RENEW OR SUBSCRIBE TO PPM
Subscription is FREE for qualified healthcare professionals in the US.
10 Articles in Volume 8, Issue #6
CES for Mild Traumatic Brain Injury
Duloxetine: A New Indication for the Treatment of Fibromyalgia
Evaluating Pain Intervention Effectiveness and Compliance
Low-level Laser Therapy for Trigeminal Neuralgia
Neurobiological Basis for Chronic Pain
Orbital-Inner Canthus Headache due to Medial Temporal Tendonitis
Pain Care for a Global Community: Part 1
Unraveling the Mysteries of Myofascial Pain Syndromes
Vitamin D for Chronic Pain
‘Head to Toe’ Nonprescription Drug History

Duloxetine: A New Indication for the Treatment of Fibromyalgia

Duloxetine (Cymbalta®, Eli Lilly & Co.) joins pregabalin (Lyrica®, Pfizer, Inc.) as the second drug to gain approval by the FDA for the treatment of fibromyalgia.

In June, the U.S. Food and Drug Administration approved duloxetine, Cymbalta®, as the second prescription medication for the treatment of fibromyalgia. This event offers health care providers more medication options for their patients and gives hope to millions of people for improvement in their pain levels and a better quality of life.

On June 16th, 2008, duloxetine (Cymbalta®, Eli Lilly & Co.) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of fibromyalgia (FM). Only one drug had been previously approved by the FDA for this indication (i.e., pregabalin—Lyrica®, Pfizer, Inc.), a state of affairs that limited treatment options for patients with FM. The approval of duloxetine represents an important milestone in the history of the disorder and affords patients another potential means by which to improve their pain and quality of life.

Fibromyalgia is a chronic pain disorder that affects approximately 2% of the general population.1 According to research criteria established by the American College of Rheumatology, a diagnosis of FM is based on: (1) a self-reported history of widespread chronic pain of at least three months duration that must be present in all four body quadrants; and (2) pain in response to palpation with 4 kilograms of force in at least 11 out of 18 prescribed tender points.2 In addition to pain and tenderness, patients frequently experience a variety of other symptoms, including sleep disturbances, functional bowel disturbances, restless legs syndrome, chronic fatigue, and morning stiffness. The disorder is also associated with an increased incidence of co-morbid anxiety and depression. Recent research has demonstrated abnormalities in brain structure and function, as well as abnormal processing of auditory and thermal stimuli, which has resulted in the development of theories related to multi-system sensory amplification as causative in symptom generation.3,4 FM patients also have abnormalities in norepinephrine, serotonin, dopamine, glutamate, and endogenous opioid concentrations in cerebrospinal fluid.

Clinical Studies

Antidepressants are commonly used to treat FM symptoms and were originally prescribed due to the observation that affective disturbances tend to co-exist in patients with the disorder.5 However, studies have shown that, in addition to their role in mood and affect, serotonin and norepinephrine play an important role in pain modulation.6,7 Accordingly, serotonin-norepinephrine reuptake inhibitors (SNRIs) appear well-suited for the treatment of the chronic pain conditions, including FM. Indeed, studies have indicated that agents capable of dual reuptake are more efficacious than those that inhibit the reuptake of either serotonin or norepinephrine separately.8 Duloxetine, a recently-developed SNRI, thus appeared to represent an ideal candidate for the treatment of FM. Duloxetine had previously been approved by the FDA for the treatment of major depressive disorder, pain diabetic neuropathy and, more recently, generalized anxiety disorder.9 It has also been demonstrated to be an effective analgesic against headache, back pain, stomach aches and regional musculoskeletal pain associated with major depressive disorder,10 and is effective in reducing pain related to diabetic neuropathy in non-depressed patients.11,12 As a dual reuptake inhibitor, duloxetine has almost no affinity for adrenergic, cholinergic, or histaminergic receptors, which reduces the occurrence of side-effects normally seen with the use of tricyclic antidepressants.13,14 The drug has been shown to be a safe and well-tolerated effective antidepressant over the entire clinically-relevant dose range.15-17

Several controlled studies have demonstrated the efficacy and safety of duloxetine in the treatment of FM symptoms. The first of these comprised a study of 207 patients with FM by ACR criteria—with and without comorbid major depression—who underwent an initial forced titration to 60 mg twice a day over a two-week period.18 Outcome measures included the total score and pain sub-score on the Fibromyalgia Impact Questionnaire (FIQ), a 20-item self-report questionnaire that measures the patient’s overall function and symptoms in the past week and includes such items as number of days feeling well, missed work, difficulty with work accomplishment, pain, morning tiredness, fatigue, stiffness, anxiety, and depression.19 Patients in the duloxetine treatment group demonstrated significantly improved FIQ total scores in comparison to those receiving placebo, but the FIQ pain score did not significantly differ between groups. In addition, investigators used the Brief Pain Inventory (BPI) as an additional measure, as well as the average pain interference score. The tender point count and tender point thresholds were measured using standard dolorimeter methods at the 18 tender points defined by ACR criteria. Patients treated with duloxetine had significantly greater improvement in BPI scores across the 12-week study and showed significant improvement in tender point count and mean threshold compared to placebo-treated controls. Patients on active treatment also showed significant improvement on the Quality of Life in Depression Scale, the Patient Global Assessment of Improvement Scale, Sheehan Disability Scale, and the Medical Outcomes Study Short Form (SF-36). Effects of duloxetine appeared to be gender-related, with greater improvement among female patients on most measures compared to placebo-treated controls. The authors speculated that the reason for gender-specific results may have been related to the small number of males in their sample, i.e., only 11% of the study population.

Notably, clinical trials in FM commonly exclude candidates from participation who have psychiatric co-morbidities. However, the study discussed above incorporated patients with and without major depressive disorder (MDD) because the inclusion of MDD in this case was judged to be important to study design given that many FM patients suffer with MDD,5 and medication effects on depression and FM pain have not been widely studied in this population. Notably, duloxetine improved pain in patients with FM regardless of depressive status, and the effects on pain were independent of the effects on mood or anxiety. The authors concluded that duloxetine was well-tolerated with similar numbers of discontinuations of treatment between the placebo and treatment groups due to side-effects, which included insomnia, constipation, and dry mouth at a more frequent incidence than among placebo-treated controls. Adverse events were considered to be mild to moderate in severity.

“Outcomes in the duloxetine-treated group were superior to placebo on quality of life and functional measures, including all domains of the SF-36.”

A second duloxetine study of similar duration evaluated two doses of duloxetine (60 mg once a day and 60 mg twice a day).20 A total of 354 female FM patients were recruited. Patients were titrated to the target dose within a three-day period in contrast to the two-week period in the previous study, which the authors suggested might have accounted for the significantly higher drop-out rate in the treatment group compared to controls. Those treated with duloxetine showed significant decreases in pain scores as well as improvements on all secondary pain measures used in the previous study. The main side-effect reported in the duloxetine treatment group was nausea, and both doses were found to have the same efficacy in treating FM pain. Thus, the authors suggested that a lower starting dose and a slower titration period may be better tolerated.

After pooling data from these two studies, Arnold et al found duloxetine resulted in significantly reduced pain from the beginning of treatment (first week) that continued throughout the three months of therapy.21 Moreover, duloxetine was superior to placebo on all efficacy measures, including mean tender point threshold, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and average interference from pain scores. Outcomes in the duloxetine-treated group were superior to placebo on quality of life and functional measures, including all domains of the SF-36.

In order to evaluate long-term efficacy, Russell and colleagues performed a study comprised of a six-month randomized, placebo-controlled multi-center, double-blind trial that recruited 520 female patients with FM to determine the safety of duloxetine in FM, with and without comorbid major depression.22 Patients received a single daily dose of duloxetine 20 mg, 60 mg, 120 mg or placebo. This study found significant improvements on the BPI at three- and six-month time points in patients receiving 60 and 120 mg/day along with significant improvement on FIQ scores at three months for both doses, and at six months for the 120 mg/day dose. The authors concluded that safety and efficacy had been demonstrated for both doses at up to at six months of treatment.

Treatment Recommendations

The manufacturer’s prescribing information indicates once-daily dose of 60 mg for the indication of FM. Doses are available in capsules containing duloxetine 20, 30 and 60 mg. Treatment is suggested to begin at 30 mg daily for one week, then allowing patients to titrate to 60 mg per day with a re-evaluation suggested four weeks after beginning treatment. Studies do not indicate significant additional benefit in doses higher than 60 mg/day, and higher doses are associated with higher rates of adverse reactions. Some patients may also respond well to starting at 30 mg per day. According to the manufacturer’s package insert, the efficacy of duloxetine for the treatment of FM has been demonstrated for up to three months of treatment with decisions based on longer duration of treatment based on patient’s response to the medication. As noted, the recent study reported by Russell and colleagues demonstrated positive results at up to six months.22 Sufficient data regarding safety in pregnancy are currently lacking; therefore, the manufacturer recommends use in pregnant women only if the benefit justifies potential risks to the fetus. Duloxetine is not currently approved for use in pediatric patients.

Contraindications to duloxetine include concurrent use of monoamine oxidase inhibitors or thioridizine. Duloxetine should not be used by patients with uncontrolled glaucoma. The manufacturer strongly warns about suicide risks with antidepressants. In addition, duloxetine may increase risk of suicidal thinking and behavior in children. Due to possible hepatotoxicity, duloxetine should not be prescribed to patients with substantial alcohol use or those with chronic liver disease, and duloxetine should be discontinued in patients who develop jaundice or other clinically significant liver dysfunction. If the medication regimen must be discontinued, patients should be slowly tapered instead of abruptly taken off of the medication. Discontinuation may result in dizziness, nausea, headache, fatigue, paresthesias, vomiting, irritability, nightmares, insomnia, diarrhea, anxiety, hyperhidrosis, and vertigo. While studies of its abuse potential have not been done in humans, animal studies have not demonstrated this potential. However, physicians should carefully evaluate patients for signs of misuse or abuse, including development of tolerance, increasing dose, and drug-seeking behavior.

The most common adverse reactions included mild-to-moderate nausea, dry mouth, constipation, somnolence, hyperhidrosis, and decreased appetite. These side-effects occurred in ≥5% of the duloxetine treatment groups and at least twice the incidence of placebo patients.

Pharmacology

The manufacturer’s package insert designates duloxetine as a selective serotonin and norepinephrine reuptake inhibitor (SNRI) with a hypothesized mechanism of action located in central pain inhibitory and anxiolytic systems through serotonergic or noradrenergic activity in the CNS. Duloxetine has been demonstrated to be a potent inhibitor of serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine does not to inhibit monoamine oxidase and has no significant affinity for adrenergic, cholinergic, histaminergic, opioid, glutamate, or gamma-aminobutyric acid (GABA) receptors in vitro. Duloxetine’s elimination half-life is 12 hours with a range of 8-17 hours. Pharmacokinetics are reported to be dose proportional over the therapeutic range. Patients normally reach steady-state plasma concentrations after three days of dosing. Hepatic metabolism involving P450 isozymes (CYP1A2 and CYP2D6) is the main mechanism of elimination. When administered orally, duloxetine is well-absorbed with a median two-hour lag until absorption. Maximal plasma concentrations occur six hours after dose, and food does not affect the maximal plasma concentration.

Conclusions

Studies have demonstrated that duloxetine is safe and efficacious for the treatment of FM symptoms thereby providing an additional option for FM patients to improve their health status and quality of life. Given that all patients may not respond to any one particular drug, the approval of duloxetine for the treatment of FM provides an important new tool to pain practitioners for the treatment of their patients that can aid in the treatment of chronic pain irrespective of depression status. However, given that there are currently no specific guidelines as to how best to choose a course of therapy based on patient parameters, clinicians must continue to make decisions based largely on trial-and-error “n-of-1” cases, and multi-disciplinary treatment is generally recommended in order to obtain optimal results.23

Studies investigating the benefits of multi-disciplinary treatment method that include prescription medications such as duloxetine would be helpful in developing specific therapeutic guidelines. Moreover, head-to-head studies comparing approved agents and other medications that have demonstrated efficacy in the treatment of the disorder are indicated to determine whether any one agent may be superior based on such factors as comorbid features or genomic factors. Finally, future studies incorporating poly-pharmaceutical approaches may ultimately be beneficial to determine the efficacy of duloxetine in the treatment of FM symptoms in combination with other medications. These considerations notwithstanding, the approval of duloxetine for the treatment of FM represents a welcome advance by providing an additional means by which to treat this common disorder.

Last updated on: January 28, 2012
close X
SHOW MAIN MENU
SHOW SUB MENU