Pain and Depression: The National Pain Foundation: My Treatment

The following article is adapted from a lecture given by NPF Board member Dr. Michael W. Loes.

Pain and Depression

Pain is an individually unpleasant sensory, emotional and perceptual experience caused by actual tissue damage or described in terms of such damage (IASP, 1979, modified). Depression also is an individually unpleasant experience causing intensely unpleasant emotional and perceptual signals.

Muscle and Bone Pain
The treatment of pain typically deals with treating acute and chronic inflammation of bones and muscles (ie, bone and muscle pain). The Latin word nociceptive often is used when describing this type of pain. Traditionally, anti-inflammatory agents are used to treat bone and muscle pain. Many of these drugs are familiar to us—ibuprofen (Advil), naproxen (Aleve), and the more expensive, newer COX-2 inhibitors such as celecoxib (Celebrex). As a group, these drugs are known as nonsteroidal anti-inflammatory drugs (NSAIDs). Although very useful, NSAIDs can have significant side effects, most notably gastrointestinal bleeding and fluid retention. There are many other pain relievers to use when the going gets rough, such as acetaminophen (Tylenol) and opioids—these are very effective for nociceptive pain.

Nerve Pain and Depression
When "nerve" or "mental emotional" pain is discussed, a common biological pathway is involved, meaning nerve pain and depression use some of the same pain messengers to carry signals to the brain. There are many different medications that treat both of these pain syndromes. Nerve pain is sub-classified as peripheral or central. Some experts assign a third category known as sympathetically mediated pain—involving the autonomic nervous system. The pain of depression involves cortical and limbic pathways. It's time that we recognized that pain and depression are like kissing/cursing cousins—a spit-fire duo that must be quelled.

Pain Messengers and Medications
Pain messengers often are referred to as neuropeptides and in some cases hormones. Following is a list of neuropeptides and hormones that play a role in pain and depression:

Neuropeptides   Hormones

Glutamate (Primary Neuron)   Serotonin

Substance P (Primary Neuron)   Noradrenalin

NMDA (N-methyl-d-aspartate) (Secondary Neuron) Dopamine

AMPA (Secondary Neuron)   GABA

Endorphins - Beta, enkeph, dynormphins   Acetylcholine

The hormones serotonin and noradrenalin are center stage players in both pain and depression so it is important to understand the medications that alter these players as well as the rest of the notable cast. Increasing the amount of central serotonin in the brain tends to raise the "gate" so that incoming signals from below the brain have a tougher time coming up. This is called increasing descending inhibition. Medications that increase the amount of central noradrenalin tend to restore neurovascular tone, so that there is less temperature dysregulation (ie, less body temperature fluctuation), less vasoconstriction (ie, narrowing of the blood vessels), decreased sweating abnormalities and lower blood pressure.

Nerve pain may be generated peripherally (ie, outside of the brain) or centrally (ie, within the brain). It is generated peripherally, for example, when a herniated disc is pressing on a nerve root. It is generated centrally when a stroke involves the thalamus and causes a difficult to describe, deep type of pain in the head or upper neck. To stop peripheral nerve pain, you must either block the peripheral messengers in the primary neurons or secondary neurons. A third way, and central to our discussion here, is to block signals within the brain using serotonin, noradrenalin, gaba-aminobutyric acid (GABA), or, in some cases, dopamine.

The important issue here is that the treatment of pain and depression have many centrally acting agents in common, meaning that many of the medications used to treat depression and alter brain signaling also act in ways to treat pain and vice versa. These include the whole spectrum of anti-depressants and many of the anti-convulsant drugs. Consequently, it should not surprise you that pain doctors commonly use anti-depressants and anti-convulsants to treat your pain.

By using anti-depressants, pain physicians are targeting not only your pain, but also mood disturbances and mental dysfunction and spiritual identity struggles. The key for doctors is "to connect with the patient" and "keep the interest of the patient as the only interest being considered." (Dr. Patch Adams, as paraphrased by Charles Mayo).

Successfully Treating Pain and Depression with Medication
The successful treatment of pain and depression is measured by how successful treatment is at reversing the symptoms listed below.

Physical   Emotional   Mental   Spiritual

Can't Eat I feel Sad Can't Talk I'm Detached

    Walk     Angry     Listen     Friendless

    Have Sex     Bitter     Watch     Alone

    Work     Nervous     Count     Bored

    Urinate     Agitated     Focus     Listless

    Move Bowels     Sleepless     Hear     Guilty

    Lie Still        Sleep     Unsaved

Determining success often is done by using global lifestyle assessment tools. These psychological tools are used by doctors to ask questions about different areas of a patient's feelings and life and then conduct follow up questions to determine improvements.

Types of Medications Used
Historically, MAO inhibitors were the first agents used to treat depression. These agents block the enzyme known as monoamine oxidase. By doing so, MAO inhibitors create havoc on the system, the most serious of which may be hypertensive crisis (ie, extremely high blood pressure). While these drugs (eg, phenelzine [Nardil]), isocarboxizid [Marplan]) are still useful, mostly for panic disorders, they have been replaced by imipramine (Tofranil) or alprazolam (Xanax).

Amitriptyline (Elavil) was the next major revolution in the group of drugs known as tricyclics. Tricyclics have been in widespread use for 20 years and have been tremendously useful for the treatment of depression and pain. Until recently, amitriptyline was thought to be the most useful agents for such serious conditions as diabetic polyneuropathy or post-herpetic neuralgia. Amitriptyline and other tricyclics such as imipramine (Tofranil), nortriptyline (Pamelor) and doxepin (Sinequan) have been very useful for sleep dysfunction and pain in low doses and also useful as a preventive measure to ward off headaches. Protriptyline (Vivactil) and desipramine (Norpramin) are much less sedating and very useful in a general working population. The major problems with these drugs are side effects such as dry mouth and constipation and, in some cases, arrhythmias (ie, abnormal heartbeat).

Largely replacing tricyclics for depression—but not for pain—are the drugs known as selective serotonin re-uptake inhibitors (SSRIs). These include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox) and citalopram (Celexa). The medications do not cause dry mouth and constipation, but they do have side effects that can be quite disturbing for some people, including sexual dysfunction (eg, loss of libido, inability to ejaculate) and hyponatremia, which is a less than normal concentration of sodium in the blood. In rare cases, patients on SSRIs can also present with "acute serotonin syndrome," a cognitive, autonomic and neuromuscular dysfunction.

There are also agents called quad-cyclics. These include trazodone (Desyrel), mirtazapine (Remeron), matoproline (Ludiomil), and nefazodone (Serzone). Trazodone is very sedating. Trazodone is widely used and is a very effective anti-depressant, but causes priapism (ie, prolonged or constant penile erection that can be painful) in a small number of men. Mirtazapine (Remeron), released in 1997, is very sedating and has strong anti-histamine properties. It is a very effective anti-depressant and has some effect on associated anxiety. Matoproline (Ludiomil) also is sedating and reasonably well tolerated. Quad-cyclics are some very mild drying effects, but do not have the usual problems with constipation and blurred vision.

Nefazodone (Serzone) is has some unique properties—it not only raises serotonin, but also blocks a specific receptor (ie, 5HT2), which causes an analgesic (ie, pain relief) as well as anti-depressant effect. There is also a central effect on nor-adrenalin that helps in treating anxiety. While having a mild sedative effect, nefazodone is known to restore sleep. Many sedatives, especially benzodiazapines, disturb the body's sleep structure. Certainly all of the SSRIs, particularly fluoxetine (Prozac), are not helpful for those with insomnia.

Most pain research studies that examine the use of anti-depressants have been for peripheral neuropathy or post-herpetic neuralgia. The agents selected in the trials have been amitriptyline (Elavil), nortriptyline (Pamelor) and desipramine (Norpramin). They have been successful. Of note is that by blocking the 5HT2 receptor, an analgesic effect (pain relief) was evident.

The Future
What's encouraging for persons in pain and pain physicians is that research is being directed at understanding the central mechanisms of anti-depressant as pain relievers. We are likely to see further research in the area of fibromyalgia where pain, depression, sleep dysfunction and irritable bowel syndrome are so prominent. As this research advances, we will be able to better appreciate the increasing dual role of these central acting medications and will be able to utilize more effectively to relieve pain and depression.