Opioids

A recently published study by McGill University researchers (Fitzcharles MA, Ste-Marie PA, Gamsa A, Ware MA, Shir Y) titled, Opioid Use, Misuse, and Abuse in Patients Labeled as Fibromyalgia, underscores the need for confirmatory tests for fibromyalgia and more effective pain treatments.

Fibromyalgia, a condition associated with nervous system dysregulation, is currently a clinical diagnosis based on signs and symptoms.  Like many other diseases and conditions, there is no confirmatory test.
In this study, 457 patients labeled with fibromyalgia in primary care were re-examined by a rheumatologist, but only 66 percent were diagnosed by the specialist. The authors stated that taking into account the new revised criteria for a diagnosis of fibromyalgia, which incorporate symptoms other than pain as components of fibromyalgia, some patients with predominant mood or psychiatric disorder and less prominent physical symptoms may be misclassified as having fibromyalgia.
Even though mood disorder is the strongest associated comorbidity with fibromyalgia, prominent mental illness can masquerade as a pain syndrome and should be recognized. Depression is most often a consequence of inadequately controlled pain.
According to the study, of the 155 people who had been misdiagnosed as having fibromyalgia, 65 of them had a current serious mental health/psychiatric problem – although the authors did not specify either the DSM diagnosis or the severity.
Of the remaining fibromyalgia patients twelve or 3 percent were considered to have drug seeking behaviors.
At entry, 144 (32%) of all patients were on daily opioid medication, with strong opioids such as oxycodone being used by 105 and weak opioids such as tramadol and codeine used by 39. However, of the 302 fibromyalgia patients remaining upon re-examination, 60 were taking strong opioids and 30 weak opioids.
The actual prevalence of opioid use by fibromyalgia patients is largely unknown according to the authors. Another study reported that use of any analgesic other than NSAIDS (medications such as aspirin, ibuprofen and naproxen used primarily to treat inflammation, mild to moderate pain) in 52% of patients.

Although opioids are not approved for use in fibromyalgia (hence this is considered off-label use of drug), the FDA has approved three prescription drugs for pain management in fibromyalgia:

• Lyrica (preglabin – an anti-seizure drug),
• Cymbalta (duloxetine hydrochloride- an antidepressant) and
• Savella (milnacipran HCl – an anti-depressant). The anti-depressants are not prescribed for depression however and are generally prescribed in much lower doses than for depression. According to the FDA, studies of these drugs show that a substantial number of people with fibromyalgia received good pain relief, but there were others who don’t benefit.

However there are very few studies of opiod use in fibromyalgia other than for tramadol.
In this study, the authors (Fitzcharles MA, Ste-Marie PA, Gamsa A, Ware MA, Shir Y) stated that opioid use was more commonly associated with lower education, unemployment, disability payments, current unstable psychiatric disorder, a history of substance abuse, and previous suicide attempts, but did not break out the differences between the two final groups of patients.
According to the Agency for Healthcare Research and Quality, an estimated 12.1 million women age 18 and older reported suffering from chronic pain in 2008 as a result of underlying medical conditions such as chronic fatigue syndrome, endometriosis, fibromyalgia and vulvodynia. Of these women, only 8.7 million reported receiving treatment that year at a total cost of $12.9 billion.

Adrienne Dwello, the guide for the about.com site for fibromyalgia and chronic fatigue syndrome, recently asked patients to comment on their experiences with opioids and garnered 92 comments.

http://trialx.com/curetalk/2011/10/off-label-use-of-opioids-to-treat-fibromyalgia-prevalent-report-mcgill-researchers/

Trazodone plus pregabalin combination in the treatment of fibromyalgia: a two-phase, 24-week, open-label uncontrolled study.

Author: Elena CalandrePiedad Morillas-ArquesRocio Molina-BareaCarmen Rodriguez-lopezFernando Rico-Villademoros
Credits/Source: BMC Musculoskeletal Disorders 2011, 12:95

Although trazodone is frequently used by fibromyalgia patients, its efficacy on this disease has not been adequately studied. If effective, pregabalin, whose beneficial effects on pain and sleep quality in fibromyalgia have been demonstrated, could complement the antidepressant and anxiolytic effects of trazodone.
The aim of the present study was to assess the effectiveness of trazodone alone and in combination with pregabalin in the treatment of fibromyalgia.

Methods:
This was an open-label uncontrolled study.Trazodone, flexibly dosed (50-300 mg/day), was administered to 66 fibromyalgia patients during 12 weeks; 41 patients who completed the treatment accepted to receive pregabalin, also flexibly dosed (72-450 mg/day), added to trazodone treatment for an additional 12-week period. Outcome measures included the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI) the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), the Brief Pain Inventory (BPI), the Short-Form Health Survey (SF-36), and the Patients'Global Improvement scale (PGI).
Emergent adverse reactions were recorded. Data were analyzed with repeated measures one-way ANOVA and paired Student's t test.

Results:
Treatment with trazodone significantly improved global fibromyalgia severity, sleep quality, and depression, as well as pain interference with daily activities although without showing a direct effect on bodily pain.
After pregabalin combination additional and significant improvements were seen on fibromyalgia severity, depression and pain interference with daily activities, and a decrease in bodily pain was also apparent. During the second phase of the study, only two patients dropped out due to side effects.

Conclusions:
Trazodone significantly improved fibromyalgia severity and associated symptomatology.
Its combination with pregabalin potentiated this improvement and the tolerability of the drugs in association was good.Trial registration: This trial has been registered with ClinicalTrials.gov number NCT-00791739.

http://7thspace.com/headlines/382593/trazodone_plus_pregabalin_combination_in_the_treatment_of_fibromyalgia_a_two_phase_24_week_open_label_uncontrolled_study.html

Antiepileptic Drugs for Fibromyalgia Reviewed

April 8, 2011

Fibromyalgia syndrome (FMS) is a difficult-to-treat chronic pain condition with relatively few specifically approved and effective pharmacotherapies. A recent review examined the relative benefits and harms of pregabalin, the only antiepileptic FDA approved for fibromyalgia, and the antiseizure medication gabapentin in the treatment of FMS. However, the evidence supporting their efficacy was somewhat disappointing.
Writing in the Journal of Pain, researchers from the Oregon Health & Science University, School of Medicine, Portland, Oregon, report conducting an extensive literature search for studies of any antiepileptic drug compared with placebo or another antiepileptic agent in a randomized controlled trial (RCT) or observational study [Siler et al. 2011]. Only 8 studies were discovered matching those inclusion criteria: 7 of pregabalin (Lyrica®) that included 2,964 subjects total, and 1 trial of gabapentin (eg, Neurontin® and generics) that enrolled 150 participants. Populations studied included predominantly women aged 47 to 50 years.
Short-term (8-14 weeks), response rates with both drugs at various doses, and reducing mean pain scores by 30% from baseline, were modestly greater than placebo — pregabalin 26% to 50%; gabapentin up to a 51%; compared with 19% to 35% response rates with placebo. [Note: these data are taken from body text of article, which differs from the abstract.] Study withdrawals due to adverse events were significantly greater in pregabalin groups compared with placebo, with relative risks increasing as dose was increased. Gabapentin had similar drop-out rates but not statistically different from placebo (possibly due to the small sample size in this trial).

Compared with placebo, both drugs had greater rates of side effects. Dizziness, headache, somnolence, and edema were the most commonly reported adverse events for both drugs. Dizziness was most common with pregabalin (38%), while headache (27%) was more prevalent with gabapentin. Additionally, weight gain was more common with pregabalin than placebo, whereas sedation and light-headedness occurred more often with gabapentin than placebo.
A follow-up analysis found that about 25% of the pain relief associated with pregabalin was significantly correlated with combined improvements in anxiety and depression. Examination of the impact of other factors such as age, race, gender, and socioeconomic status on the benefits or harms associated with pregabalin or gabapentin was not possible due to narrow inclusion criteria and limited reporting in the studies.
There were important methodological differences between the pregabalin and gabapentin trials and, without head-to-head clinical studies, the authors state it is not possible to conclude if pregabalin or gabapentin is superior. While it appeared that gabapentin was slightly more efficacious, the drug incurred significantly higher rates of headache than pregabalin and it was studied in only a single, small-scale RCT.
The authors believe that results of their review indicate that pregabalin and gabapentin can be used for the treatment of fibromyalgia with moderate benefits in the short-term. However, clinicians must be cautious not to generalize these results to other, unstudied antiepileptic drugs, and the limitations of this evidence with regard to the populations included, durations studied, and the potentials for important differences in adverse effect profiles between the drugs should be taken into account.

COMMENTARY: In a prior UPDATES article we discussed comparisons of pregabalin with duloxetine (Cymbalta®) and milnacipran (Savella®) — both of which are selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants and FDA-approved for treating FMS. All 3 drugs were found to have short-term (up to 6 months) efficacy; although they differed in their adverse effect profiles, with pregabalin appearing to be most advantageous except in patients with depressed mood. There were some limitations of the trials and none compared all 3 drugs head-to-head.
In the present review by Siler and colleagues, the internal validity of the included RCTs was judged as being rather low. This was due to unclear methods of blinding, allocation concealment, and randomization. While the gabapentin trial was government funded, the pregabalin RCTs were supported by the pharmaceutical manufacturer. All of these factors can engender significant bias in research studies, as discussed in our recent UPDATES article on “Making Sense of Pain Research: Part 3.” Both pregabalin and gabapentin were better than placebo in reducing pain in the short-term; however, in absolute terms the magnitude of beneficial effects were limited, with half of patients (at most) experiencing a 30% decrease in pain (while up to one-third had a similar response with placebo). The authors note that the Numbers-Needed-to-Treat, or NNTs, for both drugs were not impressive; specifically, for every 5 patients treated with gabapentin or 8 patients treated with pregabalin (rather than placebo) for 8 to 14 weeks, 1 additional patient would have a response of at least a 30% improvement in symptoms. According to Siler et al., NNTs of 2 to 4 are considered favorable for drug therapies [although their reference source for this assumption is unclear].
Of pregabalin responders, beneficial effects dissipated over time and only about one-third continued to have response at 6 months. While this rate of continued response was better than for those who were switched to placebo, it is still disappointing, the authors believe, considering the long-term duration of FMS symptoms in most patients.
The authors further note that, from an evidence-based medicine perspective, the major components in assessing strength of evidence are: 1) precision of estimates, 2) directness and consistency of evidence, 3) risk of bias, and 4) magnitude of effect. They believe that the overall body of evidence in their review would merit only a low strength of evidence ranking. Furthermore, the clinical applicability (external validity) of the studies was limited by the short duration of all clinical trials and the selective patient population.
A benchmark for therapeutic success in studies to date of antidepressant and antiepileptic agents for FMS appears to be a 30% improvement in symptoms. We have previously described in an UPDATE [here] that 30% to 36% improvements in pain are generally considered by patients as being moderate, with 50% or greater improvements deemed more desirable. This helps to explain why multidrug therapies that combine to increase improvement are commonplace in patients with FMS.
Indeed, Siler and colleagues recommend that better, longer-term comparative trials are needed, which adopt a more “pragmatic” design. That is, including large numbers of patients, with a wide variety of baseline symptoms and comorbidity, and taking multiple medications. However, such “real world” trials can be extremely difficult to construct, conduct, and interpret. And, as we have noted before, pharmacotherapy is only one piece of the puzzle when it comes to successful management of FMS, which often benefits more from multimodal approaches as part of a comprehensive pain management program.
http://updates.pain-topics.org/2011/04/antiepileptic-drugs-for-fibromyalgia.html

Treating Fibromyalgia in Teens and Children

A team of specialists works together to treat fibromyalgia in children and teens. This team can include a:

• Pediatric rheumatologist (a doctor who specializes in treating children with arthritis and other rheumatologic diseases)
• Psychologist
• Physical therapist

Though there currently is no cure for fibromyalgia in children (or adults), several good treatments are available to help manage its symptoms, including:
Coping strategies.One of the most effective ways to treat fibromyalgia in teens and children is by using coping strategies to manage the pain. A technique called cognitive behavioral therapy helps children with fibromyalgia learn what triggers their pain and how to deal with it. It's very helpful for improving kids' ability to function, and relieving their depression. Other behavior-based approaches to treating fibromyalgia include muscle relaxation and stress-relieving techniques (such as deep breathing or meditation).
Medication. Medications may be used to treat adults with fibromyalgia. Rheumatologists may try some of these same medicines in children. However, the safety and effectiveness of fibromyalgia drugs isn't as well studied in children as in adults.
Exercise. Exercise is an important part of fibromyalgia treatment. Children with fibromyalgia who stay active tend to have less intense pain and less depression. A physical therapist can show kids the best exercises for fibromyalgia and can teach them how to ease into an exercise program gradually so they don't get injured.
Physical therapy. Physical therapy and massage can ease some of the muscle soreness that children with fibromyalgia experience.
For teens and children who are struggling with fibromyalgia, these treatments can bring help and hope. Getting enough rest and exercise and relieving stress can help control fibromyalgia so that kids with the condition can stay symptom-free over the long term.
http://www.webmd.com/fibromyalgia/guide/fibromyalgia-in-children-and-teens?page=2