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A Randomized, Placebo-Controlled, Double-Blinded Trial of Duloxetine

MikeJackmin

Senior Member
Messages
132
A Randomized, Placebo-Controlled, Double-Blinded Trial of Duloxetine in the Treatment of General Fatigue in Patients With Chronic Fatigue Syndrome.

Arnold LM1, Blom TJ2, Welge JA2, Mariutto E3, Heller A3.

RESULTS:
The improvement in the Multidimensional Fatigue Inventory general fatigue scores for the duloxetine group was not significantly greater than for the placebo group (P = 0.23; estimated difference between groups at week 12 = -1.0 [95% CI: -2.8, 0.7]). The duloxetine group was significantly superior to the placebo group on the Multidimensional Fatigue Inventory mental fatigue score, Brief Pain Inventory average pain severity and interference scores, Short Form-36 bodily pain domain, and Clinical Global Impression of Severity score. Duloxetine was generally well tolerated.

http://www.ncbi.nlm.nih.gov/pubmed/25660434
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
A small short trial. No effect on fatigue.

CONCLUSION:
The primary efficacy measure of general fatigue did not significantly improve with duloxetine when compared with placebo. Significant improvement in secondary measures of mental fatigue, pain, and global measure of severity suggests that duloxetine may be efficacious for some chronic fatigue syndrome symptom domains, but larger controlled trials are needed to confirm these results.
 

Dolphin

Senior Member
Messages
17,567
I read this. I thought the reporting in the full paper (not necessarily the abstract) seemed reasonably fair, though one could speculate that there was a tendency to favour the drug.

The trial was funded by a drug company.
 
Last edited:

Dolphin

Senior Member
Messages
17,567
TABLE 4. Most Frequently Reported Treatment-Emergent Adverse Events
I just counted: there were 131 instances in the Duloxetine group (n=29) versus 62 in the placebo group (n=30).

Another way of doing it. There were 23 times adverse events were higher in the Duloxetine group versus 3 in the placebo group (I counted any within one percentage of each other as being no different: there were 3 of them). (I'm not talking about statistically significant differences, just the full list).
 

Dolphin

Senior Member
Messages
17,567
Some of the exclusions:

patients who, in the opinion of the investigator, were refractory to treatment or whose response was likely to be compromised by existing or future disability compensation issues;

patients who were judged before randomization to be at suicidal risk by the clinical investigator
So some (or a few) people who might not respond or who might have adverse reactions are excluded
 

Dolphin

Senior Member
Messages
17,567
The baseline mean SF-36 physical functioning scores for the duloxetine group was 63.1. According to the PACE Trial investigators (though not most other people) they were already "back to normal"/had normal physical functioning!
 

Dolphin

Senior Member
Messages
17,567
It took a lot of work to do this trial:

More than 600 potential study patients were prescreened by phone. A total of 104 patients were scheduled and screened to identify 60 who met the entry criteria. The reasons for failure on screening were as follows: did not meet the CDC criteria for CFS (n=24), most of whom (17 [71%] of 24) had exclusionary psychiatric diagnoses, lost to follow-up after the screening visit (n=8), patient decision to discontinue after the screening visit (n=6), unstable medical conditions (n=3), inability to discontinue excluded medications (n=2), and MFI general fatigue scoreo13 (n=1).

It took 6 years to complete this study because of difficulty in identifying eligible patients who met the CDC criteria for CFS and other study criteria.
 

Dolphin

Senior Member
Messages
17,567
During the 12-week therapy phase, 12 patients (20%) withdrew, 10 (33.3%) from the duloxetine group and 2 (6.7%) from the placebo group (P=0.02 by the Fisher exact test) (Figure 1).
 

Dolphin

Senior Member
Messages
17,567
One patient's treatment group assignment was unblinded owing to a serious adverse event of suicidal ideation and the efficacy data from this patient, who had been randomized to duloxetine, were not included in the modified intent-to-treat analysis.
 

Dolphin

Senior Member
Messages
17,567
Safety
Of the 60 randomized patients, a total of 3 patients discontinued the study during the therapy phase because of adverse events, with no significant differences between treatment groups (3 in the duloxetine group [10%] and 0 in the placebo group; P=0.24 using the Fisher exact test) (Figure 1). One patient who discontinued during the therapy phase reported suicidal ideation, which was assessed as being a serious adverse event and possibly related to duloxetine treatment. The patient did not have any suicidal behavior and did not require hospitalization. The ideation resolved after discontinuation of duloxetine. Other adverse events associated with discontinuation in the duloxetine-treated patients included somnolence (n=1) and constipation (n=1).
 

Dolphin

Senior Member
Messages
17,567
Duloxetine-treated patients reported nausea, somnolence, dizziness, and dry mouth significantly more frequently than placebo treated patients did. Headache was reported by significantly more placebo-treated patients than those on duloxetine (Table 4). There were no significant differences in weight change or vital signs between duloxetine- and placebo-treated patients from baseline to endpoint. Most treatment-emergent adverse events were mild to moderate in severity. There were no clinically important findings in the laboratory results or physical examinations.
2 reported weight gain in the duloxetine group versus none in the placebo group. This was a short trial (12 weeks); a longer trial might find more reports.

Here's what Wikipedia says on adverse effects https://en.wikipedia.org/wiki/Duloxetine#Adverse_effects:

Adverse effects[edit]
Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients.[34]

In a trial for major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group.[35] In a long-term study of fibromyalgia patients receiving duloxetine, frequency and type of adverse effects was similar to that reported in the MDD above. Side effects tended to be mild-to-moderate, and tended to decrease in intensity over time.[36]

Sexual dysfunction is often a side effect of drugs that inhibit serotonin reuptake. Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm). Loss of or decreased response to sexual stimuli and ejaculatory anhedonia are also possible. Frequency of treatment-emergent sexual dysfunction in long-term treatment has been found to be similar for duloxetine and SSRIs when compared in clinical trials,[37][38] while there is some evidence that duloxetine is associated with less sexual dysfunction than escitalopram when measured at 4 and 8 weeks of treatment.[38]

Postmarketing spontaneous reports[edit]
Reported adverse events which were temporally correlated to duloxetine therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatitis, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens–Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.[39]

Discontinuation syndrome[edit]
Further information: SSRI discontinuation syndrome
During marketing of other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. The withdrawalsyndrome from duloxetine resembles the SSRI discontinuation syndrome.

When discontinuing treatment with duloxetine, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. The use of a liquid form of the drug may facilitate more gradual tapering."[40]

In placebo-controlled clinical trials of up to nine weeks' duration of patients with MDD, a systematic evaluation of discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.[41]

Suicidality[edit]
The FDA requires all antidepressants, including duloxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.[42][43][44]

To obtain statistically significant results the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications. As suicidal ideation and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance.

In 2005 the United States FDA released a public health advisory noting that there had been 11 reports of suicide attempts and 3 reports of suicidialty within the mostly middle-aged women participating in the open label extension trials of duloxetine for the treatment of stress urinary incontinence. The FDA described the potential role of confounding social stressors "unclear". The suicide attempt rate in the SUI study population (based on 9,400 patients) was calculated to be 400 per 100,000 person years. This rate is greater than the suicide attempt rate among middle-aged U.S. women that has been reported in published studies, i.e., 150 to 160 per 100,000 person years. In addition, one death from suicide was reported in a Cymbalta clinical pharmacology study in a healthy female volunteer without SUI. No increase in suicidality was reported in controlled trials of Cymbalta for depression or diabetic neuropathic pain.[45]
 

Dolphin

Senior Member
Messages
17,567
In trials of duloxetine in patients with fibromyalgia, a disorder that has overlapping features with CFS, 4 the efficacy of duloxetine vs placebo on improvement in secondary measures of fatigue, as measured by the MFI, has been inconsistent. 24–26 The reasons for the inconsistent effect of duloxetine on specific domains of fatigue as measured by the MFI in fibromyalgia trials are unclear but may be related to differences in individual study design or possible differential effects of duloxetine on dimensions of fatigue. Notably, improvement in the MFI mental fatigue score was a consistent finding across the duloxetine fibromyalgia trials and is similar to the significant improvement in mental fatigue in patients with CFS in the present study.
Of the other 4 MFI subscales, there was no difference on "reduced activity" and the results were better (though none approached significance) on the other three.
 

Dolphin

Senior Member
Messages
17,567
Duloxetine was also significantly superior to placebo on secondary efficacy measures of pain including the Brief Pain Inventory average pain severity and average pain interference scores and the SF-36 bodily pain domain. In addition, the Clinical Global Impression of Severity score was significantly improved in the duloxetine group compared with the placebo group. The efficacy of duloxetine on symptoms of pain associated with CFS is consistent with its known efficacy in several chronic pain disorders: duloxetine is approved by the US Food and Drug Administration for the management of pain associated with diabetic peripheral neuropathy, management of chronic musculoskeletal pain, and management of fibromyalgia. 27 Dysfunction of serotonin and norepinephrine transmission, which mediate endogenous analgesic mechanisms via the descending inhibitory pain pathways in the central nervous system, may play a key role in pain symptoms associated with several chronic pain disorders. 28 Emerging evidence suggests that changes in descending modulatory pathways may also be involved in the development of chronic pain associated with CFS. 29,30 Duloxetine is hypothesized to reduce pain symptoms associated with CFS and chronic pain disorders by increasing serotonin and norepinephrine neurotransmission in the descending pain inhibitory pathways.
So it does look like it could be a useful drug for pain though this would need to be balanced with the side effects.
 

Dolphin

Senior Member
Messages
17,567
The baseline scores for two SF-36 domains were a lot different (and the difference was statistically significant):
Mental Health: Duloxetine: 71.0 (+/- 14.3) vs Placebo: 55.4 (+/- 20.0)
Role Emotional: 74.1 (+/-33.8) vs 38.3 (+/- 43.1)
(higher scores represent better results/fewer problems).

So hard to make a fair comparison of the differential effects here.

One possible suspicion here is about whether there was proper random allocation. Suicidality is a known possible effect with this drug (it seems) so the investigators and/or the drug company ideally wouldn't like to have any such cases from the drugs.