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Clinical and Research News
Antidepressants Show Promise In Pain Management
Psychiatric News
Volume 41 Number 5 page 30-31

Psychiatrists have long been interested in pain and pain treatment because pain and depression, as well as pain and anxiety, often go hand in hand. This interest grew during the latter half of the 20th century with the discovery that the tricylic antidepressants could counter various types of pain. Yet psychiatrists' interest in pain and pain treatment waned somewhat during the 1980s and early 1990s, when it became clear that the SSRI antidepressants were not as effective in treating pain as the tricyclics were.

In 1997, however, a new class of antidepressants made its debut on the American market—the combined selective serotonin-norepinephrine reuptake inhibitors (SNRIs). These drugs act on both serotonin and norepinephrine, as the tricylic antidepressants do, but without the latter's side effects. Specifically, the Food and Drug Administration (FDA) approved the SNRI venlafaxine in 1997 for the treatment of depression, and in 2004 approved the SNRI duloxetine not just for depression, but also for peripheral nerve pain in diabetics. Duloxetine, in fact, is the first drug approved to treat this condition, and it appears to be the first psychotropic drug that the FDA had approved for treating pain of any kind.

These developments have once again ignited psychiatrists' interest in pain and pain management. They have also set the stage for this question: Could the SNRI antidepressants counter other kinds of pain besides peripheral neuropathy in diabetics? Preliminary research findings suggest that the answer is yes.

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"Fibromyalgia is a funny disorder," Jordan Karp, M.D., a physician investigator at the University of Pittsburgh's John A. Hartford Center of Excellence in Geriatric Psychiatry, explained during a recent interview. "When joints and nerves and muscles from fibromyalgia patients are biopsied, there is no pain pathology. These are patients who hold onto pain in their brains differently from other folks; they don't let go of the pain they experience. So it is really a problem of central pain processing rather than of neuropathic pain, musculoskeletal pain, or visceral pain."

Nonetheless, there is ample evidence that the SNRIs can combat such pain. For example, Leslie Arnold, M.D., an associate professor of psychiatry at the University of Cincinnati, and colleagues conducted a 12-week trial to assess the efficacy and safety of duloxetine in countering fibromyalgia in individuals with or without current major depressive disorder.

About a fourth of the 354 women subjects had a current major depressive disorder. The subjects were randomly placed in three groups: one group received 60 mg of duloxetine daily, the second group received 60 mg twice daily, and the third group received a placebo. The researchers used the Brief Pain Inventory to assess subjects' pain both at the start and end of the study.

The researchers found that 55 percent of the subjects who had received 60 mg of duloxetine daily and 54 percent of the subjects who had received 120 mg of duloxetine daily were treatment responders—that is, they had experienced at least a 30 percent reduction in pain during the study—compared with a third of subjects receiving a placebo. Moreover, duloxetine was found to be well tolerated.

Thus, duloxetine appears to be both "effective and safe in the treatment of fibromyalgia in female patients with or without major depressive disorder," Arnold and her group concluded in their report, which is in press with the journal Pain.

Eli Lilly and Co., the manufacturer of duloxetine, is also researching the drug's potential for countering fibromyalgia pain, Tamara Hull, a senior communications associate at Lilly, told Psychiatric News. The company announced in December 2005 that its duloxetine-fibromyalgia research has now entered phase III testing.

Yet another SNRI antidepressant—milnacipran—is being developed for the treatment of fibromyalgia by Cypress Bioscience Inc. in San Diego. As Sabrina Johnson, chief financial officer of Cypress Bioscience, informed Psychiatric News, its first phase III trial pitting milnacipran against fibromyalgia pain did not reach statistical significance, but it was close to it, so the company is now conducting two more phase III trials to explore the drug's potential in countering fibromyalgia pain.

Currently, there are no FDA-approved treatments for fibromyalgia. Thus, if an SNRI antidepressant were to be approved by the FDA for such treatment, Arnold pointed out, it "would increase therapeutic options for patients, potentially reducing the morbidity associated with fibromyalgia, and improve clinician awareness and recognition of fibromyalgia."

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The SNRIs may also have the capacity to prevent migraine headaches, a Turkish study reported in the February 2005 Journal of Head and Face Pain suggests.

Suleyman Ozyalcin, M.D., an associate professor of anesthesiology at Istanbul University, and colleagues conducted what appears to be the first randomized, double-blind, placebo-controlled trial to determine whether the SNRI venlafaxine might be able to prevent migraines. Sixty subjects who were prone to migraine headaches without aura were randomly assigned to receive 75 mg daily of venlafaxine, 150 mg daily of venlafaxine, or a placebo for two months. The frequency of migraines they experienced during that period were monitored. The group receiving 150 mg daily of venlafaxine experienced significantly fewer migraines than did the placebo group.

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The SNRIs' potential for countering back pain is likewise being explored. The Department of Veterans Affairs launched a study in June 2005 to determine whether venlafaxine counters chronic neuropathic pain following spinal-cord injury. Although a number of medications have been used to treat such pain, no drug has been consistently helpful.

Craig Nelson, M.D., director of geriatric psychiatry at the University of California at San Francisco, and colleagues conducted a study on 90 subjects aged 55 years or older who had a major depressive disorder to determine whether duloxetine could combat not just depression, but also associated pain symptoms. As they reported in the March 2005 American Journal of Geriatric Psychiatry, "60 mg daily of duloxetine was significantly better than a placebo in not just countering depression, but in reducing pain, including back pain."

Karp and his coworkers will soon conduct a trial to explore novel approaches to treating older adults who have both depression and chronic back pain. The approaches will consist of combining social interventions—say, help from a partner or friend—with medications, and one of the medications that will be tested is an SNRI antidepressant.

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The SNRI antidepressants might be able to quell neuropathic pain arising from a number of sources, Rollin Gallagher, M.D., a psychiatrist and director of the Center for Pain Medicine Research and Policy at the University of Pennsylvania, speculated in an interview. For instance, they might be effective against neuropathic pain due to a herniated disc, radiation and chemotherapy treatment, toxic exposure, or postherpetic neuralgia.

The SNRI antidepressants might also be able to counter tension headaches and the pain of irritable bowel syndrome, Johnson suggested. In fact, she added, the types of pain that the SNRIs are capable of subduing may well be the same types of pains that the tricyclic antidepressants counter since the SNRIs and some of the tricyclics have similar norepinephrine-serotonin reuptake profiles.

To really harness the SNRIs' pain-fighting abilities, of course, scientists need to better understand how they work in this domain. And fortunately here, too, some research is taking place. For example, the analgesic and antidepressant effects of the SNRIs were thought to be inseparable, meaning that if a patient received an analgesic effect, it was because of the antidepressant effect. However, David Fishbain, M.D., a professor of psychiatry at the University of Miami, has now found that the two effects are entirely separate, and, as he told Psychiatric News, "the analgesic effect actually occurs before the antidepressant effect." He has submitted these findings to the journal Pain.

While the ultimate pain-fighting potential of the SNRIs is not known, the clinical implications could be substantial.

"The SNRIs will have an important role in the management of chronic pain disorders," Arnold predicted. "Both serotonin and norepinephrine are involved in the regulation of pain perception through the descending pain inhibitory pathways. The SNRIs, by increasing serotonin, and norepinephrine-mediated neurotransmission, might enhance pain inhibition."

"I've seen in patients with diabetic peripheral neuropathy and in some fibromyalgia patients both duloxetine and venlafaxine being helpful," said Karp. "I certainly think they have a role to play in pain management, particularly for patients with diabetes and fibromyalgia."

"I think the recent publications about the SNRIs will increase interest among psychiatrists, especially those treating older patients and medically ill patients, in the treatment of pain occurring in depression," Nelson said.

"The treatment of pain is not a one-medication treatment; it is using medications that affect a number of different parts of the pain-perception system," Gallagher explained. "So the SNRI antidepressants will probably have a growing role in this treatment." ▪

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