Activating endogenous opioids may not be an effective way to treat chronic pain, according to an experimental study in male rats with chronic- and acute-induced arthritis. Previous research into μ-opioid therapy for arthritis had primarily focused on changes occurring in the hours immediately following tissue inflammation, but the new study is among the first to examine the impact of μ-opioid therapy on chronic inflammation.

It was hoped that the discovery of endomorphin 1 could circumvent the therapeutic drawbacks of exogenous substances such as morphine due to its greater selectivity for the μ-opioid receptor. But the new findings, which appear in the October issue of Arthritis & Rheumatism¹, suggest that injections of endomorphin 1 have no observable effects on chronic pain. Injection of endomorphin 1 reduced knee joint afferent nerve activity in response to noxious rotation of the knee by about 75% in normal knees and by just over 50% in knees with adjuvant-induced arthritis of 48 hours duration, the authors report. These findings are based on extracellular electrophysiologic recordings from knee joint afferent fibers as well as immunohistochemistry and molecular biology.

"These observations highlight a possible inadequacy of the endogenous opioid system to alleviate chronic arthritis pain," conclude the researchers, led by Jason J. McDougall, PhD, a professor in the department of physiology and biophysics at the University of Calgary in Alberta, Canada. "By offering clear insights into the [ineffectiveness] of μ-opioid therapy, this study suggests the need for rethinking the best use of endomorphin 1 and redirecting pain management research toward more promising alternatives for long-term arthritis sufferers."
 
Results will yield better understanding of opiates in arthritis

Calling this a "nicely conducted study," Sean Mackey, MD, PhD, associate director of the pain management division at Stanford University School of Medicine in California, says that "the results may help us to better understand the efficacy of opiates in acute joint inflammation, but reduced benefit in chronic arthritis."
 
While the results were disappointing, "any time we can get a better understanding of the mechanisms responsible for chronic pain, the better off we are," Dr. Mackey says. "It will help us to eventually design better therapeutic agents."
 
When asked by CIAOMed whether the new findings would be reproducible in humans, he explains that animal studies are generally used "to guide us to where we need to go in humans, and while many times the results hold in humans, occasionally they do not. This is a nice first step that will lead to several other studies to confirm these results and extend them."

More study needed

In an editorial accompanying the new study, Zsuzsanna Helyes, MD, PhD, of the department of pharmacology and  pharmacotherapy at the University of Péc in Hungary, writes that the new study results "indicate that the effects of endomorphin 1 decrease as arthritis progresses into the chronic phase and highlight a potential inadequacy in the ability of the endogenous opioid system to inhibit joint inflammation and consequent pain."

Because of this, Dr. Helyes says, "the therapeutic value of peripheral μ-opioid receptor agonism in chronic arthritis and consequent pain should be viewed with caution, and further investigations are needed to elucidate its real clinical significance." Dr. Helyes points out that the new findings contradict older studies.                                     

References

1. Li Z, Proud D, Zhang C, et al. Chronic arthritis down-regulates peripheral μ-opioid receptor expression with concomitant loss of endomorphin 1 antinociception.  Arthritis Rheum. 2005;52:3210-3219

2. Helyes, Z. Role of peripheral μ-opioid receptors in arthritis: Are they potential targets for therapy? Arthritis Rheum. 2005;52:2955-2959.