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Patients with fibromyalgia got no more pain relief from low-dose naltrexone than from placebo in a randomized trial, researchers said, dashing hopes that the opioid receptor antagonist might succeed where others have failed.

In the 99-patient trial, those assigned to naltrexone reported a mean 1.3-point decline in pain intensity after 12 weeks, compared with a decrease of 0.9 points in a placebo group (P=0.27), according to Karin Due Bruun, MD, PhD, of Odense University Hospital in Denmark, and colleagues. Given that pain was rated on an 11-point scale, the difference of 0.4 points would not have been clinically important even if it had achieved statistical significance.

But naltrexone showed signs of providing a genuine benefit for cognition. Patients' ratings of memory problems did improve significantly more in the naltrexone group (-1.4 vs -0.5 points on the 11-point scale, P=0.004), the researchers . "We suggest that future trials investigate this further," Due Bruun's group concluded.

Moreover, the researchers cautioned that the drug could have brought real pain relief to a minority of patients. "[T]here is a risk that clinically meaningful improvements for individual patients can be obscured by small mean group differences," they wrote.

, two researchers agreed with the latter sentiment. Winfried Häuser, MD, of Technische Universität in Munich, and Mary-Ann Fitzcharles, MD, of McGill University in Montreal, noted that "[f]ibromyalgia is a heterogenous condition with a variable intensity of symptoms and disability, and as yet no clearly defined pathophysiological mechanisms for all patients," and therefore "there is no one solution for all."

Naltrexone not only prevents activation of μ-opioid receptors, but also has other effects including blockade of Toll-like receptor 4, seen as a potential player in many of fibromyalgia's myriad symptoms, Häuser and Fitzcharles observed. Low-dose naltrexone has been for many years.

Nevertheless, the pair weren't particularly enthusiastic about naltrexone for this indication. "At this time we recommend that off-label treatment of patients who have responded to low-dose naltrexone should not be terminated," they wrote, "but we recommend against initiating low-dose naltrexone for low-dose naltrexone-naive patients with fibromyalgia pending the results of additional adequately powered studies with distinctive inflammatory and autoantibody patient profiles."

Due Bruun and colleagues organized the new trial, , to provide the first rigorous test of naltrexone for fibromyalgia. Patients were recruited from the Odense area who had received diagnoses of fibromyalgia, confirmed according to American College of Rheumatology criteria during screening. Eligibility also required a baseline pain score of at least 4 on a 10-point scale. Participants were randomized 1:1 to naltrexone in 1.5-mg pills or placebo for 12 weeks. Dosing started at one pill per day and could be escalated to as many as four per day by week 4, at which point dosing was stabilized at the highest tolerated level.

Mean patient age was about 50 and all were women. Mean pain score at baseline was 6.3 out of 10, and ratings of memory problems averaged 5.7 out of 10.

Besides pain intensity and memory, other outcomes included ratings of fatigue, tenderness, sleep quality, anxiety, depression, stiffness, general physical function, and health-related quality of life.

Among these, only memory showed a significant difference, and as Häuser and Fitzcharles noted, it was no longer significant when the statistics were corrected for the multiple comparisons.

Still, roughly one-quarter of the naltrexone group reported a 50% improvement in pain intensity, versus just 14% of the placebo group, which the investigators considered a clinically relevant point to consider in interpreting the overall findings. Due Bruun and colleagues explained that they had powered the trial primarily to detect a 1-point difference in pain intensity, and thus may have been underpowered for other outcomes.

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