Milnacipran: The next wonder drug?


Every once in a while, a new pharmaceutical drug appears that dramatically changes the medical approach to a particular illness. A good example of this is the antidepressant Prozac ®.

Prozac was patented in 1977 and launched into the world marketplace in 1987. By the spring of 1990 Prozac had appeared on the cover of Newsweek, Time, and the New Yorker and was proclaimed the new “wonder drug,” as well as a powerful new weapon in the fight against depression.

Now another new drug- Milnacipran, may have an even greater impact on the market place. It is certainly positioned to improve the quality of life of a vast number of people.

According to the World Health Organization, 121 million people currently suffer from depression worldwide. An estimated 5.8% of men and 9.5% of women will experience a depressive episode in any given year. Equally as important, 2% to 4% of the population in industrialized nations suffer from one of a number of debilitating chronic pain syndromes including Fibromyalgia (FMS), Chronic Fatigue Syndrome (CFS), and Systemic Lupus Erythematosus (SLE). These syndromes have challenged physicians and patients alike, since they are difficult to characterize and even more difficult to treat.

SLE is a bit different because it is an autoimmune disease where the body has turned on itself. The person with SLE can manufacture antibodies to over 116 different endogenous proteins and fight off these proteins as if they were foreign, dangerous viruses or bacteria.

FMS and CFS are chronic pain illnesses which are characterized by widespread musculoskeletal aches, pains, stiffness, soft tissue tenderness, general fatigue, and sleep disturbances. Patients with FMS or CFS experience a wide range of symptoms which may include headaches, migraines, impaired memory and concentration, dry eyes and mouth, vision problems, Raynaud’s phenomenon, and other neurological disturbances.

These illnesses are quite debilitating and present many unique challenges. The patient actually looks quite well and in most instances, the blood tests are normal. It is easy to assume this individual is not physically ill at all. The problem must all be “in his/her head” and a visit to the psychiatrist is in order. These syndromes have only recently been recognized. In fact, the experts still question whether FMS and CFS are two different diseases, or just different presentations of the same disease. With the average patient waiting about 5 years for the correct diagnosis, the diagnosis of FMS and CFS is often a diagnosis of exclusion.

The clinician must rule out other diseases and base their diagnosis on a number of clinical criteria defined by the American College of Rheumatology (ACR). There are still physicians who question whether FMS and CFS are true disease entities. The patient is facing a host of baffling, invisible, unpredictable, painful, and exhausting symptoms and when he/she finally turns to the physician for help, answers do not come quickly. It is no wonder that chronic pain conditions such as FMS, CFS, and SLE share a number of clinical characteristics with depression.

Indeed, chronic pain can lead to depression and depression can cause chronic pain. I should point out however, that is quite possible to suffer the debilitating fatigue and widespread pain that so often accompany these conditions and experience no depression at all. The exciting fact is this new antidepressant Milnacipran, appears to be extremely useful in treating the most intractable aspects of all these syndromes and perhaps many more confusing, painful syndromes that are a part of life in the 21st century.

Milnacipran is the first in a new class of antidepressants that are Norepinephrine Serotonin Reuptake Inhibitors (NSRIs). Milnacipran has an equal preference for norepinephrine and serotonin and it is clear that both norepinephrine and serotonin are involved in depression and chronic pain.

Since the early 1990’s the preferred pharmacologic treatment for depression has been the SSRIs such as Prozac and Paxil ®. This is largely due to the improved tolerability of the SSRIs over the older antidepressants such as amitriptyline (Elavil ®) which are tricyclic antidepressants (TCAs), although the SSRIs are not without side effects- the most notable side effect being sexual dysfunction.

Now for more than a decade, the treatment of depression has relied upon the single acting SSRIs, but in many ways, the SSRIs fall short. This is because moderate to severe depression is more effectively treated by the older TCAs because these agents target more than serotonin. The vast body of evidence now shows that drugs that increase serotonin alone, or norepinephrine alone, are equally effective in treating depression. However, norepinephrine is clearly more important in treating pain. Until recently, the most effective way to increase both norepinephrine and serotonin was through administering a TCA.

The TCAs affect 6 different targets, and as a consequence, they have numerous side-effects including dry mouth, weight gain, drowsiness, fatigue, confusional states, disorientation, cardiac abnormalities and the list goes on. When you are suffering from a baffling, chronic illness and your major complaints are “brain fog,” pain and debilitating fatigue, the last thing you want to do is take a medication that can cause fatigue or confusion. Trust me, I can tell you this from my own personal experience. That is why Milnacipran is a potential lifeline for so many people. Unlike many drugs in its category, Milnacipran is NOT metabolized through the cytochrome p450 system. This means the medication is not likely to interact with other medications.

On a personal level, I can tell you that I have been challenged by SLE for the last 13 years. SLE is one of many autoimmune diseases that can cause widespread pain, extreme fatigue, and a host of other symptoms. Unlike FMS and CFS; SLE can be life-threatening, but it can also be quite mild, as it is in my case. In SLE your immune system can attack anything… any of the major organs including the kidneys, the heart, the lungs, the blood system and the brain. My special challenge has been the brain. I have suffered from brain fog, cognitive dysfunction, and severe migraine syndromes. About 2 years ago I developed an extremely difficult neuropathic pain condition called trigeminal neuralgia, secondary to the SLE. Trigeminal neuralgia is called the suicide disease and were it not for the medications I have gotten from IAS, I might have considered something that extreme. I tried all the medications that are used to treat this disease including the anti-epileptic drugs such as Neurontin ® and Topamax ®. In addition, I tried the TCAs. I could not tolerate the side effects of these medications. Eventually the pain became manageable with a regime of long acting and short acting opioids. Those drugs were the choice of last resort.

But now, for a little over 2 weeks I have begun taking Milnacipran (brand name Ixel ®). According to the clinical trials, one should begin to see the pain reduction benefit at about week number 8. I am happy to report I have already reduced my pain medication by one third and I remain completely hopeful that this reduction is just the beginning.

In addition, I seem to have much more energy. The phase II clinical trials in the US were recently completed and the results were amazingly positive. No one dropped out of the trial because of side effects, which is virtually unheard of. Plus I have spoken to numerous rheumatologists who are involved in treating people with FMS and CFS, and they just cannot wait until this medication is available. As professionals they feel the previous therapies they have offered their patients have met with limited success. It is wonderful that there is now a medication that promises to improve the quality of life of so many people.

Milnacipran may become the next wonder drug, and in a few years time be on the front covers of those well known public magazines I mentioned earlier, but remember you heard it here first!

This is part 2 of a feature, in which Nutritionist Karen Kaufmann MS, keeps us informed of her progress, and how she has been using “unapproved” products and “approved” products in an “off-label” way to help control and treat her condition. In particular Karen informs us about her experiences the latest drug development of Milnacipran.

Update on Milnacipran

When I wrote “The Next Wonder Drug” article for the Summer 2004 Antiaging Magazine, I had been taking Milnacipran, (brand name Ixel) for about 2 weeks. As I sit at my desk today, the sky is bright blue, the air is clear, and there is a hint of the crispness that portends another beautiful fall season in New England. So this seems like a perfect opportunity to share my personal experience with Milnacipran and a number of other smart drugs that help me maintain an excellent quality life, in spite of the health challenges I face.

I suffer from a debilitating chronic illness called Systemic Lupus Erythematosus (SLE). SLE is a chronic disorder of the immune system that causes inflammation in various parts of the body. For most people lupus is mild, affecting only a few body organs; for others, it may cause serious and even life threatening problems.

The body’s immune system normally makes proteins called antibodies that protect the body against viruses, bacteria, and other foreign materials. These foreign materials are called antigens. In an immune disorder like lupus, the immune system loses the ability to distinguish between foreign substances (antigens) and its own cells and tissues. The immune system then makes antibodies directed against ‘self.‘ These antibodies, called autoantibodies, react with the ‘self’ antigens to form immune complexes. These immune complexes build up in various tissues and cause inflammation, injury to tissues, and pain. These immune complexes can deposit in the joints, connective tissue, or any organ such as the heart, the lungs, the kidneys, the liver, and the brain. It can also cause all sorts of blood disorders including thrombocytopenia, (a low platelet count), hemolytic anemia, or a hypercoaguable state where the person is in danger of forming arterial or venous blood clots.

No two people with lupus have the exact same symptoms, but almost universally, people with lupus suffer from joint pain in numerous joints at the same time and an indescribable fatigue. In my case the illness is also affecting my central nervous system. The American College of Rheumatology (ACR) in 1999 came up with a list of 19 criteria that could be present when lupus involves the brain. I am going to list some of them here so that you get a sense of just how diverse and complex this disease is.

  • Acute Confusional State
  • Anxiety Disorder
  • Asceptic Meningitis
  • Autonomic Disorder
  • Cerebrovascular Disease
  • Cognitive Dysfunction
  • Demyelinating Syndrome
  • Headache
  • Mononeuropathy (single/multiplex)
  • Mood disorders
  • Movement disorders
  • Cranial neuropathy
  • Psychosis
  • Seizures
  • Transverse myelitis

So you see, the challenge can be as simple as a headache or as serious as psychosis. I experience cognitive dysfunction (which I call brain fog), cluster migraines, and as mentioned in my previous article, atypical trigeminal neuralgia.

During my last flare I faced a new challenge- serious depression. Many people would say of course you would become depressed. You are in tremendous pain and have unbearable fatigue. But in this case the depression was caused by the disease process itself. How lupus causes all these different things remains a mystery and there are probably a number of different things happening at once.

Perhaps because lupus affects women to men in an 8:1 ration, perhaps because the disease is so complex; very little is actually known about the cause or the pathogenesis of the disease. In 30 years there has not been a drug developed specifically to treat lupus. Medical therapies are grounded in symptomatic relief, and often the medication is worse than the disease itself. Doctors prescribe nonsteroidal anti-inflammatories at the outset, but most patients wind up having to take strong immunosuppressive agents such as prednisone or chemotherapy drugs. I never considered that an option. I have been focused on maintaining my quality of life with lifestyle changes (diet and exercise), nutritional supplements (sometimes taken to offset the side-effects of the medications I must take), and taking the best smart drugs (nootropics) available. I do this, so if and when medical science finds a reasonable treatment for this disease, I will still have some brain cells left to take advantage of it! And I must say, in the 14 years I have dealt with this chronic illness I have done very well.

I want to let you know how I got here. After 20 plus weeks on the Milnacipran, I have been able to cut my pain medication in half, and the depression is in remission, so I can once again take pleasure in the little things. I found Milnacipran extremely easy to tolerate, (which is a little strange for me, because I have experienced numerous adverse drug reactions with many medications my physicians have prescribed). It was eight or nine years ago when I first discovered IAS and began a program to protect my gray matter. One of the first nootropics I incorporated into my health regiment, (which already included CoQ10 and Idebenone), was Piracetam. I am no expert at these things so I can only refer you to the extensive article James South, MA wrote on subject; Piracetam- The original Nootropic.

At that time my symptoms were fairly benign but I knew my brain was under assault and I wanted to do everything that seemed rational to protect my neurons. In designing a program for yourself, you always want to consider the risk/benefit ratio. Could the possible side effects outweigh the potential benefit?

In the case of Piracetam, the side effect profile was excellent, so that is where I began. The Piracetam broke the ice for me and as I was in for a penny, why not go in for the pound?

The next smart drug I added was Pyritinol. Again, I am no expert, so the best resource I can refer you to is James South’s article on the subject; Pyritinol- The Antioxidant, Immune-Enhancing, Anti-Rheumatoid Arthritis Nootropic.

The most compelling reason for me to take this drug was the fact that pyritinol is extremely beneficial to people who are recovering from cerebral trauma and strokes. One of the possible causes of cognitive dysfunction in people with SLE is they may be experiencing tiny and numerous transient ischemic attacks (TIAs).

In the case of lupus and the brain, there is so much speculation because MRIs are not sensitive enough to be helpful, and we don’t routinely do a brain biopsy to see what sort of damage is occurring. Despite my best efforts to keep myself well through diet, exercise, nutritional supplements and smart drugs; I was still plagued by bouts of unbelievable fatigue. If you have never suffered from chronic fatigue syndrome, fibromyalgia, Lyme disease or another debilitating systemic illness, it is difficult to understand the kind of fatigue I am talking about. This is a whole body fatigue, “fatigued to the bone”, and a fatigue that does not resolve with sleep.

One of the smart drugs that went a long toward giving me life back is Modafinil. Again, I will refer you to IAS’s website for more detailed information.

Modafinil was a drug originally developed for narcolepsy (sleeping in the daytime). It definitely increases wakefulness and alertness for me, without making me feel ‘wired’ and without interfering with my sleep. Many doctors will prescribe Ritalin for their patients who experience the type of fatigue I am reporting. However, Ritalin is an amphetamine and does not fare well on my risk/benefit ratio. Whereas, Modafinil not only increases my energy level, but it truly helps dissipate my ‘brain fog’.

The last smart drug in my personal portfolio is Memantine. Again, for more detailed technical information on Memantine, go to IAS’s website.

Memantine was originally approved for Alzheimer’s disease and it is an NMDA receptor antagonist. There is a rheumatologist in the New York area who has been researching lupus and the brain for many years. She now postulates that some of the cognitive dysfunction in SLE is being caused by immune complexes binding to the NR2 receptor. It is exactly this receptor that Memantine protects. In addition, the NMDA receptors are definitely involved in some types of neuropathic pain conditions. Neuropathic pain is the most difficult pain to treat successfully. Unpublished studies did demonstrate Memantine was helpful in alleviating certain types of neuropathic pain such as post herpetic neuralgia, facial pain, and pelvic pain. Adding Memantine did help me achieve better pain control, but even if it did not, the research that it can protect certain neurons under fire in my case is quite compelling.

As I stated in my previous article, I believe that if it wasn’t for the access I have to these ground breaking medications I wouldn’t be alive today.

I hope I haven’t bored you with my personal saga. It is my deepest wish that others can benefit from the many things I have learned as I continue this journey toward optimal health.