vivo using electrophysiological approaches. For instance, by

determining the capacity of reuptake inhibitors to suppress the firing of 5-HT and norepinephrine

neurons, reliable potency estimates can be obtained. As reuptake transporters are

dose-dependently inhibited from their systemic injection, 5-HT and norepinephrine accumulate at

the cell body level of such neurons that will activate their respective autoreceptors, thereby

decreasing firing activity. Using this approach, duloxetine suppresses the firing rate of 5-HT

neurons by 50% with an intravenous dose of 0.1 mg/kg and suppresses the firing rate of

norepinephrine neurons to the same level with a dose of 0.5 mg/kg (Kasamo et al. 1996). This in

vivo ratio of 1:5 is quite different from the in vitro affinity ratio of 1:12 (Vaishnavi et al. 2004; see

Table 23–1). In contrast, using the same in vivo technique, the dose of milnacipran necessary to

inhibit the firing rate of 5-HT neurons by 50% is 5.7 mg/kg (Mongeau et al. 1998). The latter

results therefore suggest that milnacipran is much less potent in inhibiting 5-HT reuptake than

duloxetine.

Assessments of 5-HT and Norepinephrine Reuptake in Humans

Reuptake of neurotransmitters in humans cannot be assessed as directly as it can in the brains of

laboratory animals. Several approaches can, however, provide useful estimates. For instance, 5-HT

reuptake inhibition can be estimated using blood platelet uptake of radioactive 5-HT because

platelets do not synthesize 5-HT and they have a 5-HTT that is nearly identical to the one present on

5-HT neurons in the brain. And because more than 90% of the 5-HT in blood is in platelets, whole

blood can be used to measure 5-HT depletion by a reuptake inhibitor, making assessment simpler.

Using this peripheral assay, duloxetine produces a dose-dependent depletion of the 5-HT level that

reaches only about 60% with a 60-mg dose, an effect that is significantly inferior to that seen with

the TCA clomipramine at a dose of 100 mg (Turcotte et al. 2001). Likewise, milnacipran produces a

64% inhibition of 5-HT uptake with the usual recommended dose of 100 mg (Puozzo et al. 1985).

Using a similar assay, SSRIs produce a greater than 80% inhibition with clinically effective doses

(Gilmor et al. 2002).

Occupancy of the 5-HTT in the human brain is possible to assess directly using carbon 11

( 11C)–labeled ligands of these transporters and positron emission tomography (PET). The minimalPrint: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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effective doses of the SSRIs and venlafaxine for treating depression all result in at least 80%

occupancy of the 5-HTT (Meyer et al. 2004). A daily dose of 60 mg, but not 40 mg, of duloxetine

produces sustained 80% occupancy (Takano et al. 2006). To our knowledge, milnacipran has not

been tested using this approach.

Occupancy of the NET in the human brain is currently not possible because a PET ligand, validated

with standard norepinephrine reuptake inhibitors (NRIs), is still lacking. A variety of peripheral

measures can, however, be used. In particular, the intravenous tyramine pressor test has produced

consistent results. Tyramine penetrates into peripheral norepinephrine terminals through the NET

and releases norepinephrine in a calcium-independent manner, thereby transiently elevating the

systolic blood pressure. Any drug effectively blocking the NET attenuates this pressor response in a

dose-dependent manner. The SSRIs paroxetine and sertraline do not affect this response, whereas

the TCAs desipramine, nortriptyline, and clomipramine attenuate it, as is also the case with the

selective NRIs maprotiline, reboxetine, and atomoxetine (Blier et al. 2007; Gobbi et al. 2003;

Harvey et al. 2000; Slater et al. 2000; Turcotte et al. 2001). Venlafaxine significantly attenuates the

tyramine response only at dosages in the 225–375 mg/day range in depressed patients (Aldosary et

1. 2007; Debonnel et al. 2007). Duloxetine exerts a clear effect only at 120 mg/day (Vincent et al.

2004), whereas milnacipran, to our knowledge, has not been tested using this model. A variety of

other peripheral measures suggest that duloxetine may begin to inhibit norepinephrine reuptake at

60 mg/day (Chalon et al. 2003; Turcotte et al. 2001; Vincent et al. 2004).

Taken together, these results obtained in humans indicate that duloxetine is a potent 5-HT reuptake

inhibitor at a dosage of 60 mg/day. The exact degree of norepinephrine reuptake inhibition

occurring in humans at 60 mg/day remains uncertain, but at 120 mg/day it reaches a

physiologically relevant level without any doubt. A definite answer to the degree of norepinephrine

reuptake inhibition produced by duloxetine in the human brain awaits both the availability of a PET

ligand for the NET and a comparison with clinically effective doses of selective NRIs such as

desipramine. Such experiments will also serve to determine the NET reserve beyond which the

overall function of the norepinephrine system is altered, as was determined for the 5-HTT (i.e.,

80%; Meyer et al. 2004).

With regard to milnacipran, it appears that it acts preferentially on the norepinephrine reuptake

process because it has been easy to find evidence of this action in the brain of laboratory animals

even with low doses, whereas 5-HT reuptake inhibition can only be documented with high doses.

Robust 5-HT reuptake inhibition (>80%) in humans appears to be achieved only with

supratherapeutic doses (i.e., 300–400 mg; Palmier et al. 1989).

MECHANISM OF ACTION

Administration of SNRIs results in a rapid inhibition of reuptake transporters in the brain. However,

their therapeutic effect on depression is delayed at least 2 weeks. Extensive electrophysiological

and microdialysis studies in laboratory animals have provided consistent results showing a similar

delay before SNRIs produce a net enhancement of 5-HT and/or norepinephrine transmission,

thereby explaining their therapeutic lag in treating depression (see Blier 2006 for a review). In

brief, SNRIs that are potent 5-HT reuptake inhibitors initially suppress the firing of 5-HT neurons

through the activation of 5-HT1A autoreceptors on their cell bodies, as a result of 5-HTT inhibition.

After 2–3 weeks of sustained administration, the firing rate returns to normal in the presence of

sustained reuptake inhibition, due to 5-HT1A autoreceptor desensitization. At this time, there is a

net enhancement of 5-HT transmission in the forebrain (Bel and Artigas 1993; Blier and de

Montigny 1983; Rueter et al. 1998a, 1998b).

Regarding SNRI inhibition of the NET, the firing rate of norepinephrine neurons is promptly

diminished as a result of the activation of the 2-adrenergic autoreceptors on their cell bodies. After

2–3 weeks of sustained administration, the firing rate remains attenuated because the cell body

2-adrenergic autoreceptors do not become desensitized. In contrast, 2-adrenergic autoreceptors on

norepinephrine terminals generally do become desensitized, leading to a net enhancement of

norepinephrine transmission in the forebrain in the presence of sustained norepinephrine reuptakePrint: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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inhibition (Invernizzi and Garattini 2004; Rueter et al. 1998a, 1998b; Szabo and Blier 2001).

PHARMACOKINETICS AND DISPOSITION

Absorption and Distribution

Duloxetine is available in an enteric formulation. It is rapidly absorbed after oral administration,

and its absorption is not altered by food. Plasma levels are proportional to doses, up to the

maximum recommended dose of 60 mg twice daily. It is highly bound to plasma proteins, to an

extent of about 90%. Its plasma elimination half-life is approximately 12 hours (Sharma et al.

2000). With repeated administration, duloxetine levels therefore reach a steady-state level after

about 3 days.

Milnacipran has low (13%) and nonsaturable plasma protein binding. It is rapidly absorbed after

oral administration and has high bioavailability, and its absorption is not affected by food intake. It

has no active metabolite, and its elimination half-life is 8 hours. Steady-state levels are thus

achieved within 3 days, with no drug accumulation occurring during prolonged dosing, and the drug

is cleared from the body within 3 days of treatment cessation. It is eliminated by the kidneys as

essentially the parent compound and glucuronide, the inactive glucuronic acid conjugate (Puozzo

and Leonard 1996).

Metabolism and Elimination

Duloxetine is extensively metabolized through various pathways (Skinner et al. 2003). Numerous

metabolites are found in circulation, none of which is believed to contribute to its therapeutic

activity. Duloxetine is metabolized mainly by cytochrome P450 1A2 and 2D6 isoenzymes.

The cytochrome P450 system is not involved in the metabolism of milnacipran (Briley 1998). Its

metabolism is mediated mainly through phase II conjugation. Approximately 50%–60% of the drug

is recovered in the urine as the parent compound and 20% as its glucuronic acid conjugate, the

remainder being excreted mainly as an N-dealkyl metabolite and its glucuronic acid conjugate, and

in negligible amounts as an N-didealkyl metabolite and a hydroxy metabolite (Puozzo et al. 2002).

INDICATIONS AND EFFICACY

Duloxetine has been approved by the FDA for use in treating major depressive disorder, diabetic

peripheral neuropathic pain, fibromyalgia, and generalized anxiety disorder; it is also approved in

Europe for treating stress urinary incontinence. Additional common off-label uses include other

neuropathic pain/chronic pain disorders.

Milnacipran is used to treat major depressive disorder in various countries, although it has not yet

received FDA approval for that indication. It was recently approved in the United States for the

treatment of fibromyalgia.

Depression

Duloxetine

To date, 12 placebo-controlled studies have evaluated the antidepressant efficacy of duloxetine at

dosages of 40–120 mg/day. Many of these had an active drug comparator group. Efficacy was

measured by remission, the optimal outcome measure, or by response. Remission can be

operationally defined as a score of less than or equal to 7 on the 17-item Hamilton Rating Scale for

Depression (Ham-D) or a score of less than or equal to 10 on the Montgomery-Åsberg Depression

Rating Scale (MADRS). Response is often defined as a 50% reduction in the MADRS or Ham-D score

from baseline to endpoint. These studies and non-placebo-controlled duloxetine trials are

summarized in Tables 23–2 and 23–3.

TABLE 23–2. Duloxetine versus placebo and/or active SSRI or SNRI comparator in acute studies (

12 weeks) of depressionPrint: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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Study Duration

(weeks)

Sample

size

Duloxetine

dosage

(mg/day)

Comparator

used

Comparator

dosage

(mg/day)

Placebo? Results

Goldstein

et al. 2002

8 173 120 Fluoxetine 20 Yes Duloxetine>placebo

No difference with

fluoxetine

Nemeroff

et al.

2002a

8 194 120 Fluoxetine 20 Yes No difference in

remission rates at

endpoint

Nemeroff

et al.

2002a

8 354 40, 80 Paroxetine 20 Yes No difference in

remission rates at

endpoint

Detke et

1. 2002b

9 245 60 None — Yes Duloxetine>placebo

Detke et

1. 2002a

9 267 60 None — Yes Duloxetine>placebo

Goldstein

et al. 2004

8 353 40, 80 Paroxetine 20 Yes Duloxetine 80 (but not

40)>placebo

No difference between

duloxetine 80 and

paroxetine

Detke et

1. 2004

8 354 80, 120 Paroxetine 20 Yes Duloxetine (80 and

120)>placebo

Paroxetine = placebo

Perahia et

1. 2006b

8 392 80, 120 Paroxetine 20 Yes Duloxetine (80 and

120)>placebo

Paroxetine = placebo

Raskin et

1. 2007

8 311 60 None — Yes Duloxetine>placebo

Nierenberg

et al. 2007

8 684 60 Escitalopram 10 Yes No difference between

any groups at endpoint

Khan et al.

2007

8 278 60 Escitalopram 10–20 No Escitalopram>duloxetine

Brecht et

1. 2007

8 327 60 None — Yes Duloxetine>placebo

1. Lee et
2. 2007

8 478 60 Paroxetine 20 No Duloxetine = paroxetine

Perahia et

1. 2008

12 667 120 Venlafaxine 225 No Duloxetine =

venlafaxine

Note. SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor. “>”

denotes significantly greater effect; “=” denotes no difference.

aThese failed studies were reported in this review but were not conducted by Dr. Nemeroff.

TABLE 23–3. Duloxetine versus placebo and/or active SSRI comparator in continuation studies

(>12 weeks) of depression

Study Duration

(weeks)

Sample

size

Duloxetine

dosage

Comparator

used

Comparator

dosage

Placebo? ResultsPrint: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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(mg/day) (mg/day)

Pigott

et al.

2007

32 684 60–120 Escitalopram 10–20 Yes Duloxetine =

escitalopram;

placebo group

underpowered due

to length of trial

Wade

et al.

2007

24 295 60 Escitalopram 20 No Duloxetine =

escitalopram

Note. SSRI = selective serotonin reuptake inhibitor. “=” denotes no difference.

Head-to-head comparisons with SSRIs have yielded mixed results, which appear to be heavily

influenced by dosing regimens (see Tables 23–2 and 23–3). In a recent 8-week, placebo-controlled

comparison of duloxetine 60 mg/day and escitalopram 10 mg/day, the two drugs produced similar

statistically significant improvement versus placebo on the primary efficacy measure of onset of

efficacy and similar response and remission rates at endpoint (Nierenberg et al. 2007).

In a recent meta-analysis of six Phase II/III studies that compared duloxetine with two SSRIs

(fluoxetine or paroxetine) in outpatients with major depressive disorder, duloxetine 40–120

mg/day was reported to be an effective antidepressant, with an overall efficacy profile equal to that

of fluoxetine and paroxetine at 20 mg/day (Thase et al. 2007). For patients stratified as having

moderate to severe symptoms, the remission rates with duloxetine were statistically superior to

those with the SSRIs (see Table 23–3). Another recent meta-analysis of nine randomized,

controlled trials (RCTs) evaluating high doses of duloxetine in patients with severe depression

concluded that duloxetine 120 mg/day produced significantly greater baseline-to-endpoint

improvement than placebo on several of the 17 Ham-D items (Shelton et al. 2007).

Milnacipran

A meta-analysis of three short-term (4- to 8-week), double-blind, acute efficacy multicenter trials in

inpatients and outpatients with moderate to severe depression found that milnacipran exerts a

superior antidepressant effect compared with placebo at dosages of 50 and 100 mg twice daily but

not at a dosage of 25 mg twice a day (Lecrubier et al. 1996; Macher et al. 1989).

Several studies have compared milnacipran with SSRIs or TCAs in the treatment of depression

(Table 23–4). In comparison with the TCA imipramine, milnacipran has been noted to have equal

efficacy, but superior tolerability (Puech et al. 1997). A recent meta-analysis concluded that there is

insufficient evidence to suggest a difference in response rates between milnacipran and any SSRI:

Pooling response rates of the agents revealed an overall response rate of 62.1% for milnacipran

and 57.5% for the SSRIs (Papakostas and Fava 2007). To date, no continuation studies (>12

weeks’ duration) have been published comparing the efficacy of milnacipran to that of any SSRI.

There is no maximal recommended dose of milnacipran, but it is important to mention that the

highest daily dose tested so far, 300 mg, was tested in only 41 patients and for only 2 weeks

(Ansseau et al. 1991).

TABLE 23–4. Milnacipran versus placebo and/or active SSRI comparator in acute studies ( 12

weeks) of depression

Study Duration

(weeks)

Sample

size

Milnacipran

dosage

(mg/day)

Comparator

used

Comparator

dosage

(mg/day)

Placebo? Results

Macher

et al.

1989

4 58 100 None — Yes Milnacipran>placeboPrint: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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Study Duration

(weeks)

Sample

size

Milnacipran

dosage

(mg/day)

Comparator

used

Comparator

dosage

(mg/day)

Placebo? Results

Ansseau

et al.

1991

4 127 150–300 Fluvoxamine 200 No Milnacipran =

fluvoxamine

Ansseau

et al.

1994

6 190

100a

Fluoxetine 20 No Fluoxetine>milnacipran

Lecrubier

et al.

1996b

6–8 644 50, 100,

200

None — Yes Milnacipran 100 and 200

(but not 50)>placebo

Guelfi et

1. 1998

12 289 100–200 Fluoxetine 20 No Milnacipran = fluoxetine

Clerc

2001

6 113 100 Fluvoxamine 200 No Milnacipran>fluvoxamine

Sechter

et al.

2004

6 302 100 Paroxetine 20 No Milnacipran = paroxetine

1. S.

Lee et al.

2005

6 70 100 Fluoxetine 20 No Milnacipran = fluoxetine

Note. SSRI = selective serotonin reuptake inhibitor. “>” denotes significantly greater effect; “=” denotes no

difference.

aMilnacipran was given once daily; this was in contrast to the other studies, in which it was administered on a

twice-daily basis.

bThis is a composite of two positive controlled studies.

Generalized Anxiety Disorder

Three placebo-controlled studies have had positive results showing a therapeutic action with

duloxetine in patients with generalized anxiety disorder (Allgulander et al. 2007). Dosing strategies

are similar to those used in major depression.

Neuropathic Pain/Chronic Pain

TCAs and SNRIs clearly produce significant relief of physical symptoms such as pain in depression

and in a variety of pain syndromes (Stahl et al. 2005). Potentiation of the activity of 5-HT and

norepinephrine is believed to result in central pain inhibition through descending modulatory

pathways (Sussman 2003).

Duloxetine

Duloxetine exerts a prompt and substantial analgesic effect beyond its antidepressant action

(Perahia et al. 2006a). Duloxetine has shown efficacy in the treatment of diabetic peripheral

neuropathy in randomized, placebo-controlled trials (Fishbain et al. 2006; Wernicke et al. 2006).

Response tends to occur early in therapy and has been associated with significant improvement in

functional outcomes (Armstrong et al. 2007; Pritchett et al. 2007b).

In a recent 8-week study of patients with major depressive disorder and at least moderate pain of

unknown etiology, a fixed dosage of duloxetine (60 mg/day) significantly reduced pain measures at

endpoint from baseline compared with placebo (Brecht et al. 2007). The mean average pain score at

8 weeks was close to 3 on the Brief Pain Inventory—Short Form, which can be considered a mildPrint: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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level of pain compared with the moderate or higher levels of pain indicated by baseline scores

(Brecht et al. 2007). Similarly, elderly patients with depression treated with duloxetine (60

mg/day) for 8 weeks reported significantly greater improvement in back pain scores and amount of

time in pain compared with placebo recipients (Raskin et al. 2007).

An RCT of duloxetine 60 mg/day demonstrated greater efficacy than placebo in reducing overall

shoulder pain and back pain in depressed patients, as well as time spent with pain (Detke et al.

2002b). Overall pain severity and back pain improved the most. Improvements were assessed with

the visual analog scales of pain severity, measuring overall pain, back pain, headaches, shoulder

pain, interference with daily activities, and time in pain.

Milnacipran

The capacity of milnacipran to relieve chronic pain has been reported in open trials, but no RCTs

have been published to date.

Fibromyalgia

A 12-week RCT of duloxetine 120 mg/day versus placebo in patients with fibromyalgia, some of

whom were also diagnosed with depression, found significant improvement in pain scores in

duloxetine recipients and greater improvement in tender points compared with placebo recipients

(Arnold et al. 2005). Duloxetine 120 mg/day improved fibromyalgia symptoms and pain severity

regardless of the extent of the accompanying depressive disorder. The drug has received FDA

approval for this indication.

A placebo-controlled study of milnacipran in fibromyalgia patients showed that 37% of the patients

treated with 100 mg of milnacipran twice daily experienced a significant reduction in pain intensity

of 50% or more compared with 14% of placebo recipients (Vitton et al. 2004). Here, too,

milnacipran recently received FDA approval for this indication.

Stress Urinary Incontinence

Duloxetine has been investigated in the treatment of stress urinary incontinence, with 40 mg twice

daily being the recommended dosage (Norton et al. 2002). Serotonin and norepinephrine increase

excitatory glutamate transmission in the Onuf nucleus in the sacral spinal cord, which facilitates

urethral sphincter contraction (Thor 2003). This is presumably the mechanism for the beneficial

effect of duloxetine in the treatment of this problem.

The capacity of milnacipran to treat stress urinary incontinence has not been reported to date.

SIDE EFFECTS AND TOXICOLOGY

Duloxetine

In clinical trials to date, the safety and tolerability of duloxetine in the dosage range of 40–120

mg/day have been assessed. In an 8-month study, the most common treatment-emergent adverse

events included nausea, dry mouth, vomiting, yawning, and night sweats (Pigott et al. 2007). Most

of these emerged early, within the first 8 weeks. Other studies have reported insomnia,

somnolence, headaches, ejaculation disorders, diarrhea, constipation, and dizziness as common

adverse events with duloxetine (Detke et al. 2002a, 2002b; Khan et al. 2007; Nierenberg et al.

2007).

The rates of nausea with duloxetine appear to be comparable to those found with other SNRIs and

with SSRIs. Nausea is transient and usually present at treatment initiation. A starting dosage of 60

mg/day appears to provide the best combination of clinical response and tolerability (Bech et al.

2006; Pritchett et al. 2007a). Clinicians may, however, consider starting at a lower dosage, 30

mg/day, for patients for whom tolerance is a concern. Duloxetine 30 mg/day offers the advantage

of a lower rate of nausea as a treatment-emergent adverse event (in one study, 16% vs. 33% with

duloxetine 60 mg/day; Dunner et al. 2005). A recent study indicates that the tolerability of

duloxetine at an initial dosage of 60 mg/day can be improved if the drug is taken with food, to the

point of being comparable to the tolerability at an initial dosage of 30 mg/day (Whitmyer et al.Print: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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2007).

Duloxetine has not been associated with weight gain, and in one study it was in fact noted to be

associated with a mean 1-kg weight loss (Nierenberg et al. 2007). This decrease was a statistically

significant difference compared with the lack of effect that placebo and escitalopram had on weight.

Changes in blood pressure and heart rate do not appear to be clinically significant. Pooled data on

735 patients treated with duloxetine 40–120 mg/day showed that 0.7% had a 10-mm Hg increase

in systolic or diastolic blood pressure compared with 0.4% of patients receiving placebo. Heart rate

was increased by less than 1 beat per minute (Schatzberg 2003).

Rates of sexual dysfunction, including anorgasmia, erectile dysfunction, delayed ejaculation, and

decreased libido, appear to be low with duloxetine. Researchers found that after 8 months,

categorical outcomes shown on a questionnaire about changes in sexual functioning did not differ

significantly between duloxetine and escitalopram groups (Pigott et al. 2007). In clinical practice,

however, sexual dysfunction with any drug that potentially inhibits 5-HT reuptake does create some

problems in a significant proportion of patients.

Rates of discontinuation due to adverse events have not differed significantly in placebo and active

comparator groups in acute or longer-term studies. However, it appears that study subjects who

discontinue duloxetine due to adverse events often do so during the early study visits (Nierenberg

et al. 2007; Perahia et al. 2008; Pigott et al. 2007), which may suggest poorer initial tolerability.

Milnacipran

Analysis of a database of more than 3,300 patients concluded that the adverse-event profile of

milnacipran is comparable to that of the SSRIs, except that with the SSRIs a higher frequency of

nausea and anxiety is seen, whereas milnacipran is associated with a higher incidence of dysuria

(Puech et al. 1997). Weight gain is uncommon, and sedation may be reported. Data on the

occurrence of sexual dysfunction with milnacipran have not been reported, but its prevalence is

estimated to be low compared with the prevalence of sexual dysfunction seen with venlafaxine and

much lower than that seen with SSRIs (Stahl et al. 2005). The lower incidence of nausea and sexual

dysfunction with milnacipran versus SSRIs may be taken as indirect evidence of its lower 5-HT

reuptake inhibition potential, these two treatment-emergent adverse events being classically

induced by potent 5-HT reuptake inhibitors.

Blood pressure increases with milnacipran are minimal. A 12-week randomized, double-blind study

comparing milnacipran dosages of 100 mg/day and 200 mg/day versus fluoxetine 20 mg/day in

289 depressed inpatients found no significant changes in blood pressure in any of the group (Guelfi

et al. 1998). Tachycardia, a heart rate of greater than 100 beats per minute, was seen in 0% of

patients receiving fluoxetine, 3% of patients receiving milnacipran 100 mg/day, and 6% of patients

receiving milnacipran 200 mg/day. A review of more than 4,000 patients treated with milnacipran

showed that the mean increase in blood pressure was less than 1 mm Hg and the mean increase in

heart rate was 3.6 beats per minute (Puech et al. 1997). Given that an increase of heart rate is a

thumbprint of potent norepinephrine reuptake inhibition, this increase is consistent with the

capacity of milnacipran to effectively block norepinephrine reuptake. No cardiotoxicity has been

reported with overdoses of up to 2.8 g/day, which is 28 times the recommended daily dose

(Montgomery et al. 1996).

Analysis of the long-term safety of milnacipran (in 715 patients receiving milnacipran for >6

months, 189 for >12 months, as reported by Puech et al. 1997) has shown that most adverse events

appear within the first 3 months of treatment and that the incidence decreases steadily thereafter.

More important, no treatment-emergent adverse events developed during long-term treatment.

DRUG–DRUG INTERACTIONS

Inhibitors of cytochrome P450 1A2, such as ciprofloxacin, increase plasma levels of duloxetine, and

their use may require that duloxetine dosages be reduced or that duloxetine use be avoided. When

duloxetine is coadministered with a cytochrome P450 2D6 inhibitor of moderate potency, such as

bupropion or diphenhydramine, duloxetine levels may increase. Generally, however, suchPrint: Chapter 23. Duloxetine and Milnacipran http://www.psychiatryonline.com/popup.aspx?aID=427740&print=yes…

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alterations of duloxetine levels are not clinically significant.

Duloxetine does not inhibit or induce the activity of cytochrome P450 1A2, 2C9, or 3A4 systems. It

does, however, moderately inhibit the activity of the 2D6 enzyme. If duloxetine is prescribed with

an agent metabolized by 2D6, clinicians should use doses that are approximately half those usually

recommended for the concomitant medication. Duloxetine does not potentiate the psychotropic

effects of ethanol or benzodiazepines.

Because milnacipran is not metabolized by the cytochrome P450 pathways, it does not produce

pharmacokinetic drug–drug interactions. However, both milnacipran and duloxetine can have a

serious, potentially lethal pharmacodynamic interaction if given concomitantly with a monoamine

oxidase inhibitor (MAOI) due to the risk of serotonin syndrome. To avoid this catastrophic outcome,

an MAOI must never be administered until at least 5 days after duloxetine or milnacipran has been

discontinued. A longer washout period must be respected when switching from an MAOI to an SNRI.

A washout period of at least 14 days should elapse before starting any SNRI.

CONCLUSION

At their minimal effective dosages, duloxetine (60 mg/day) and milnacipran (100 mg/day) potently

block the reuptake of 5-HT and norepinephrine, respectively. In the case of duloxetine, it is difficult

to imagine that increasing the subtherapeutic dosage of 40 mg/day, at which it does not perform as

an SSRI, to 60 mg/day would produce marked norepinephrine reuptake inhibition when the in vivo

5-HT–norepinephrine reuptake potency ratio is 1:5. In the case of milnacipran, a 100-mg dose

produces suboptimal platelet 5-HT reuptake inhibition. Duloxetine at its maximal recommended

dosage (120 mg/day) and milnacipran in its upper therapeutic range (200 mg/day) are dual

reuptake inhibitors, but none of the three SNRIs currently available can be considered a balanced

serotonin–norepinephrine reuptake inhibitor.

Duloxetine and milnacipran have demonstrated efficacy for the treatment of depression and pain

syndromes, with emerging evidence also suggesting a potential role for duloxetine in the treatment

of stress urinary incontinence and some anxiety disorders. These medications are generally well

tolerated, with most adverse events occurring early in treatment, being mild to moderate in

severity, and having a tendency to decrease or disappear with continued treatment.

Either of these two drugs may be used as a first-line treatment for depression because they are not

toxic in overdosage and they can be used at therapeutic dosages from treatment initiation onward

with minimal side effects. Furthermore, data suggest that treatment with a dual reuptake inhibitor

is superior to treatment with an antidepressant with only one mechanism of action, such as an SSRI

(Nemeroff et al. 2008; Poirier and Boyer 1999; Thase et al. 2007). Consequently, duloxetine and

milnacipran may be useful in patients whose conditions have been resistant to treatment with

SSRIs or NRIs, provided that they are used at dosages in the upper end of the therapeutic range.

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