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