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6 Articles in Volume 1, Issue #4
Breaking Down the Barriers of Pain: Part 4
Facing Reimbursement Challenges
Getting Back on Track
Taking the Hurt Out of Pain
The Mind-body Connection
The Neural Plasticity Model of Fibromyalgia Theory, Assessment, and Treatment: Part 2

The Mind-body Connection

Frequently, pain physicians must treat the depression that often accompanies chronic pain.

Pain and depression often go hand in hand, especially for patients who suffer from chronic, long-term conditions that produce unremitting pain. So how is managing depression different in these patients, when it is often a side effect of, yet predominant over the pain?

“The incidence of depression in chronic pain patients is much higher than in the general population,” notes Bill McCarberg, MD. Dr. McCarberg, chairman of the managed care committee and on the board of directors for the American Pain Society, has practiced for more than 20 years, specializing in family practice, geriatrics, and pain management.

“Anywhere between five and seven percent of the general population in the United States suffers from depression that is severe enough to be classified as clinical depression. In the chronic pain population, however, those figures reach as high as 60 percent,” continues Dr. McCarberg.

He goes on to explain that in the 1800s, when patients who were wealthy suffered from depression, the standard treatment was to put them on a boat to set sail around the world and get away from the stresses of life. At that time, it usually took about nine months to make such a trip, and patients often showed marked improved by the time they returned home. “In reality, over the past century, we’ve discovered that depression generally lasts about nine months,” states Dr. McCarberg, “so when I’m treating patients pharmaceutically for depression, I make sure they stay on medication for that length of time. Once they start showing improvement, I begin to ramp down the dosage and see if the improvement continues. However, with patients also suffering from chronic pain, I continue with analgesics for as long as they need them, and some have symptoms for years.”

While Dr. McCarberg sees a limit to the time patients are treated with antidepressants, Martin Fields, MD, indicates that treatment can last for years. “Antidepressants are not short-term medications and can be used for substantial periods of time,” he remarks. “Most of these are benign medications designed for long-term use and have no outer limits.” In addition to being in private practice, Dr. Fields is associate professor of psychiatry at Loyola University in Chicago, Illinois.

Syed Nasir, MD, exclusively treats patients suffering from the chronic pain associated with cancer. “Pain is the number one complaint is these patients,” he notes. “It’s just the nature of the disease.” He continues that the general perception of cancer feeds into and increases the patient’s suffering; patients may have no physical pain, but still suffer from depression. Dr. Syed Nasir is one of the few neuro-oncologists in the country and a member of the staff at Culicchia Neurological Clinic.

To treat the depression associated with chronic pain, all three physicians agree that either tricyclic antidepressants (TCAs) or a newer class of compounds, selective serotonin reuptake inhibitors (SSRIs), are the agents of choice. TCAs include desipramine (known as Norpramin or Pertofrane), nortriptyline (Pamelor, Aventyl), imipramine (Janimine, Tofranil), amitriptyline (Elavil), and doxepin (Adapin, Sinequan, Zonalon). These compounds inhibit the nerve cells’ ability to reuptake norepinephrine, and usually takes from two to three weeks for their effects to become evident. Some compounds are considered to be heterocyclic antidepressants, acting to some degree on both serotonin and norepinephrine.

The SSRIs, on the other hand, selectively inhibit the body’s ability to reuptake serotonin. This class includes citalopram (Cipramil), fluoxetine (Prozac), fluvoxamine (Faverin), paroxetine (Seroxat), and sertraline (Lustral). As with the TCAs, it may take a week or two for effects of treatment to be noticeable. And while the SSRIs are a newer class of compound and may currently be prescribed more frequently than the TCAs, some sources indicate that their popularity may be due more to dosing convenience, an improved safety profile, and aggressive marketing rather than a superiority of efficacy.

In July of 1998, the FDA approved a new, highly selective SSRI, citalopram hydrobromide, sold under the trade name Celexa. Chemically unrelated to other SSRIs, its high selectivity may result in fewer side effects and a lower risk of drug interaction.

Dr. Nasir notes that TCAs should be used with caution in patients with cardiac problems, since they can cause an abnormal heart rate. Dr. McCarberg points out that other side effects of TCAs include dry mouth, constipation, blurred vision, and dizziness, the last two of which can be especially problematic for the elderly and lead to an increased incidence of falls. “Elderly patients have to be started on an escalating dose, because most can’t tolerate a full dosage,” he explains.

Indeed, these physicians agree that any of these drugs should be started at the lowest possible dose and titrated up to the dosage appropriate to treat the patient most effectively with the least likelihood of side effects. “Low doses very often suffice when the depression is associated with a pain syndrome,” observes Dr. Fields. Dr. Nasir notes that antidepressants may have the added benefit of alleviating pain along with the depression because of their soothing qualities, which can be especially true when the pain is of neuropathic origin due to nerve compression. Sometimes he prescribes a sleep aid along with an antidepressant. “Often these patients aren’t sleeping or eating well, all of which causes a vicious cycle. And chemotherapy tends to sap their strength,” he explains, “so I may add something like Ambien to help facilitate sleep.”

Dr. Nasir describes a relatively new approach to treating cancer patients for pain. “We start trying to make the patient comfortable at diagnosis, when only about 25 percent of them are experiencing pain. By the end of life, more than 90 percent are in pain, but we don’t need to wait until then to help them. With aggressive evaluation and treatment of both the cancer and the pain, we can do a better job of addressing this problem as it starts to happen.”

Dr. McCarberg agrees that antidepressants seem to be very effective at also relieving pain, and he sometimes uses a combination of antidepressants. “They seem to have an analgesic effect independent of their antidepressant effects,” he remarks, but he also notes the resistance many patients express to taking antidepressants. “It’s very difficult as a practitioner to convince patients that they’re not weak or crazy — that they have a real condition that can be treated and that there are very good treatments that are available.” He tries to prescribe by targeting the patient’s disability, noting that Prozac, being very energizing, works best when taken in the morning, while Elavil, which is more sedating, works best at night. If anorexia accompanies the patient’s depression, he finds that doxepin helps to stimulate the appetite.

In the past, a third group of antidepressants, monoamine oxidase inhibitors (MAOI), were commonly used to treat depression and anxiety, but after the introduction of TCAs and SSRIs these were prescribed less frequently. MAOIs also have a greater potential for drug-drug interactions with both TCAs and SSRIs.

An article in American Medical News in August 2000 notes that at that time there were more than 100 new drugs in the pipeline for treating a variety of diseases falling under the umbrella of mental illness, including depression and anxiety. With neuroscience research becoming one of the fastest growing fields, pharmaceutical companies are expected to invest around $6 billion in a single year on these types of compounds. Research is targeting new drugs with more specificity of action and fewer side effects, with one new class focused on blocking the action of peptides, rather than neurotransmitters.

One relatively recent entrant to the market of antidepressants is bupropion, which goes under the trade name of Wellbutrin and is also indicated as a smoking-cessation medication (Zyban). Bupropion is neither a TCA nor an SSRI, although its mechanism of action is believed to be related to its ability to inhibit, albeit weakly, norepinephrine, serotonin, and dopamine along with its long-term noradrenergic effects. It falls into a class known as monocyclic aminoketones and is chemically related to phenylethylamines.

Mirtazapine, sold under the trade name Remeron, belongs to a group of compounds known as piperazino-azepines and was approved by the FDA in 1996. Rather than inhibiting the reuptake of serotonin or norepinephrine like TCAs and SSRIs, mirtazapine is believed to increase the release of both of these compounds from nerve cells in the brain. It is also a potent antagonist of 5-HT2 and 5-HT3 receptors-both serotonin receptors, as well as histamine (H1) receptors.

Another compound unrelated to TCAs, SSRIs, and MAOIs is trazodone, a triazolopyridine derivative, which goes by the trade names of Desyrel and Trialodine. It appears to increase the availability of serotonin and can be used to treat any type of depression, as well as some pain syndromes. Another novel compound is venlafaxine hydrochloride, sold under the brand name Effexor XR, an extended-release formulation capsule. Its indications include depression and generalized anxiety disorder.

Serzone (nefazodone), a synthetically derived phenylpiperazine, is another new antidepressant that has shown promising results in patients who do not respond to SSRIs or TCAs. It’s the first in a class of 5-HT2 blockers, and also appears to inhibit the reuptake of serotonin and noradrenaline. In addition, sexual dysfunction, which Dr. McCarberg indicates is seen in up to 40 to 50 percent of patients on antidepressants, is not seen as frequently with nefazodone, and sleep quality may be better than with other antidepressants.

Compounds currently in clinical trials tend to focus on either an increased specificity of action or decreasing side effects or the risk of drug interactions. Sepracor, a Massachusetts-based pharmaceutical company, is testing two drugs that are isomers of Prozac. Efficacy data are promising, with the added benefit of a shorter half-life for the drug, which may make it more suitable for treating both the elderly and adolescents.

Research is targeting new drugs with more specificity of action and fewer side effects, with one new class focused on blocking the action of peptides, rather than neurotransmitters.

Eli Lilly has two compounds in its pipeline for the treatment of depression, duloxetine and OFC — a combination of olanzapine and fluoxetine — with projected launch dates of 2002 and 2003, respectively. Solvay Pharmaceuticals also has a number of antidepressant compounds in its pipeline, including DU125530, a 5-HT1A antagonist, in Phase II trials and SLV308, being tested at earlier stages for depression, panic disorders, and Parkinson’s disease. Solvay discovered the first selective SSRI, Luvox.

Dr. Fields concludes, “patients who suffer depression due to pain have many factors that are involved in its genesis. They can have difficulty in their family relationships, socioeconomic factors, job-related or other stresses.” As research into neuroscience continues, new antidepressant compounds are continually being discovered, and scientists will acquire more and more keys to relieving patients of their suffering.

Last updated on: December 28, 2011
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