Cochrane Overview of Pharmacological Treatments For Fatigue

[Cort]

Cochrane Database Syst Rev. 2010 Nov 10;11:CD006788.
Pharmacological treatments for fatigue associated with palliative care.
Peuckmann V, Elsner F, Krumm N, Trottenberg P, Radbruch L.

Medical Faculty RWTH, Universitatsklinikum Aachen, Hauptgebude, Aufzug B 1, Etage 1, Flur 1, Raum-Nr.5, Pauwelsstrae 30, Aachen, Germany, 52074.
Abstract
BACKGROUND: In healthy individuals, fatigue is a protective response to physical or mental stress, often relieved by rest. By contrast, in palliative care patients fatigue can be severely debilitating, thereby impacting daily activity and quality of life, often with rest not counteracting fatigue. Fatigue frequently occurs in patients with advanced disease and modalities treating cancer often contribute or cause fatigue. Further complicating issues are its multidimensionality, subjective nature, and lack of a consensus definition of fatigue. Pathophysiology is not fully understood and evidence-based treatment approaches are needed.

OBJECTIVES: The objective was to determine efficacy of pharmacological treatments on non-specific fatigue in palliative care. The focus was on patients at an advanced stage of disease, including cancer and other chronic diseases associated with fatigue, aiming to relieve fatigue. Studies aiming at curative treatment (e.g. surgical intervention for early breast cancer) were not included.

SEARCH STRATEGY: We searched EMBASE; Psych Lit, CENTRAL and MEDLINE to June 2009.

SELECTION CRITERIA: We considered randomised controlled trials (RCTs) concerning adult palliative care with focus on pharmacological treatment of fatigue. The primary outcome had to be non-specific fatigue (or related terms such as asthenia).

DATA COLLECTION AND ANALYSIS: Results were screened and included if they met the selection criteria. If two or more studies were identified that investigated a specific drug in a population with the same disease, meta-analysis was conducted. In addition, comparison of type of drug investigated in a specific population as well as comparison of frequent adverse effects of fatigue treatment was done by creating overview tables.

MAIN RESULTS: More than 2000 publications were screened, and 22 met inclusion criteria. In total, data from 11 drugs and 1632 participants were analysed. Studies investigating amantadine, pemoline, and modafinil in participants with Multiple Sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue could be used for meta-analysis. Amantadine in MS and methylphenidate in cancer patients showed a superior effect. Most studies had low participant numbers and were heterogenous.

AUTHORS' CONCLUSIONS: Based on limited evidence, we cannot recommend a specific drug for treatment of fatigue in palliative care patients. Surprisingly, corticosteroids have not been a research focus for fatigue treatment, although these drugs are frequently used. Recent fatigue research seems to focus on modafinil, which may be beneficial although there is no evidence currently. Amantadine and methylphenidate should be further examined. Consensus regarding fatigue assessment in advanced disease is needed.

Conclusions - much more research is needed - which makes sense; fatigue has only recently become a topic of interest. Amantadine, modafinil and methyphenidate are possibilities.

 

[Cort]

Amantadine - antiviral interestingly enough

From Phoenix Rising - http://aboutmecfs.org/Trt/TrtAmantadine.aspx

Amantadine is an antiviral and central nervous system stimulant that inhibits viral infection of the cell and increases dopaminergic activity in the brain.

Amantadine was first approved to treat the Asian flu (Influenza A) but was subsequently found to assist in the treatment of muscle stiffness and muscle control in Parksinson's and in the treatment of carbon monoxide poisoning. Amantadine improves fatigue and muscle control and reduces muscle stiffness in some multiple sclerosis (MS) patients. Its most common use to short-term treatment of the flu.

Amantadine interferes with a viral protein needed to 'uncoat' a virus once it enters the cell. Amantadine's mode of action in the central nervous system is unclear but appears to involve increased dopamine and perhaps norepinephrine release.

Amantadine May Be Helpful in Chronic Fatigue Syndrome (ME/CFS) because of its antiviral activities and because it may enhance the activity of a part of the central nervous system (dopaminergic functioning) that may be underactive in chronic fatigue syndrome (ME/CFS). Amantadine can effect several symptoms (fatigue, muscle stiffness) found in ME/CFS/FM.

 

[Cort]

Methylphenidate -

http://aboutmecfs.org/Trt/TrtRitalin.aspx

Ritalin Is a central nervous system stimulant. Created in 1954, Ritalin is commonly prescribed for attention deficit disorder (ADHD).

Ironically, given its stimulant properties Ritalin has a calming effect on ADHD patients and enhances concentration. Ritalins mode of action is not known but it is believed to increase dopamine and/or serotonin levels.

Ritalin May Work in Chronic Fatigue Syndrome (ME/CFS) because it increases concentration and may increase the levels of neurotransmitters that may be low in the disease.

Chronic Fatigue Syndrome (ME/CFS) Physicians Report. Dr. Teitelbaum believes Ritalin is underused in ME/CFS. Dr. Bateman uses both Ritalin and Adderall but in general prefers Adderall. Ritalin can exacerbate sleep problems in some patients.

Studies A small trial of Ritalin found increased thinking ability and reduced daytime sleepiness in chronic fatigue syndrome (ME/CFS) patients.

Dose Dr. Bateman recommends 5-20 mg. 2-3xs a day. Dr. Teitelbaum recommends 10-30 mgs. taken 3xs a day with a maximum of 60 mgs./day. Dr. Rowe recommends that ME/CFS patients with orthostatic intolerance take low doses in the beginning (5 mg in morning) and then repeated, if necessary, 4 hours later. Double the dose (10 mg) and then possibly split it (5 mg/5mg.) in pm.

Side Effects Ritalin has a lower incidence of side effects than Dexedrine. At lower doses it is usually well tolerated. Side effects can include sleeping difficulties, stomach pains, potentially addictive, headaches, palpitations, high blood pressure. Because of its potential for addiction if misused Ritalin is a Schedule II drug and requires frequent doctor visits.

 

[Cort]

Provigil

Modafinal - Provigil

http://aboutmecfs.org/Trt/TrtProvigil.aspx

Provigil (Modafinil) Is a central nervous system stimulant. Approved in 1998 by the FDA Provigil is a new class of wakefulness promoting drugs. It is less likely to cause jitteriness, anxiety or fatigue than traditional stimulants. It is approved to treat narcolepsy (daytime sleepiness) and its effectiveness is being examined in many diseases including multiple sclerosis, cancer-related fatigue and Parkinsons disease

Provigil May Work in Chronic Fatigue Syndrome (ME/CFS) and FM Because many patients have symptoms of ADD, such as lack of attention, poor concentration and Provigil can help with this. Provigil is also prescribed for daytime sleepiness, which many chronic fatigue syndrome (ME/CFS)patients have, and obstructive sleep apnea, which some do.

Chronic Fatigue Syndrome (ME/CFS) /Fibromyalgia Studies one small double-blinded study found Provigil only very modestly improved cognition in ME/CFS. The authors suggested that those chronic fatigue syndrome (ME/CFS)patients with excessive daytime sleepiness may benefit.
Chronic Fatigue Syndrome (ME/CFS) Physicians Report - Dr. Lapp reports Provigil is safe, offers little risk of habituation and improves fatigue, mental clarity, attention deficits and depression. Dr. Teitelbaum recommends Provigil for energy and daytime sleepiness (narcolepsy). Because he is unclear about its long term effects, however, he prefers Dexedrine. Dr. Natelson finds Provigil helps in about a quarter of his patients, another quarter find no improvement and sensitivity issues preclude it from being used in the remaining half. Dr. Podell also reports that Provigil is effective in a significant minority of his patients. Dr. Bateman has found Provigil can worsen sleep in patients with disturbed sleep patterns. One drawback is the high cost. of the drug.

Chronic Fatigue Syndrome (ME/CFS) Patients Report Reports of Provigil's effectiveness have been mixed; some ME/CFS patients do very well, others do not. .

Dose The standard recommended dose is 200 mgs./day taken in the morning.
Side Effects Provigil has been well tolerated in clinical studies with mild to moderate side effects such as headache, nausea, nervousness, etc. in a small percentage of patients.

Warning Serious rash or hypersensitivity reactions may occur in a very small percentage of patients. Click here for more.

 

[Dolphin]

Link to free full text

Link to free full text
http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD006788/pdf_fs.html
or
follow full text link at:
http://www2.cochrane.org/reviews/en/ab006788.html

Has no mention of "myalgic" or "chronic fatigue"

 

[Sushi]

De Meirleir sometimes gives Amantadine - Cort's note: "antiviral interestingly enough"

I've taken ritalin and also adderall (4 mixed amphetamines) at low doses. Adderall worked better for me as the 4 amphetamines phase in and out with different half lives--so the ups and downs aren't as sudden. I took them for OI--they worked for me at low doses. I don't take them anymore cause I don't need them so much and want to minimize drugs.

I also tried Provigal and it felt awful for me. Others like it. It costs the earth!

Just my 2 cents!

Sushi

 

[Hope123]

Interesting angle, Cort.

Haven't read this article but just to give some context re: care of palliative patients, when it comes to this point, health care professionals often will use medicines off-label, over the usual doses, or with side effects long-term because comfort/ quality of life is the main focus and not length of life, avoiding future co-morbidities, etc.

For example, they mentioned steroids. Steroids do have acute serious side effects (e.g. delirium for one) but the main concerns for most people taking it long-term are conditions like gut bleeding, immune suppression, osteoporeosis, etc. -- conditions that palliative care professionals are less concerned with since palliative care patients are near the end of life and likely would die before they get those conditions. In addition, there is something called the "double effect" -- e.g. if a drug administered helps with symptoms but as a side effect hastens or causes death, it is deemed OK in both the medical ethics and legal world when it comes to palliative care as long as the patient/ family understand the intent.

So, the balance of risks and benefits is different.

 

[Cort]

De Meirleir sometimes gives Amantadine - Cort's note: "antiviral interestingly enough"

I've taken ritalin and also adderall (4 mixed amphetamines) at low doses. Adderall worked better for me as the 4 amphetamines phase in and out with different half lives--so the ups and downs aren't as sudden. I took them for OI--they worked for me at low doses. I don't take them anymore cause I don't need them so much and want to minimize drugs.

I also tried Provigal and it felt awful for me. Others like it. It costs the earth!

Just my 2 cents!

Sushi

I met someone for whom Ritalin worked really well - he was back doing Triathlons although he said he still had other symptoms.. What a group we are!!!

I did think it was interesting that an antiviral is being considered a possible treatment for fatigue.

 

[wciarci]

Early in my disease my doctor had me on sterioids, they worked for a while and then nothing (except to make me fat and puffy). Then I tried provigil and hated it. It was a very caffinated, nervous energy that did not help concentration at all. B12 is much better

Just my 2cents

Wendy

 

[Dolphin]

Early in my disease my doctor had me on sterioids, they worked for a while and then nothing (except to make me fat and puffy).

I know somebody with ME/CFS who was put on steroids who got diabetes within 2 years (she was in her late 40s).

 

[Mette]

steroids in CFS

I know somebody with ME/CFS who was put on steroids who got diabetes within 2 years (she was in her late 40s).

It is a question of dose. I have taken steroids for 20 years low dose (prednisone 2.5/5mg a day), and at the same time being aware of need for calcium and Dvit supplementation. I have no problems. Also please remember how common diabetes is in the general population.

 

[Dolphin]

It is a question of dose. I have taken steroids for 20 years low dose (prednisone 2.5/5mg a day), and at the same time being aware of need for calcium and Dvit supplementation. I have no problems. Also please remember how common diabetes is in the general population.

I'm no expert but can believe what you say (although still think there is a good chance it brought on diabetes in her case). She was on 10mg a day of prednisone.

I wanted to try thyroid medication as I had a highish TSH (around 5). I read some of the pros/cons of cortisone. Some said the threshold was 20mg hydrocortisone (equivalent to 5mg/day prednisone). Below that wouldn't cause suppression of the adrenals. I took some hydrocortisone for a while.

 

[Mette]

I'm no expert but can believe what you say (although still think there is a good chance it brought on diabetes in her case). She was on 10mg a day of prednisone.

I read some of the pros/cons of cortisone. Some said the threshold was 20mg hydrocortisone (equivalent to 5mg/day prednisone). Below that wouldn't cause suppression of the adrenals.

The threshold is the equivalent to the daily production in the body ie 7.5mg/day (non-obese adults). However, the lower the safer, and there is always some suppression of the adrenals. But with CFS we don't know why many patients have those low values of cortisone except there must be some dysregulation somewhere in the system. All I want to say is that one shouldn't be frightend by the steroids if they can help you. In my case it helps lessen rheumatic symptoms (arthritic pain and vasculitis).

 

[August59]

I met someone for whom Ritalin worked really well - he was back doing Triathlons although he said he still had other symptoms.. What a group we are!!!

I did think it was interesting that an antiviral is being considered a possible treatment for fatigue.

Man - If I ever got back to walking to the end of my street (300 yards), I would think I was cured! I can't imagine a "triathalon", but he is surely an inspiration!!!!

If I could afford to go to a doctor, I'm sure I would be better than I am. Having to quit clonazepam, tizanidine and hydrocortisone all in the same month has been rough. I tapered them down over a 2 months time, but still!!

 

[August59]

I'm no expert but can believe what you say (although still think there is a good chance it brought on diabetes in her case). She was on 10mg a day of prednisone.

I wanted to try thyroid medication as I had a highish TSH (around 5). I read some of the pros/cons of cortisone. Some said the threshold was 20mg hydrocortisone (equivalent to 5mg/day prednisone). Below that wouldn't cause suppression of the adrenals. I took some hydrocortisone for a while.

There several papers that state that prednisone is 5 - 7 times stronger than hydrocortisone. 10 -15 mg a day of hydrocortisone makes an enormous difference in my daily life. I went to fairly productive to house bound within the 2 months it took me to taper off (stopped tizanidine and clonazepam at bedtime also). I can say that most of it is inflammation and tapering off has changed my thyroid (TSH went up) and testosterone levels (went down) either directly or indirectly.

 

[Dolphin]

There several papers that state that prednisone is 5 - 7 times stronger than hydrocortisone. 10 -15 mg a day of hydrocortisone makes an enormous difference in my daily life. I went to fairly productive to house bound within the 2 months it took me to taper off (stopped tizanidine and clonazepam at bedtime also). I can say that most of it is inflammation and tapering off has changed my thyroid (TSH went up) and testosterone levels (went down) either directly or indirectly.

I'm no expert on hydrocortisone - I wasn't reading research papers generally at that stage. The books as I recall said 4 times and I have just checked now and this conversion tool http://www.globalrph.com/steroid.cgi also says 4 times. That was just an aside I made. Although if it is 7 times, then the other poster in this thread who mentioned a threshold of 7.5mg means an equivalent threshold of 52.5mg; their dosage of 2.5-5mg prednisone would then be taking the equivalent of 17.5-35mg hydrocortisone.

Anyway, I took it for many months, on its own and with thyroid medication as I wasn't convinced low dose hydrocortisone was that different but didn't make much difference to me.

 

[JulieR]

Provigil

I've had good success with Provigil. It is indeed hugely expensive, but there are Indian generics at about 1/10 the cost. There are a number of different varietes of generics; for me, Modalert is effective but the others are not, though that seems to vary from individual to individual. Buying from India is scary, but my experiences have been OK.

 

[FunkOdyssey]

focalin (dexmethylphenidate) is a cleaner version of ritalin that works well for me and enables me to perform my duties at a cognitively demanding job where I would otherwise be completely useless. Amphetamines seem to be harsher on the mind and body and I worry that they would accelerate the course of the disease and cause long-term decline in health. They also seem more disruptive of sleep which I would attribute to their long-half lives.

I worry that methylphenidate may have negative effects too though. It seems that any drug which increases the availability of dopamine in the CNS accelerates replication of viruses closely related to XMRV (HIV, SIV). Some specific drugs which have been shown to be harmful in HIV and SIV include amphetamine, selegiline, and l-dopa. Another thread either here or on me-cfs forum is discussing this right now. It wouldn't be too much of a stretch to extrapolate those findings to methylphenidate and XMRV. Or maybe it would. Just thinking out loud.

 

[Desdinova]

I tried Modafinil Provigil my sleep specialist prescribed it. After getting past the sticker shock I gave it a serious try. For me it would either do

1. Improved my fatigue a noticeable amount, although by no means coming anywhere close eliminating it.
2. Do nothing at all
3. Make my brain feel like it was going a thousand miles per hour sometimes boarding on making me feel like I was flipping out.

Because of the variation in out comes almost day to day and only a slight improvement in my fatigue on occasion coupled with the price it just wasn't worth it. It was a hard decision to make since even the slight improvement was still a welcome one. It was like getting your head up above the water to grab a gasp of air while you’re drowning. It was good but not good enough to save you from your situation.