Fatigue, Fibromyalgia, Pain, Sleep
Conditions
Keywords
fibromyalgia, Pain, Sleep, Fatigue
Brief summary
Amrix (Cyclobenzaprine hydrochloride Extended release capsules) is approved by the FDA as a muscle relaxant, indicated for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions. Cyclobenzaprine ER (Amrix TM) has a distinct pharmacokinetic profile providing early systemic exposure and consistent plasma concentration over several hours. Overall, a single dose of Amrix 30 mg is similar to that of cyclobenzaprine immediate release 10 mg three times daily. This ER formula should improve compliance, with similar efficacy and possibly less side effects as is often the case with slower release formulations. There are clinical studies showing that cyclobenzaprine can alleviate pain secondary to Fibromyalgia induced muscle tone. This multi-layered evidence base suggests that cyclobenzaprine may be able to alleviate pain in fibromyalgia. Theoretically in fibromyalgia, pain is interpreted centrally and possibly occurs due to said muscle spasm . Cyclobenzaprine may relieve this pain, thus allowing patients to function better during the day and sleep better at night. Cyclobenzaprine has tricyclic antidepressant structure which may also allow pain signal dampening in the spinal cord as well, similar to amitriptyline which is used off-label for neuropathic pain as well. Fibromyalgia (FM) is an illness that may involve medical, rheumatologic, autoimmune, sleep, endocrine and psychiatric pathology. It is a syndrome of recurrent pain at trigger points. Greater than 90% of these patients will report fatigue as a key symptom as well. There are several investigation lines into the treatment of FM induced pain. Exercise, behavioral therapy, amitryptiline, duloxetine, tramadol, sodium oxybate, pregabalin all have randomized trials and almost all focus on pain. There are very few studies evaluating cyclobenzaprine and none studying to Cyclobenzaprine ER formulation. None evaluate pain reduction, sleep and fatigue improvement. Cyclobenzaprine is a drug with minimal adverse effects (dry mouth, dizziness, fatigue, constipation, somnolence, nausea, and dyspepsia). It may have a safer tolerability profile than some of the FM medications noted above. As cyclobenzaprine is often studied and often added as an augmentation agent to patients' regimens who suffer from acute painful musculoskeletal conditions, the authors feel that cyclobenzaprine would also be effective in this population. The authors wish to conduct a study to determine if cyclobenzaprine ER is safe and tolerable in the treatment of FM induced pain, and secondary fatigue and insomnia. This initial study may allow for continued regulatory studies with this product in FM subjects. The authors propose a double-blind placebo controlled study to determine if cyclobenzaprine ER is safe and effective in reversing FM induced pain, and secondary fatigue and insomnia.
Interventions
DRUGcyclobenzaprine ER (AMRIX)
active drug
DRUGplacebo
matching placebo for cyclobenzaprine ER (AMRIX)
Sponsors
Cephalon, Inc.
State University of New York - Upstate Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
If possible, 60 subjects will be included in this study. * All males/females of any race are eligible if aged between 18 and 65 and * Subjects must speak English and have capacity to receive and utilize informed consent * Agree to use barrier method contraception or are infertile x 2 years due to medical condition or surgery * Have been formally diagnosed by a Board Certified Rheumatologist using the ACR 1990 research criteria for fibromyalgia * Report that pain is a key distressing symptom of their FM * Have a score of \> 4 on the Visual Analogue Pain Scale (VAPS)
Exclusion criteria
Subjects cannot * Be pregnant or be attempting to conceive at present (urine bHCG must be negative) * Have an active substance abuse problem with last use within the past 90 days (outside of nicotine) * Use cardiac QTc prolonging medications i.e., tricyclic antidepressants * Use p4502D6 major inhibiting medications as cyclobenzaprine levels may increase * Have a known medical condition outside of FM that causes pain, i.e., diabetic neuropathy * Have a known medical condition or other medication use that relatively contraindicates cyclobenzaprine use (i.e., hypersensitivity concomitant use of monoamine oxidase (MAO) inhibitors, seizures, known cardiac abnormalities, recent MI. hepatitis, stroke, or psychosis * Has a prior history of cyclobenzaprine use and failure (failure due to side effects may be allowed at P.I. discretion) * Be receiving daytime/nighttime sedating medication with clear chronological impact on fatigue UNLESS fatigue predates sedating medication or said medication has been steadily dosed \> 4 weeks * Other medications known to alleviate pain (i.e., Gabapentin, Pregabalin, Amitryptiline, Duloxetine,Venlafaxine, Carbamazepine, Tramadol, etc) unless they have been at steady dose more than 6 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analogue Pain Scale at 8 Weeks Post Treatment | 8 weeks | Visual Analogue Pain Scale -Change in baseline subjective pain based on a 10 point scale (1= no pain, 10 = severe pain) from baseline (T=Zero, prior to drug/placebo treatment) to week 8. Higher scores are worse |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brief Fatigue Inventory at 8 Weeks Post Treatment | baseline to 8 weeks | Brief Fatigue Inventory- Change in baseline subjective fatigue based on this scale (1= no fatigue, 10 = severe fatigue) from baseline (T=Zero, prior to drug/placebo treatment) to week 8 where higher scores are worse |
| Fibromyalgia Impact Questionnaire Scores at 8 Weeks Post Treatment | from baseline to 8 weeks | Change in baseline subjective fibromyalgia symptoms based on a 100 point scale (0 = no fibromyalgia or minimum score, 100 = severe fibromyalgia and maximal score) from baseline (T=Zero, prior to drug/placebo treatment) to week 8 |
Countries
United States
Participant flow
Recruitment details
radio and billboard ads were used to recruit subjects who were then screened a a psychiatric based practice
Pre-assignment details
subjects had to meet eligibility criteria
Participants by arm
| Arm | Count |
|---|---|
| Cyclobenzaprine ER | 16 |
| Placebo | 12 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 5 |
Baseline characteristics
| Characteristic | Cyclobenzaprine ER | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 12 Participants | 28 Participants |
| Region of Enrollment United States | 16 participants | 12 participants | 28 participants |
| Sex: Female, Male Female | 15 Participants | 10 Participants | 25 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 16 | 1 / 12 |
| serious Total, serious adverse events | 0 / 16 | 0 / 12 |
Outcome results
Primary
Visual Analogue Pain Scale at 8 Weeks Post Treatment
Visual Analogue Pain Scale -Change in baseline subjective pain based on a 10 point scale (1= no pain, 10 = severe pain) from baseline (T=Zero, prior to drug/placebo treatment) to week 8. Higher scores are worse
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cyclobenzaprine ER | Visual Analogue Pain Scale at 8 Weeks Post Treatment | 4.8 units on a scale |
| Placebo | Visual Analogue Pain Scale at 8 Weeks Post Treatment | 5.7 units on a scale |
p-value: 0.869t-test, 2 sided
Secondary
Brief Fatigue Inventory at 8 Weeks Post Treatment
Brief Fatigue Inventory- Change in baseline subjective fatigue based on this scale (1= no fatigue, 10 = severe fatigue) from baseline (T=Zero, prior to drug/placebo treatment) to week 8 where higher scores are worse
Time frame: baseline to 8 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cyclobenzaprine ER | Brief Fatigue Inventory at 8 Weeks Post Treatment | 4.7 score on a scale |
| Placebo | Brief Fatigue Inventory at 8 Weeks Post Treatment | 4.8 score on a scale |
Comparison: Visual Analogue Pain Scale (VAPS). The final visit VAPS at 8th week will be compared against baseline VAPS scores for both treatment groupsp-value: 0.486t-test, 2 sided
p-value: 0.486t-test, 1 sided
Secondary
Fibromyalgia Impact Questionnaire Scores at 8 Weeks Post Treatment
Change in baseline subjective fibromyalgia symptoms based on a 100 point scale (0 = no fibromyalgia or minimum score, 100 = severe fibromyalgia and maximal score) from baseline (T=Zero, prior to drug/placebo treatment) to week 8
Time frame: from baseline to 8 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cyclobenzaprine ER | Fibromyalgia Impact Questionnaire Scores at 8 Weeks Post Treatment | 59 units on a scale |
| Placebo | Fibromyalgia Impact Questionnaire Scores at 8 Weeks Post Treatment | 51 units on a scale |
p-value: 0.869t-test, 2 sided
p-value: 0.275t-test, 1 sided