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14 Articles in Volume 18, Issue #2
Ask the Expert: Is there evidence to prescribe cyclobenzaprine long-term?
Challenging the Chronic Pain Personality Profile
Designer Peptide May Prevent Chemo-Induced Neuropathy
Inside the Cancer Pain Research Consortium
Intrathecal Drug Therapy for Cancer-Related Pain
Managing Cancer Pain in an Era of Modern Oncology
Mapping Complex Pain: A Case Study
Medication Overuse Headache: Inaccurate and Overdiagnosed
Pain and Fall Risk in the Elderly
Reporting Quality of Care in Cancer Pain Management
Sharing the Risk: An Update to DEA & Doctors Working Together
The Intensifying Conflict Between Opioid Control and Pain Control
Two Mobile Apps Aim to Target Patient Compliance & Safety
Why Prescribers Need to Adopt Abuse-Deterrent Opioids

Ask the Expert: Is there evidence to prescribe cyclobenzaprine long-term?

Long-term use of cyclobenzaprine requires further study to confirm its efficacy.

Cyclobenzaprine is a commonly prescribed oral skeletal muscle relaxant for the treatment of painful musculoskeletal conditions.1 Several studies have shown favorable evidence in using cyclobenzaprine to treat various muscular conditions, including fibromyalgia, neck pain, and lower back pain.2,3 Most studies evaluating the efficacy and safety of cyclobenzaprine were indicated for short-term use (< 20 days).1-3 There are limited data for longer term use (> 21 days) of cyclobenzaprine for conditions of fibrositis and fibromyalgia.3,4 Data from these studies may be difficult to extrapolate use of cyclobenzaprine for other chronic pain conditions, but more studies evaluating efficacy and safety for long-term use in various conditions have emerged.5

Potential Pain Applications for Cyclobenzaprine

A very low dose, sublingual (SL) formulation of cyclobenzaprine is under development by Tonix Pharmaceuticals (New York, NY). This formulation is thought to increase the rate of absorption, compared to an oral tablet, and bypass first-pass metabolism in the liver.5

Cyclobenzaprine is structurally similar to tricyclic antidepressants, which may help predict its potential long-term use in various neurological conditions, such as fibromyalgia and mood imbalances.6 Common adverse effects that may limit or challenge long-term use of cyclobenzaprine include somnolence, dry mouth, and dizziness.1 From a case report, the authors suggested that due to cyclobenzaprine’s tricyclic properties, it may also be associated with symptoms of serotonin-syndrome when combined with potentiating drugs.7 Currently, SL, very low dose cyclobenzaprine is being studied in patients with fibromyalgia and post-traumatic stress disorder (PTSD).5

In a separate double-blind study,8 patients with fibromyalgia were assessed for efficacy of very low dose cyclobenzaprine in relieving pain symptoms and sleep dysfunction over eight weeks. Thirty-six patients (97% women) were randomized to either receive 1 mg or 4 mg of cyclobenzaprine once nightly or placebo. Symptoms of pain, tenderness, fatigue, moods, and sleep physiology were evaluated from baseline to two months. Pain, fatigue, and tenderness were measured using seven point ordinal scales (0 to 6) with 6 being the worst possible discomfort. Sleep physiology was analyzed with sleep electroencephalography (EEG). Mean pain scores decreased from 2.3 to 1.7 in the cyclobenzaprine group against no change in patients in the placebo group. Overall, patients in the cyclobenzaprine group experienced improvements in pain scores.8

The Hospital Anxiety and Depression (HAD) scale, a 14-item questionnaire assessing depression and anxiety, produces a score ranging from 0 to 42. Higher scores have been associated with an increased incidence of depression and anxiety. Patients in the cyclobenzaprine group saw a decrease from 13.7 to 10.4 in mean HAD scores compared to 15.7 to 15.1 among those receiving placebo.8 Of the 18 patients analyzed in the very low dose cyclobenzaprine treated group, seven (39%) experienced headache, six (33%) experienced dry mouth, and four (22%) experienced somnolence versus three (17%), one (6%), and two (11%) receiving placebo, respectively. No serious adverse events were reported.8

Fibromyalgia and Very Low Dose Sublingual Treatment

Another blinded study, BESTFIT,9 was conducted to evaluate the efficacy and safety of sublingual, very low dose cyclobenzaprine (2.8 mg) versus placebo in patients with fibromyalgia. A total of 205 patients were randomized to receive either cyclobenzaprine or placebo at bedtime. A majority of the patients were female (95.1%). All measures were followed from baseline to 12 weeks. The primary outcome measures were mean change in daily pain scores (weekly average). Patients reported their daily pain score on a numerical rating scale (NRS) from 0 to 10. Secondary outcomes included a 30% responder analysis of pain scores, change in sleep disturbance, patient global impression of change and fibromyalgia impact questionnaire scores.9

Patient global impression of change (PGIC) was assessed using a seven-point scale (1=very much improved; 2=much improved; 7=very much worse) to assess patient perception of change in symptoms. A fibromyalgia impact questionnaire (FIQ-r) score, consists of three domains: functional, overall, and symptoms. The researchers asked 21 questions evaluated on an 11-point NRS (0 to 10 with 10 being the worst). A mean reduction in pain for the cyclobenzaprine group was reported at 1 (SD + 2.57) versus a decrease of 0.95 (SD + 2.74) with placebo.9

Secondary outcome results indicated that 35 patients (34%) from the cyclobenzaprine group showed at least a 30% improvement in pain scores compared to 21 (20.6%) patients receiving placebo. For every eight patients who received the cyclobenzaprine, one patient appeared to experience at least a 30% improvement in their pain score versus placebo. The number of patients in the cyclobenzaprine group whose PGIC score was one or two (30.1% versus 16.7% with placebo). FIQ-R scores in the cyclobenzaprine group decreased by 15.59 points versus 8.54 with placebo, indicating better improvement of symptoms but the data was highly variable among the study population.9

Patients in the cyclobenzaprine group experienced more adverse events than those receiving the placebo. The most common side effect in cyclobenzaprine-treated patients was oral hypoesthesia occurring in 45 (44%) patients compared to two (2%) patients receiving placebo. Patients that completed this study were given the option to participate in an extension study to evaluate long-term safety.9 No statistical analyses were provided for outcomes.

Prescribing Cyclobenzaprine for Fibromyalgia Challenged by Hypoesthesia

Findings from a 12-month, open-label trial reported on the long-term safety and efficacy of sublingual, very low dose cyclobenzaprine in patients with fibromyalgia.10 This study was an extension of the BESTFIT trial in which researchers evaluated primary outcome measures of adverse events based on severity and relationship to medication. Secondary outcomes included change in pain scores from baseline and responder analysis. Patients who completed the initial trial (n = 158) received 2.8 mg of cyclobenzaprine at bedtime in this study. Participants were unaware of which therapy they had received in the BESTFIT trial. A total of 79 patients had previously received placebo, and the same number had received cyclobenzaprine.

At 12 months, a similar number of patients reported at least one new adverse event among both groups. However, 18 of the 79 (23%) versus 9 of the 79 (11%) withdrew in the placebo-cyclobenzaprine and cyclobenzaprine-cyclobenzaprine groups, respectively. There was no difference in secondary outcomes except in responder analysis (PGIC). The mean change from baseline in NRS assessments of average pain based on 24-hour recall are described in Table I.

More patients from the cyclobenzaprine-cyclobenzaprine treatment group in both studies reported a PGIC score of either 1 or 2 (40.5% vs. 21.5%) at 12 months. Serious adverse events were reported by 6% of the cyclobenzaprine-cyclobenzaprine group versus 4% of the placebo-cyclobenzaprine group. The most common adverse event from the cyclobenzaprine-cyclobenzaprine group was sinusitis (12.7% vs. 1.3%), and from the placebo-cyclobenzaprine group oral hypoesthesia (27.9% vs. 1.3%).10 No statistical analyses were provided for any outcomes. Based on these results, no efficacy was noted for long-term use, while side effects were frequently reported.10

Lastly, a multicenter, randomized, double-blind study evaluated the efficacy and safety of sublingual, very low dose cyclobenzaprine (5.6 mg) versus placebo in patients with military-related PTSD.11 The primary outcome was mean change of a clinician-administered PTSD scale. Secondary outcome measures were assessment of disruptions of social life/leisure activates, school/work activities, and quality of sleep using the Sheehan Disability Scale. All measures were assessed at 12 weeks. Patients meeting inclusion criteria were those with a diagnosis of PTSD consistent with the Diagnostic Symptoms Manual (DSM-5) criteria.12 The study is currently recruiting patients with an anticipated competition of October 2018.11

Efficacy Remains Uncertain

Although cyclobenzaprine is commonly used in the acute setting of musculoskeletal conditions, a new formulation—a very low dose sublingual formulation—is under consideration for long-term use in symptom control of fibromyalgia and is being studied for PTSD. Adverse effects of long-term use are similar to short-term use of oral cyclobenzaprine. Studies for sublingual use shows it may also be associated with hypoaesthesia, which was more predominant during the first 12 weeks of use but can limit its use.

Long-term use of sublingual very low dose cyclobenzaprine (12 months) shows it does not maintain effectiveness in treating symptoms of fibromyalgia. Ongoing research for use of sublingual, very low dose cyclobenzaprine for symptoms of PTSD is currently under investigation.

Last updated on: April 9, 2018
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