Paroxetine-CR (Paxil-CR) in the Treatment of Patients With Fibromyalgia Syndrome
Condition: Fibromyalgia Syndrome
MeSH terms: Fibromyalgia; Myofascial Pain Syndromes; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      Objective: Although there is a high comorbidity of depressive and/or anxiety disorders with
      fibromyalgia, information on the clinical implications of this comorbidity is limited. We
      investigated whether a history of depressive and/or anxiety disorders was associated with
      response to treatment in a double blind, randomized, placebo controlled trial of paroxetine
      controlled release (CR) in fibromyalgia.

      Method: One hundred and sixteen fibromyalgia subjects were randomized to receive paroxetine
      CR (dose 12.5-62.5 mg/day) or placebo for 12 weeks. The Mini International Neuropsychiatric
      Interview (M.I.N.I-plus) was used to ascertain current or past diagnoses of depressive and
      anxiety disorders. Patients with current depressive or anxiety disorders were excluded, but
      those with past diagnoses were enrolled in the trial. Subjective depression and anxiety were
      assessed using the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI);
      subjects were excluded if they scored greater than 23 on the BDI. Health Status was
      determined using the 36-Item Short Form Health Survey (SF-36), the Sheehan Disability Scale
      (SDS), the Perceived Stress Scale (PSS) and the Pittsburgh Sleep Quality Index (PSQI). The
      primary outcome was treatment response defined as ≥ 25% reduction in the Fibromyalgia Impact
      Questionnaire (FIQ) score. Secondary outcomes included changes in scores on the Clinical
      Global Impression-Severity and Improvement (CGI-S and CGI-I respectively), the Visual
      Analogue Scale for Pain (VAS) scores and number of tender points.
    

Detailed description: 
      Introduction

      Despite the skepticism of some physicians over the very existence of a condition called
      Fibromyalgia syndrome (FMS), most agree that this is a common condition seen in pain clinics.
      The syndrome is characterized by widespread pain (1) persistent fatigue (2), and non
      restorative sleep (3), and generalized morning stiffness (4). Other syndromes are also
      frequently seen and include headaches, TMJ, irritable bowel syndrome, depression, anxiety,
      paresthesias and memory loss. FMS may be primary or secondary to other disease states.
      Conditions like hypothyroidism may mimic FMS. The prevalence of depression is about 30-35%
      (1). FMS affects more women than men (20:1) and the prevalence increases with age so that
      about 7% of women over 70 years of age are affected compared to the prevalence rate of about
      2% in the general population.

      The diagnosis is based on patients complaints of pain and a clinical examination of multiple
      tender points (11/18) as defined by the ACR criteria for FMS (8) or (11 or less) per
      Copenhagen declaration. There is no specific laboratory test for FMS.

      The causes are unknown, but many investigators believe that FMS encompasses a spectrum of
      diseases with a common pathogenic pathway. Links between FMS and non-restorative deep sleep
      has been reported (2). Other changes frequently seen in FMS patients include elevated
      interleukin-2 (3), low levels of serum serotonin and its precursor tryptophan (4) and
      elevated substance -P levels (5). There has been increasing interest in the effect of
      serotonin on pain in recent years. Serum serotonin levels have been shown to be significantly
      lower in fibromyalgia patients than in those without fibromyalgia (6). Evidence is available
      to suggest that administration of the serotonin precursor tryptophan improves pain symptoms
      in a variety of patient cohorts. (7)

      Treatment is generally multidisciplinary with an emphasis on active patient participation,
      cognitive behavioral therapy, physical modalities and medications. (9). A review of the
      literature reveals that there is no consensus for the pharmacological treatment for FMS. A
      rational polypharmacy is advocated with medications used to improve pain, sleep, fatigue and
      other associated symptoms. (10) Oral agents utilized for symptomatic relief include
      acetaminophen, non-steroidal anti-inflammatory medications, and steroids. Each is associated
      with potentially serious medical sequelae with chronic use, and results have been
      disappointing. Cyclobenzaprine (flexeril) has shown efficacy for FMS though common side
      effects, such as dry mouth and drowsiness, can limit its use. (11) Benzodiazepines and
      opiates, which are also utilized for FMS are potentially addictive. Modafinil (Provigil) has
      been used to treat the fatigue associated with FMS (12). Case reports have indicated the
      usefulness of atypical antipsychotics like olanzapine for the treatment of FMS symptoms (13).
      No one medication has been found to control all the symptoms of FMS and the goal of therapy
      is to improve pain, function and quality of life by combining the least amount of
      medications.

      There have been 21 controlled trials involving antidepressants, most involving tricyclic
      antidepressants. A recent meta analysis revealed that compared to placebo, the effect sizes
      for tricyclic antidepressants were substantially larger than zero for all measurements (14).
      Two randomized placebo controlled trials have examined the SSRI fluoxetine (20 mg per day for
      6 weeks) (15,16) and two have examined the SSRI citalopram (20-40 mg per day for 8 weeks)
      (17, 18) in the treatment of FMS. These studies had equivocal results; but the trials were
      limited by a high dropout rate in the placebo group, a brief trial duration and small sample
      sizes.

      In a more recent study, Wetherhold et al, examined 82 women with fibromyalgia, randomized to
      receive either paroxetine (20 mg/day), nabumetone (2000 mg/day) or a combination of
      paroxetine (20 mg/day) and nabumetone (2000 mg/day). Patient received each treatment regimen
      for a period of 8 weeks. The study demonstrated that the combination regimen was superior to
      nabumetone alone, but not to paroxetine alone, in improving the signs and symptoms of
      fibromyalgia - suggesting that paroxetine was responsible for the improvement in the combined
      regimen (19).

      Thus, a non-addictive oral agent, with dual action (NE and 5 HT reuptake blockade) and a
      relatively benign side effect profile such as paroxetine (Paxil), has the potential to be a
      significant addition to the treatment of FMS. Moreover, paroxetine's side effect profile is
      favorable to tricyclic antidepressants and therefore would likely be a preferable treatment
      option if effective. A recent extended release preparation of paroxetine (Paxil CR) is
      prudentially absorbed in the intestine rather than the stomach and is reported to have a more
      favorable GI side effect profile and may be particularly suitable for the study. The agent
      could be used alone or adjunctively to decrease the patient's requirement for other analgesic
      medications.

      This study proposes to study Paxil CR, a selective serotonin reuptake inhibitor, to treat FMS
      with particular emphasis on its effect on the full constellation of symptoms associated with
      this disorder and quality of life improvement in this patient population.

      In our experience physicians from multiple specialties (family
      medicine/neurology/physiatry/rheumatology/pain medicine/psychiatry) are increasingly
      discussing anecdotal reports of the efficacy of SSRIs in treating FMS symptoms. This study
      protocol is intended to evaluate the efficacy of this practice. It is our hypothesis that
      paroxetine will be shown to be an effective addition to the treatment as defined below.

      Study Design:

      Randomized, double blind, parallel group, flexible dose, placebo controlled 12-week study.

      Subject number: One hundred and twenty five.

      Study Schedule: (see attached schedule of evaluations)

      Patients will be screened for eligibility based on a confirmed diagnosis of FMS (per report
      of rheumatologist or treating specialist). Only those meeting eligibility criteria
      (inclusion/exclusion criteria) will be permitted to give informed consent to enter the study.
      Psychological assessments will be performed using standardized questionnaires at screening,
      baseline and defined time points in the study as described in the schedule of evaluations.
      After a blood draw for routine labs to exclude other potential treatable conditions, and
      pregnancy test (for women), urine testing for illicit drugs and EKG, the participants will
      enter a one- week placebo lead-in period; those that show a less than 25% reduction on FIQ
      will enter the randomization phase. The routine labs will include the CBC with differential,
      SMA-7, liver function tests, thyroid panel, Anti Nuclear antibody (ANA), Rheumatoid factor
      (Rh factor), Anti Polymerase Antibody (APA), C-Reactive protein and Erythrocyte Sedimentation
      Rate (ESR). Patients will be instructed to swallow the tablets whole and not to crush or chew
      them via labels on the medication bottles. Eligible study participants will be randomized to
      either paroxetine or placebo (60 patients in each arm). Those in the active treatment group
      will receive doses of Paxil CR in the following manner: week 1: 12.5 mg per day, week 2: 25
      mg per day, week 3: 37.5 mg per day, wk 4: 50 mg per day and week 5: 62.5 mg per day.
      Patients who do not tolerate higher doses will be maintained on the minimum tolerated dose.
      The placebo arm will be treated identically except for the content of the capsules. The total
      duration of active treatment will be 12 weeks. Patients will be seen weekly for the first 4
      weeks and biweekly thereafter. After the final visit, the study medication will be tapered
      over 2 weeks.

      Unblinding procedures in case of emergency:

      A list of patient randomization numbers and corresponding treatments will be available with
      local Pharmacy. In case of emergency local pharmacy can be called (24 hours) to reveal the
      study assignment of the patients. Once blind is broken, the patient will be immediately
      discontinued from the study but will be evaluated and treated as warranted by their clinical
      condition.
    

Intervention name(s): Paroxetine CR; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Those in the active treatment group will receive doses of Paxil CR in the following manner: week 1: 12.5 mg per day, week 2: 25 mg per day, week 3: 37.5 mg per day, wk 4: 50 mg per day and week 5: 62.5 mg per day.; Same shape Placebo
Other intervention name(s): Paxil CR
Intervention MeSH terms: Paroxetine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Fibromyalgia; Paroxetine