Dr. Jay Goldstein: A-Z TREATMENTS
GOLDSTEIN PROTOCOL
Dr. Jay Goldstein (now retired) was a psychiatrist and psychopharmacologist. He published over forty papers in peer-reviewed journals, often related to pharmacotherapy, and pioneered the use of medications for off-label applications. Dr. Goldstein also wrote five medical books, most of them about CFS/ME.
Dr. Goldstein's approach to treating CFS/ME was so novel, and his ideas concerning the role of the midbrain so ground-breaking, that it is well worth looking at his methods and treatments. Dr. Goldstein's case studies shed light on many of the neurological deficits experienced by people with CFS/ME, as well as the treatments that might alleviate them. In light of recent studies documenting brain anomalies and nervous system excitoxicity in CFS/ME patients, Dr. Goldstein's work was clearly ahead of its time.
In a nutshell, Dr. Goldstein's theory – as laid out in his book, Betrayal by the Brain – was that CFS/ME is essentially a communication problem. He described CFS/ME as a “neurosomatic” illness, that is, a disorder of central nervous system processing. The purpose of his treatments was essentially to reset the brain, specifically the limbic system, via pathways going to the brain (these are referred to as “afferent”), so that the CNS would return to its normal functioning.
Typically, when Dr. Goldstein saw new patients, he would test them sequentially with minute quantities of many psychoactive drugs in order to 1) identify the source of the problem, and 2) establish which drugs would be most effective. This method allowed Dr. Goldstein to assess the patient rapidly, and at minimal cost. Dr. Goldstein halted sequential trials when the patient was “virtually asymptomatic.” Dr. Goldstein claimed that using this protocol most patients were dramatically improved in one or two office visits.
Many of Dr. Goldstein's treatments are still in use by CFS/ME clinicians, but so far no one has so thoroughly explained their neurological effects on CFS/ME.
The following is taken from Dr. Goldstein's book, Betrayal by the Brain, “Treatment Protocol for Physicians,” and “Tiptoe Through The Treatments: A Brief Guide To Some of What's New Since Betrayal by The Brain."
_____________________________________________________________
A Typical Neurosomatic New Patient Treatment Protocol
Agents tried sequentially Onset of Action Duration of action
1. Naphazoline HCL 0.1% gtt ┬OU 2 - 3 seconds 3 - 6 hours
2. Nitroglycerin 0.04 mg sublingual 2 - 3 minutes 3 - 6 hours
3. Nimodipine 30 mg po 20 - 40 minutes 4 - 8 hours
4. Gabapentin 100-800 mg po 30 minutes 8 hours
5. Baclofen 10 mg 30 minutes 8 hours
6. Oxytocin 5-10 U IM or BID
or
Syntocinon 1-2 puffs TID 15 minutes - 72 hrs 12 - 24 hours
7. Pyridostigmine 30 - 60 mg po 30 minutes 4 - 6 hours
8. Hydralazine 10 - 25 mg po 30 - 45 minutes 6 - 12 hours
9. Mexiletine 150 mg po 30 - 45 minutes 6 - 8 hours
10. Tacrine 10 mg 30 minutes 4 - 6 hours
11. Risperidone 0.25 - 0.5 mg 45 - 60 minutes 8 - 12 hours
12. Pindolol 5 mg BID 15 minutes - 7 days 12 hours
13. Lamotrigine 25 - 50 mg QD 30 - 45 minutes 24 hours
14. Sumatriptan 3 - 6 mg SQ 15 - 30 minutes 16 hours
15. Ranitidine 150 mg BID 1 hour - 1 week 12 - 24 hours
16. Doxepin HCL elixir 2 - 20 mg HS 1 hour variable
17. Sertraline 25 - 50 mg QAM
or
Paroxetine 10 - 20 mg QAM 1 hour - 8 weeks 1 - 2 days
18. Bupropion 100 mg TID 30 minutes - 8 weeks 8 - 24 hours
19. Nefazodone 100 - 300 mg BID 2 - 8 weeks 24 hours
20. Venlafaxine 37.5 - 75 mg BID 1 - 4 weeks 24 hours
21. Glycine powder 0.4 Gm/Kg/day in juice
or
Cycloserine 15 - 20 mg QD 1 hour 24 hours
22. Felbamate 400 mg 30 minutes 6 - 8 hours
23. Lidocaine 200-300 mg
A-Z Treatments (Comments are by Dr. Goldstein)
Acetazolamide (Diamox): This drug is a carbonic anhydrase (CA) inhibitor which is routinely used as a cerebral vasodilator in nuclear medicine. Patients will occasionally have a reduction in symptomatology with acetazolamide. Acetazolamide 250 mg eliminated the pain of a 41-year-old female patient with post-traumatic fibromyalgia, helped her feel very relaxed, and markedly reduced her other symptoms.
Acetyl-L-Carnitine: In theory, a good drug. It should work as an acetyl group donor to increase acetylcholine, and the carnitine has already been shown to be effective in a double-blind experiment by the Drs. Plioplys. Acetyl-L-carnitine also increases the levels of nerve growth factor (which are four times normal in the spinal fluid of FMS patients) and increases other transmitters like adenosine and ATP. In practice, a semi-dud.
Adderall: An amphetamine combination that a few patients find more energizing than plain dexedrine. Only about a third of CFS patients have a good response to stimulants, which act by squeezing dopamine (DA) and norepiniphrine (NE) out of neurons and glia. If these transmitters are much too low already, giving stimulants will further lower the signal-to-noise ratio and increase symptoms.
Amantadine: A weak NMDA antagonist. Helpful for a few patients. Doses higher than the PDR recommends may be more effective, but there is an increased risk of adverse drug reactions when exceeding this dose. Israelis have given 100 mg IV with good results in neurogenic pain. IV amantadine is not available in the USA. Amantadine, ketamine, dextromethorphan, and a new MNDA antagonist, memantine, can be used in trigger point injections as well as gel applications for local pain.
Ambien: The best sleeping pill. Does not cause dependence except in unusual circumstances.
Aricept: A cholinesterase inhibitor marketed for Alzheimer's disease. Has the advantage of once-a-day dosing and no requirement for liver function test. Does not work as well as Cognex, perhaps because it is not a potassium channel blocker. Cognex has several effects on neurotransmitters relevant to CFS/FMS.
Ascorbic Acid (Vitamin C): Recent research into the role of ascorbic acid in the brain (which has the highest concentrations of this substance in the entire body) has shown that this agent may be beneficial in certain patients with CFS. Ascorbate has been found to be neuroprotective, particularly by inhibiting the redox site of the NMDA receptor and diminishing calcium influx. Trials of high-dose oral ascorbic acid have been generally disappointing. Administration of ascorbic acid is done via IV doses of 25 to 50 grams diluted in half-normal saline of Ringer's lactate over a period of about 90 minutes. Adding magnesium sulfate is recommended because ascorbic acid can cause magnesium shifts from extracellular to intracellular compartments. It is beneficial to add 500 mg of calcium gluconate since ascorbic acid is a calcium chelator and could possibly lower serum calcium. Responders to IV ascorbic acid generally feel considerably better in most respects the day after treatment.
Baclofen: A greatly under used medication. A GABA-B agonist with few ADRs, it has an immediate onset of action and is still in my top 10.
Vitamin B12: Besides being vital to transmethylation (which helps to synthesize NE), B12 2g. orally in AM decreases inappropriate daytime melatonin secretion, thereby aiding in the treatment of the delayed sleep-wake cycle many CFS patients experience. Very large doses (10 g) may aid transmethylation.
BuSpar: The ideal anxiolytic in all respects except efficacy. Best used as an SSRI augmentation agent, especially combined with Visen (not generic Pindolol). Augmentation strategies, of which there are many, do not work nearly as well in CFS as they do in major depression disorder.
Clonidine: Another greatly underused drug. Can be good for central pain, ADD, anxiety. Helps all symptoms in some patients. Eliminates nightmares. Safe and cheap. Comes in a patch that lasts all day. Better than Zanaflex, another alpha-2 agonist. Tolerance and depression have not been much of a problem. Adverse drug reactions to clonidine can be reversed by yohimbine, an alpha-2 antagonist. Guanfacine (Tenex) is a less sedating alpha-2 antagonist with a 24-hour duration of action.
Dexedrine: An effective stimulant. Makes some patients calm also. May synergize with Ultram. Desoxyn may be better but has neurotoxicity. Many patients like Adderall more.
Depakote: In the CFS population its only value is in migraine prophylaxis, for which it is excellent.
Dilantin: Useless in every CFS patient I have treated with it.
DHEA: Theoretically excellent, it is a neurosteroid which is a GABA antagonist, not necessarily a good thing for some patients. Pregnenolone should be the best neurosteroid (low in PMS).
Felbamate (Felbatol): Not used much because of requirement for hematologic and liver function test monitoring. Should be tried in every treatment-resistant patient. May work when nothing else does, especially for intractable headaches. It may cause headaches, however. There's no free lunch.
Gabapentin (Neurontin): Gabapentin, an antiepileptic drug with a novel mechanism of action, has become one of my five favorite medications (the others are oxytocin, nimopidine, baclofen, and intravenous lidocaine) to treat neurosomatic disorders.
Gabitril: The only GABA reuptake inhibitor (like Prozac is a serotonin reuptake inhibitor). Very effective and very safe if you follow PDR dosing suggestions. Increase the dose too rapidly and the patient may get delirious or manic. Effects are reversible with flumazenil if necessary.
Gingko Biloba: Useful only for sexual dysfunction induced by serotonin reuptake inhibitors (SRIs). Inhibits platelet aggregation. Rare reports of brain hemorrhage. This adverse reaction raises the risk/benefit ratio.
Ginseng Saponins: Works a little like nitroglycerin, which converts to nitric oxide. Increases energy slightly.
Gotu Kola: A mild stimulant with no apparent adverse reactions.
Honey Bee Venom: As with any "natural product," bee venom has a multitude of ingredients. Patients should be skin tested for bee venom allergy first. Major constituents from my point of view are phospholipase A2 (PLA2), which makes arachidonic acid, the precursor to eicosanoids (prostaglandins, leukotrienes, etc.), dopamine and NE. When it works, the patient often feels like he has been injected with rocket fuel. Effects last about one to two weeks. Has made three patients worse, two of whom were father and daughter. Patients should have an Epi-Pen (if available) and an antihistamine with them at all times. Plaquenil antagonizes PLA2. Arachidonic acid combines with effianolamine in the brain to make anandamide, an endogenous cannabinoid (like marijuana).
H2 Receptor Antagonists: The first treatments I developed for CFS were cimetidine and ranitidine. I based this therapy on my successful experience treating acute infectious mononucleosis with cimetidine. When a CFS patient responds to an H2 antagonist (I use ranitidine), the onset of action is similar to that seen in acute infectious mononucleosis, i.e. one or two days at a dose of 150 mg b.i.d. Usually all symptoms are ameliorated. Some patients are unable to take any does of ranitidine because it makes them “hyper.”
Hydergine: The most underused effective medication in the PDR. Extremely safe. A dopamine and acetylcholine agonist. There is nothing else like it. Other dopamine agonists seem to be restricted in action to the nigrostriatal dopaminergic tract, which is not important in CFS symptoms. Not the case with Hydergine, which is quite helpful for alertness, especially in those sedated by Baclofen. As with most medications listed, it can sometimes help all symptoms.
Oxytocin: Oxytocin has a wide range of behavioral effects. Oxytocin neurons project to many areas of the limbic system, as well as to the frontal cortex. Oxytocin is involved in maternal behavior, female and male sexual behavior, feeding, social behavior, and memory. It also has effects on cardiovascular, autonomic, and thermoregulatory processes. Approximately one-fifth of my patients have a good response to IM oxytocin after failing to respond to numerous oral agents. Cognitive clarity is the most responsive symptom, with fibromyalgia and pain being second.
Kava-Kava: One of the two best "natural products" for CFS. May take up to eight weeks to have an effect. No adverse drug reactions.
Ketamine: The best single agent for CFS/FMS and all other neurosomatic disorders. Known best as an NMDA receptor antagonist (the NMDA receptor is one of the several receptors for the excitatory amino acid glutamate), it increases dopamine in the limbic system, a very important objective in CFS. I administer it by slow intravenous infusion or in PLO gel for transdermal (through the skin) absorption. The intravenous route is more effective, but transdermal application can be done daily, and if effective, can obviate peaks and valleys and need for IVs. I have seen no cases of Ketamine abuse among my patients. Ketamine is one component of my "resurrection cocktail," for patients who have been bedridden for more than a year and whom I may only see once. The others are IV ascorbate, IV lidocaine, IV thyrotropin- releasing hormone (which raises all biogenic amines plus acetylcholine), Nimotop, and Neurontin (still the most effective oral agent but is being pushed by Tasmar). I am doing trials with Ketamine eyedrops.
Klonopin: The benzodiazepine to use if you are going to use one. Affects neurosteroid biosynthesis.
Kutapressin: I don't know how this drug works, but some patients have immediate symptomatic improvement after 2 ml IM. I don't usually prescribe it otherwise since there are so many immediate-acting options. It does increase bradykinin, and adverse drug reactions may be treated with drugs like Vasotec (ACE inhibitors).
Lamictal: One of the new anti-epileptic drugs. All of them increase GABA, and most of them are N-methyl-d-aspartate (NMDA) antagonists. Works immediately. The main adverse drug reaction is a rash, which can be minimized by gradual dosage escalations. Affects all symptoms. 50-100 mg of Larnictal and 800-1200 mg of Neurontin have rendered euthymic in 30 minutes every patient with acute manic excitement I have treated. Zyprexa and Rilutek could be added to this cocktail if necessary. Lamictal is also an antidepressant and may also work over four weeks or so.
IV lidocaine: In addition to its actions mentioned in Betrayal by the Brain, it also acts as an NMDA antagonist. It is the second best treatment. I have given it about a thousand times without a serious adverse drug reaction. Patients have come with great difficulty from other states or countries with the common lament of "If you can't help me I'm going to kill myself' (I hear this about twice a week). At least two patients, achieving complete symptomatic relief with IV lidocaine, returned home and could not find a physician or nursing service to administer it. Since they could not move to southern California, they were again bedridden and had to crawl to the bathroom. Not able to live this way any longer, they committed suicide, a worse outcome than the lidocaine toxicity, which never happens. Many physicians will not prescribe any of the medications I use, even if they help their patients a lot. Some medium-sized cities have not one physician who will care for CFS patients. I must treat them from afar, a hazardous practice medicolegally.
Marinol: Marinol-deta-9-tetrahydrocannobinol is a medication I use rarely, because of the medicolegal implications. Among other things, it is a dopamine agonist in the limbic system (at the nucleus accumbens, a key structure in CFS), but an indirect one. It is also a calcium channel blocker. A few patients get total symptomatic relief with Marinol when one hundred other medications have failed. One such patient is applying for disability only because she cannot afford it. It is one of the last and best options for treating the diffuse pain of FMS, and is good for atypical facial pain. In five years it should be used routinely in many situations.
Methadone: Another drug I don't use very often, and for the same reason, although California has passed a law that physicians cannot be prosecuted for using opioids responsibly to treat chronic pain. Thus, it is less risky for me. Physicians in some states are afraid to prescribe it. It is the opioid of choice. Besides being an agonist at the mu opioid receptor, it is an NMDA receptor antagonist (like Ketamine), and blocks the serotonin transporter (like SRIs). I described its use as an antidepressant about 15 years ago in the medical literature. It is very cheap, does not produce much opioid euphoria, and often ameliorates all neurosomatic symptoms.
Nicotine Patch or Gum: I have been prescribing nicotine in these forms for a long time. Nicotine is analgesic, probably by virtue of its stimulating secretion of dopamine and norepinephrine. It binds to the nicotinic cholinergic receptor and can also have profound effects on mood, energy, and cognition. An occasional patient will have worsening of symptoms with nicotine.
Papaverine SA: Marketed many years ago as a vasodilator, this medication will probably be discontinued shortly. It is the only drug available that inhibits adenylate cyclase, thereby increasing cyclic AMP, which you may recall from biology class as being pretty important. There is an experimental antidepressant, rolipram, which has a similar mode of action. It preferentially affects energy, alertness, and cognition, and has very few adverse drug reactions. It is a top-10 drug (cheap, too).
Pentazocine (Talwin):Occasionally, an extremely treatment-resistant individual has felt much better after taking pentazocine plus naloxone (Talwin-Nx).
Spironolactone (Aldactone): Spironolactone (a mineralocorticoid receptor antagonist) has been used for several years to treat premenstrual syndrome. My experience with spironolactone is that it helps only occasionally, but the effect is rapid (30 minutes or so), and thus can be assessed while the patient is in the office.
St. John's Wort (Hypericum): The other good "natural" remedy for CFS.
Tasmar (Tolcapone): Neither an exotic location on the Silk Road nor a Mafia-run turnpike in Chicago, Tasmar is a unique agent. It inhibits the enzyme catechol-ortho-methyltransferase (COMT), one of the two enzymes (monomine oxidase is the other) that metabolizes dopamine and norepinephrine. Tasmar degrades them in the synaptic cleft. I have been waiting for this drug for years. It is marketed for Parkinson's disease, and most physicians have not heard of it yet. It can work as monotherapy, either acutely or after four weeks or so. It may be more effective (immediately) when combined with a dopamine agonist such as Requip (quinpirole) or a reversible inhibitor of monoamine oxidase (RIMA) such as meclobemide, which due to the wisdom of the FDA is available in every other industrialized country in the world but the USA. The package insert advises against combining it with irreversible MAOIs such as Nardil and Pamate, so I have not done so. This combination would leave reuptake as the only mechanism to terminate the post-synaptic effect of catecholamines, although rats do quite well on the two drugs. An accountant, unable to work for three years, is back to work now on meclobemide and Tasmar. Adding Sinemet may enhance the action of Tasmar, since it is metabolized to dopamine. Sinemet may be given instead of Requip or Mirapex, or concomitantly. Requip and Mirapex are useful in that they are D3 agonists also. The D3 receptor is located primarily in the limbic system. Since COMT is a methyl group acceptor, it may work better by combining it with S-adenosylmethionine (SAMe), a methyl group donor with no adverse drug reactions, effective in FMS and depression. SAMe is available in many other countries, and certain buyer's clubs will supply you with it. Tasmar inactivates COMT, allowing SAMe to transfer methyl groups to precursors so that more norepinephrine can he formed. This process is termed "transmethylation" and is too complicated to discuss further in this column. Interested readers may consult the work of John R. Sinythies and R.J. Baldessarini and go from there.
Topamax: Another new AED, Topamax has a little more affinity for the ANWA glutamate receptor, as well as the NMDA receptor. It has very few adverse drug reactions, and when it works, is quite energizing. Agonists at the third major class of glutamate receptor, the "metabotropic," of which there are of course various subtypes, are being developed as anxiolytics.
Viagra: I don't have enough money to buy stock in anything, but buying Pfizer a few months ago would have been almost as good as buying Microsoft in 1985. This drug works by inhibiting type 5 phosphodiesterase, one of the six known enzymes to degrade cyclic GMP (as important as cyclic AMP, but maybe not covered in biology class). Type 5 is supposed to be specific for the corpus cavemosurn of the penis and probably the clitoris as well. It is not all that specific, though, at least in my patients, who frequently experience flushing and headache. When Viagra works in CFS/FMS, patients experience a reduction in all symptoms. One patient whom I have been treating for 10 years had not responded to one medication until she took Viagra, whereupon she felt almost normal. Nitroglycerin and hydralazine, which stimulate cyclic GMP by different mechanisms, had not helped her.
Zyprexa: One of the new "atypical neuroleptics," with Risperdal and Seroquel, Zyprexa can he used as a sleeping aid, antidepressant, anxiolytic, and of special relevance to my practice, is probably the most effective treatment for borderline personality disorder. You can look up the symptoms in the DSM-IV, personality disorder.
SOURCES:
“Treatment Protocol for Physicians.” The National Forum: http://www.ncf-net.org/forum/jay.htm
Dr. Goldstein's summary of his protocol for physicians.
Goldstein, Jay A. Betrayal by the Brain: The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders. Binghamton, New York: Haworth Medical Press, 1996.
This book is filled with valuable information about how the CFS/ME brain works, and how medications affect it, but you will need a background in biochemistry to make full use of it.
“The Neuropharmacology of Chronic Fatigue Syndrome.” Jay Goldstein: http://www.cfids-cab.org/cfs-inform/Optimists/goldstein98.html
In this article, Dr. Goldstein provides an in-depth discussion of diagnosis, tests, associated disorders, and neurological findings in CFS/ME patients. From these, Dr. Goldstein draws the conclusion that other than limbic encephalopathy there is no other no other mechanism that could create the constellation symptoms found in CFS/ME.
Dr. Jay Goldstein (now retired) was a psychiatrist and psychopharmacologist. He published over forty papers in peer-reviewed journals, often related to pharmacotherapy, and pioneered the use of medications for off-label applications. Dr. Goldstein also wrote five medical books, most of them about CFS/ME.
Dr. Goldstein's approach to treating CFS/ME was so novel, and his ideas concerning the role of the midbrain so ground-breaking, that it is well worth looking at his methods and treatments. Dr. Goldstein's case studies shed light on many of the neurological deficits experienced by people with CFS/ME, as well as the treatments that might alleviate them. In light of recent studies documenting brain anomalies and nervous system excitoxicity in CFS/ME patients, Dr. Goldstein's work was clearly ahead of its time.
In a nutshell, Dr. Goldstein's theory – as laid out in his book, Betrayal by the Brain – was that CFS/ME is essentially a communication problem. He described CFS/ME as a “neurosomatic” illness, that is, a disorder of central nervous system processing. The purpose of his treatments was essentially to reset the brain, specifically the limbic system, via pathways going to the brain (these are referred to as “afferent”), so that the CNS would return to its normal functioning.
Typically, when Dr. Goldstein saw new patients, he would test them sequentially with minute quantities of many psychoactive drugs in order to 1) identify the source of the problem, and 2) establish which drugs would be most effective. This method allowed Dr. Goldstein to assess the patient rapidly, and at minimal cost. Dr. Goldstein halted sequential trials when the patient was “virtually asymptomatic.” Dr. Goldstein claimed that using this protocol most patients were dramatically improved in one or two office visits.
Many of Dr. Goldstein's treatments are still in use by CFS/ME clinicians, but so far no one has so thoroughly explained their neurological effects on CFS/ME.
The following is taken from Dr. Goldstein's book, Betrayal by the Brain, “Treatment Protocol for Physicians,” and “Tiptoe Through The Treatments: A Brief Guide To Some of What's New Since Betrayal by The Brain."
_____________________________________________________________
A Typical Neurosomatic New Patient Treatment Protocol
Agents tried sequentially Onset of Action Duration of action
1. Naphazoline HCL 0.1% gtt ┬OU 2 - 3 seconds 3 - 6 hours
2. Nitroglycerin 0.04 mg sublingual 2 - 3 minutes 3 - 6 hours
3. Nimodipine 30 mg po 20 - 40 minutes 4 - 8 hours
4. Gabapentin 100-800 mg po 30 minutes 8 hours
5. Baclofen 10 mg 30 minutes 8 hours
6. Oxytocin 5-10 U IM or BID
or
Syntocinon 1-2 puffs TID 15 minutes - 72 hrs 12 - 24 hours
7. Pyridostigmine 30 - 60 mg po 30 minutes 4 - 6 hours
8. Hydralazine 10 - 25 mg po 30 - 45 minutes 6 - 12 hours
9. Mexiletine 150 mg po 30 - 45 minutes 6 - 8 hours
10. Tacrine 10 mg 30 minutes 4 - 6 hours
11. Risperidone 0.25 - 0.5 mg 45 - 60 minutes 8 - 12 hours
12. Pindolol 5 mg BID 15 minutes - 7 days 12 hours
13. Lamotrigine 25 - 50 mg QD 30 - 45 minutes 24 hours
14. Sumatriptan 3 - 6 mg SQ 15 - 30 minutes 16 hours
15. Ranitidine 150 mg BID 1 hour - 1 week 12 - 24 hours
16. Doxepin HCL elixir 2 - 20 mg HS 1 hour variable
17. Sertraline 25 - 50 mg QAM
or
Paroxetine 10 - 20 mg QAM 1 hour - 8 weeks 1 - 2 days
18. Bupropion 100 mg TID 30 minutes - 8 weeks 8 - 24 hours
19. Nefazodone 100 - 300 mg BID 2 - 8 weeks 24 hours
20. Venlafaxine 37.5 - 75 mg BID 1 - 4 weeks 24 hours
21. Glycine powder 0.4 Gm/Kg/day in juice
or
Cycloserine 15 - 20 mg QD 1 hour 24 hours
22. Felbamate 400 mg 30 minutes 6 - 8 hours
23. Lidocaine 200-300 mg
A-Z Treatments (Comments are by Dr. Goldstein)
Acetazolamide (Diamox): This drug is a carbonic anhydrase (CA) inhibitor which is routinely used as a cerebral vasodilator in nuclear medicine. Patients will occasionally have a reduction in symptomatology with acetazolamide. Acetazolamide 250 mg eliminated the pain of a 41-year-old female patient with post-traumatic fibromyalgia, helped her feel very relaxed, and markedly reduced her other symptoms.
Acetyl-L-Carnitine: In theory, a good drug. It should work as an acetyl group donor to increase acetylcholine, and the carnitine has already been shown to be effective in a double-blind experiment by the Drs. Plioplys. Acetyl-L-carnitine also increases the levels of nerve growth factor (which are four times normal in the spinal fluid of FMS patients) and increases other transmitters like adenosine and ATP. In practice, a semi-dud.
Adderall: An amphetamine combination that a few patients find more energizing than plain dexedrine. Only about a third of CFS patients have a good response to stimulants, which act by squeezing dopamine (DA) and norepiniphrine (NE) out of neurons and glia. If these transmitters are much too low already, giving stimulants will further lower the signal-to-noise ratio and increase symptoms.
Amantadine: A weak NMDA antagonist. Helpful for a few patients. Doses higher than the PDR recommends may be more effective, but there is an increased risk of adverse drug reactions when exceeding this dose. Israelis have given 100 mg IV with good results in neurogenic pain. IV amantadine is not available in the USA. Amantadine, ketamine, dextromethorphan, and a new MNDA antagonist, memantine, can be used in trigger point injections as well as gel applications for local pain.
Ambien: The best sleeping pill. Does not cause dependence except in unusual circumstances.
Aricept: A cholinesterase inhibitor marketed for Alzheimer's disease. Has the advantage of once-a-day dosing and no requirement for liver function test. Does not work as well as Cognex, perhaps because it is not a potassium channel blocker. Cognex has several effects on neurotransmitters relevant to CFS/FMS.
Ascorbic Acid (Vitamin C): Recent research into the role of ascorbic acid in the brain (which has the highest concentrations of this substance in the entire body) has shown that this agent may be beneficial in certain patients with CFS. Ascorbate has been found to be neuroprotective, particularly by inhibiting the redox site of the NMDA receptor and diminishing calcium influx. Trials of high-dose oral ascorbic acid have been generally disappointing. Administration of ascorbic acid is done via IV doses of 25 to 50 grams diluted in half-normal saline of Ringer's lactate over a period of about 90 minutes. Adding magnesium sulfate is recommended because ascorbic acid can cause magnesium shifts from extracellular to intracellular compartments. It is beneficial to add 500 mg of calcium gluconate since ascorbic acid is a calcium chelator and could possibly lower serum calcium. Responders to IV ascorbic acid generally feel considerably better in most respects the day after treatment.
Baclofen: A greatly under used medication. A GABA-B agonist with few ADRs, it has an immediate onset of action and is still in my top 10.
Vitamin B12: Besides being vital to transmethylation (which helps to synthesize NE), B12 2g. orally in AM decreases inappropriate daytime melatonin secretion, thereby aiding in the treatment of the delayed sleep-wake cycle many CFS patients experience. Very large doses (10 g) may aid transmethylation.
BuSpar: The ideal anxiolytic in all respects except efficacy. Best used as an SSRI augmentation agent, especially combined with Visen (not generic Pindolol). Augmentation strategies, of which there are many, do not work nearly as well in CFS as they do in major depression disorder.
Clonidine: Another greatly underused drug. Can be good for central pain, ADD, anxiety. Helps all symptoms in some patients. Eliminates nightmares. Safe and cheap. Comes in a patch that lasts all day. Better than Zanaflex, another alpha-2 agonist. Tolerance and depression have not been much of a problem. Adverse drug reactions to clonidine can be reversed by yohimbine, an alpha-2 antagonist. Guanfacine (Tenex) is a less sedating alpha-2 antagonist with a 24-hour duration of action.
Dexedrine: An effective stimulant. Makes some patients calm also. May synergize with Ultram. Desoxyn may be better but has neurotoxicity. Many patients like Adderall more.
Depakote: In the CFS population its only value is in migraine prophylaxis, for which it is excellent.
Dilantin: Useless in every CFS patient I have treated with it.
DHEA: Theoretically excellent, it is a neurosteroid which is a GABA antagonist, not necessarily a good thing for some patients. Pregnenolone should be the best neurosteroid (low in PMS).
Felbamate (Felbatol): Not used much because of requirement for hematologic and liver function test monitoring. Should be tried in every treatment-resistant patient. May work when nothing else does, especially for intractable headaches. It may cause headaches, however. There's no free lunch.
Gabapentin (Neurontin): Gabapentin, an antiepileptic drug with a novel mechanism of action, has become one of my five favorite medications (the others are oxytocin, nimopidine, baclofen, and intravenous lidocaine) to treat neurosomatic disorders.
Gabitril: The only GABA reuptake inhibitor (like Prozac is a serotonin reuptake inhibitor). Very effective and very safe if you follow PDR dosing suggestions. Increase the dose too rapidly and the patient may get delirious or manic. Effects are reversible with flumazenil if necessary.
Gingko Biloba: Useful only for sexual dysfunction induced by serotonin reuptake inhibitors (SRIs). Inhibits platelet aggregation. Rare reports of brain hemorrhage. This adverse reaction raises the risk/benefit ratio.
Ginseng Saponins: Works a little like nitroglycerin, which converts to nitric oxide. Increases energy slightly.
Gotu Kola: A mild stimulant with no apparent adverse reactions.
Honey Bee Venom: As with any "natural product," bee venom has a multitude of ingredients. Patients should be skin tested for bee venom allergy first. Major constituents from my point of view are phospholipase A2 (PLA2), which makes arachidonic acid, the precursor to eicosanoids (prostaglandins, leukotrienes, etc.), dopamine and NE. When it works, the patient often feels like he has been injected with rocket fuel. Effects last about one to two weeks. Has made three patients worse, two of whom were father and daughter. Patients should have an Epi-Pen (if available) and an antihistamine with them at all times. Plaquenil antagonizes PLA2. Arachidonic acid combines with effianolamine in the brain to make anandamide, an endogenous cannabinoid (like marijuana).
H2 Receptor Antagonists: The first treatments I developed for CFS were cimetidine and ranitidine. I based this therapy on my successful experience treating acute infectious mononucleosis with cimetidine. When a CFS patient responds to an H2 antagonist (I use ranitidine), the onset of action is similar to that seen in acute infectious mononucleosis, i.e. one or two days at a dose of 150 mg b.i.d. Usually all symptoms are ameliorated. Some patients are unable to take any does of ranitidine because it makes them “hyper.”
Hydergine: The most underused effective medication in the PDR. Extremely safe. A dopamine and acetylcholine agonist. There is nothing else like it. Other dopamine agonists seem to be restricted in action to the nigrostriatal dopaminergic tract, which is not important in CFS symptoms. Not the case with Hydergine, which is quite helpful for alertness, especially in those sedated by Baclofen. As with most medications listed, it can sometimes help all symptoms.
Oxytocin: Oxytocin has a wide range of behavioral effects. Oxytocin neurons project to many areas of the limbic system, as well as to the frontal cortex. Oxytocin is involved in maternal behavior, female and male sexual behavior, feeding, social behavior, and memory. It also has effects on cardiovascular, autonomic, and thermoregulatory processes. Approximately one-fifth of my patients have a good response to IM oxytocin after failing to respond to numerous oral agents. Cognitive clarity is the most responsive symptom, with fibromyalgia and pain being second.
Kava-Kava: One of the two best "natural products" for CFS. May take up to eight weeks to have an effect. No adverse drug reactions.
Ketamine: The best single agent for CFS/FMS and all other neurosomatic disorders. Known best as an NMDA receptor antagonist (the NMDA receptor is one of the several receptors for the excitatory amino acid glutamate), it increases dopamine in the limbic system, a very important objective in CFS. I administer it by slow intravenous infusion or in PLO gel for transdermal (through the skin) absorption. The intravenous route is more effective, but transdermal application can be done daily, and if effective, can obviate peaks and valleys and need for IVs. I have seen no cases of Ketamine abuse among my patients. Ketamine is one component of my "resurrection cocktail," for patients who have been bedridden for more than a year and whom I may only see once. The others are IV ascorbate, IV lidocaine, IV thyrotropin- releasing hormone (which raises all biogenic amines plus acetylcholine), Nimotop, and Neurontin (still the most effective oral agent but is being pushed by Tasmar). I am doing trials with Ketamine eyedrops.
Klonopin: The benzodiazepine to use if you are going to use one. Affects neurosteroid biosynthesis.
Kutapressin: I don't know how this drug works, but some patients have immediate symptomatic improvement after 2 ml IM. I don't usually prescribe it otherwise since there are so many immediate-acting options. It does increase bradykinin, and adverse drug reactions may be treated with drugs like Vasotec (ACE inhibitors).
Lamictal: One of the new anti-epileptic drugs. All of them increase GABA, and most of them are N-methyl-d-aspartate (NMDA) antagonists. Works immediately. The main adverse drug reaction is a rash, which can be minimized by gradual dosage escalations. Affects all symptoms. 50-100 mg of Larnictal and 800-1200 mg of Neurontin have rendered euthymic in 30 minutes every patient with acute manic excitement I have treated. Zyprexa and Rilutek could be added to this cocktail if necessary. Lamictal is also an antidepressant and may also work over four weeks or so.
IV lidocaine: In addition to its actions mentioned in Betrayal by the Brain, it also acts as an NMDA antagonist. It is the second best treatment. I have given it about a thousand times without a serious adverse drug reaction. Patients have come with great difficulty from other states or countries with the common lament of "If you can't help me I'm going to kill myself' (I hear this about twice a week). At least two patients, achieving complete symptomatic relief with IV lidocaine, returned home and could not find a physician or nursing service to administer it. Since they could not move to southern California, they were again bedridden and had to crawl to the bathroom. Not able to live this way any longer, they committed suicide, a worse outcome than the lidocaine toxicity, which never happens. Many physicians will not prescribe any of the medications I use, even if they help their patients a lot. Some medium-sized cities have not one physician who will care for CFS patients. I must treat them from afar, a hazardous practice medicolegally.
Marinol: Marinol-deta-9-tetrahydrocannobinol is a medication I use rarely, because of the medicolegal implications. Among other things, it is a dopamine agonist in the limbic system (at the nucleus accumbens, a key structure in CFS), but an indirect one. It is also a calcium channel blocker. A few patients get total symptomatic relief with Marinol when one hundred other medications have failed. One such patient is applying for disability only because she cannot afford it. It is one of the last and best options for treating the diffuse pain of FMS, and is good for atypical facial pain. In five years it should be used routinely in many situations.
Methadone: Another drug I don't use very often, and for the same reason, although California has passed a law that physicians cannot be prosecuted for using opioids responsibly to treat chronic pain. Thus, it is less risky for me. Physicians in some states are afraid to prescribe it. It is the opioid of choice. Besides being an agonist at the mu opioid receptor, it is an NMDA receptor antagonist (like Ketamine), and blocks the serotonin transporter (like SRIs). I described its use as an antidepressant about 15 years ago in the medical literature. It is very cheap, does not produce much opioid euphoria, and often ameliorates all neurosomatic symptoms.
Nicotine Patch or Gum: I have been prescribing nicotine in these forms for a long time. Nicotine is analgesic, probably by virtue of its stimulating secretion of dopamine and norepinephrine. It binds to the nicotinic cholinergic receptor and can also have profound effects on mood, energy, and cognition. An occasional patient will have worsening of symptoms with nicotine.
Papaverine SA: Marketed many years ago as a vasodilator, this medication will probably be discontinued shortly. It is the only drug available that inhibits adenylate cyclase, thereby increasing cyclic AMP, which you may recall from biology class as being pretty important. There is an experimental antidepressant, rolipram, which has a similar mode of action. It preferentially affects energy, alertness, and cognition, and has very few adverse drug reactions. It is a top-10 drug (cheap, too).
Pentazocine (Talwin):Occasionally, an extremely treatment-resistant individual has felt much better after taking pentazocine plus naloxone (Talwin-Nx).
Spironolactone (Aldactone): Spironolactone (a mineralocorticoid receptor antagonist) has been used for several years to treat premenstrual syndrome. My experience with spironolactone is that it helps only occasionally, but the effect is rapid (30 minutes or so), and thus can be assessed while the patient is in the office.
St. John's Wort (Hypericum): The other good "natural" remedy for CFS.
Tasmar (Tolcapone): Neither an exotic location on the Silk Road nor a Mafia-run turnpike in Chicago, Tasmar is a unique agent. It inhibits the enzyme catechol-ortho-methyltransferase (COMT), one of the two enzymes (monomine oxidase is the other) that metabolizes dopamine and norepinephrine. Tasmar degrades them in the synaptic cleft. I have been waiting for this drug for years. It is marketed for Parkinson's disease, and most physicians have not heard of it yet. It can work as monotherapy, either acutely or after four weeks or so. It may be more effective (immediately) when combined with a dopamine agonist such as Requip (quinpirole) or a reversible inhibitor of monoamine oxidase (RIMA) such as meclobemide, which due to the wisdom of the FDA is available in every other industrialized country in the world but the USA. The package insert advises against combining it with irreversible MAOIs such as Nardil and Pamate, so I have not done so. This combination would leave reuptake as the only mechanism to terminate the post-synaptic effect of catecholamines, although rats do quite well on the two drugs. An accountant, unable to work for three years, is back to work now on meclobemide and Tasmar. Adding Sinemet may enhance the action of Tasmar, since it is metabolized to dopamine. Sinemet may be given instead of Requip or Mirapex, or concomitantly. Requip and Mirapex are useful in that they are D3 agonists also. The D3 receptor is located primarily in the limbic system. Since COMT is a methyl group acceptor, it may work better by combining it with S-adenosylmethionine (SAMe), a methyl group donor with no adverse drug reactions, effective in FMS and depression. SAMe is available in many other countries, and certain buyer's clubs will supply you with it. Tasmar inactivates COMT, allowing SAMe to transfer methyl groups to precursors so that more norepinephrine can he formed. This process is termed "transmethylation" and is too complicated to discuss further in this column. Interested readers may consult the work of John R. Sinythies and R.J. Baldessarini and go from there.
Topamax: Another new AED, Topamax has a little more affinity for the ANWA glutamate receptor, as well as the NMDA receptor. It has very few adverse drug reactions, and when it works, is quite energizing. Agonists at the third major class of glutamate receptor, the "metabotropic," of which there are of course various subtypes, are being developed as anxiolytics.
Viagra: I don't have enough money to buy stock in anything, but buying Pfizer a few months ago would have been almost as good as buying Microsoft in 1985. This drug works by inhibiting type 5 phosphodiesterase, one of the six known enzymes to degrade cyclic GMP (as important as cyclic AMP, but maybe not covered in biology class). Type 5 is supposed to be specific for the corpus cavemosurn of the penis and probably the clitoris as well. It is not all that specific, though, at least in my patients, who frequently experience flushing and headache. When Viagra works in CFS/FMS, patients experience a reduction in all symptoms. One patient whom I have been treating for 10 years had not responded to one medication until she took Viagra, whereupon she felt almost normal. Nitroglycerin and hydralazine, which stimulate cyclic GMP by different mechanisms, had not helped her.
Zyprexa: One of the new "atypical neuroleptics," with Risperdal and Seroquel, Zyprexa can he used as a sleeping aid, antidepressant, anxiolytic, and of special relevance to my practice, is probably the most effective treatment for borderline personality disorder. You can look up the symptoms in the DSM-IV, personality disorder.
SOURCES:
“Treatment Protocol for Physicians.” The National Forum: http://www.ncf-net.org/forum/jay.htm
Dr. Goldstein's summary of his protocol for physicians.
Goldstein, Jay A. Betrayal by the Brain: The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders. Binghamton, New York: Haworth Medical Press, 1996.
This book is filled with valuable information about how the CFS/ME brain works, and how medications affect it, but you will need a background in biochemistry to make full use of it.
“The Neuropharmacology of Chronic Fatigue Syndrome.” Jay Goldstein: http://www.cfids-cab.org/cfs-inform/Optimists/goldstein98.html
In this article, Dr. Goldstein provides an in-depth discussion of diagnosis, tests, associated disorders, and neurological findings in CFS/ME patients. From these, Dr. Goldstein draws the conclusion that other than limbic encephalopathy there is no other no other mechanism that could create the constellation symptoms found in CFS/ME.
ampligen
DESCRIPTION. Ampligen (poly I:poly C12U) is a mismatched double-stranded RNA (ribonucleic acid) with immodulatory and antiviral properties. Because Ampligen has not yet been approved by the Food and Drug Administration (FDA), its use to date has been experimental.
BACKGROUND. In the early 1980s, a molecule called Poly(I)-Poly(C) was found to inhibit tumor growth and stimulate interferon production. As a result, it was used in a number of cancer trials. However, it was discovered that the substance made patients quite ill with serious side effects. Although Poly(I)-Poly(C) was extremely toxic, the toxicity decreased significantly when the structure of the RNA was altered. Fortunately, the effectiveness of the new substance (Ampligen) was not diminished, despite the change in structure.
In 1987 Ampligen was used experimentally in a small group of patients with AIDS (acquired immunodeficiency syndrome). The positive results of this trial seemed to confirm the claim that Ampligen works by enhancing natural killer cell function and influencing the 2-5A synthetase pathway. This pathway is vital in the defense against viral infections. According to Dr. Robert Suhadolnick of Temple University in Philadelphia, there are defects in key components in the antiviral system in some CFS/ME patients, the most notable of which are low latent 2-5A synthetase and upregulated RNase (ribonuclease) L activity (Journal of Interferon and Cytokine Research, 1997). Ampligen is believed to correct both of these defects.
USES IN CFS/ME. In August 1988, Dr. Daniel Peterson, a pioneer in CFS/ME treatment, was the first physician to use Ampligen on an extremely ill patient with CFS/ME. Because of the severity of the patient's illness, Dr. Peterson was able to obtain permission from the FDA to use Ampligen under compassionate care status. The results were impressive and encouraging. One year into therapy the patient had recovered near-normal function in some areas and demonstrated a 46-point increase in IQ. This justified the next pilot study by Dr. Peterson, as well as several other formal studies conducted independently.
At the 1990 CFIDS Conference in Charlotte, North Carolina, and at the Cambridge Symposium, Dr. Peterson reported positive results after treating 15 patients with Ampligen. At the end of 24 weeks, most of the patients demonstrated increased performance status (using Karnofsky scores) and exercise tolerance (as measured by treadmill testing). Cognitive improvement was demonstrated by improved memory and increased IQ scores. No significant toxicity was reported. Ampligen's antiviral properties were confirmed by evidence that human herpesvirus 6 (HHV-6) reactivation was absent after treatment and abnormal components of the 2-5A pathway returned to normal range. It is of interest that of the two or three patients who did not respond to Ampligen therapy, the only significant pretreatment distinction was measurable differences in 2-5A synthetase pathways.
The encouraging results of Dr. Peterson's study paved the way for a larger FDA-approved double-blind study in 1991 involving 92 patients in four U.S. cities. Again the results were encouraging. Many of the participants had been severely disabled before treatment and required assistance for simple daily activities. More than half of those in the study who received Ampligen demonstrated improvement and many were able to carry out daily activities with minimal assistance.
A study performed in Brussels, Belgium (presented at the 1996 American Association for Chronic Fatigue Syndrome
(AACFS) Conference) to evaluate the safety and efficacy of intravenously administered Ampligen also showed encouraging results. Eleven patients with myalgic encephalomyelitis (ME) were given intravenous Ampligen twice a week for 24 weeks. The Belgian physicians reported that at the end of 24 weeks, all 11 experienced some improvement. In addition, no adverse effects to treatment were noted. These positive results paved the way for expanded trials. It was hoped that with an expansion of clinical trials to Canada and Belgium, and Ampligen's
subsequent approval for Canada's Emergency Drug Release Program, that the drug would soon be approved for use in the U.S.
Unfortunately, since 1996 little progress has been made in obtaining FDA approval of the drug. A seemingly endless series of lawsuits, missed deadlines and administrative setbacks effectively quashed the widespread support the drug had enjoyed in the 90s. To cap the matter, in 2009, after the completion of Phase III of Ampligen's drug trials, the FDA refused to grant Ampligen “new drug,” status which, in effect, relegated Ampligen once more to clinical trials.
Recently,the results of a multi-center Phase III Ampligen trial were reported in the medical journal, PLoS ONE. (This Phase III trial took place between 1998 and 2004.) Much like previous studies, the trial found that Ampligen was of marginal benefit to some, but not all, severely ill patients. Notwithstanding these less than impressive results, Hemispherx Biopharma again filed for approval of the drug with the FDA.
On December 20, 2012 a committee of advisers to the US Food and Drug Administration (FDA) voted 9–4 against approving the drug. The committee determined that the drug had not been shown to be effective or safe. The committee's decision was undoubtedly taken into consideration on February 4th, 2013 when the FDA formally announced that it would not approve Ampligen. The FDA recommended that Hemispherx conduct at least one additional clinical trial, complete various nonclinical studies and perform a number of data analyses. Given the expense of the additional requirements, there is some question as to whether Hemispherx can afford to continue seeking FDA approval for the drug.
PROTOCOL. Because this drug is still, after more than twenty years, in the trial phase, treatment protocols are still evolving. Ampligen is quite fragile, which makes administration difficult (it must be given intravenously). Two intravenous infusions a week of between 10 mg - 400 mg are given over a 6- to 12-month period, though some doctors recommend a course of treatment up to 18 months for more severely ill patients. Longer courses of treatment seem to produce longer lasting results.
PROS. No other drug has received more attention from the CFS/ME community than Ampligen. But even in the wake of delays, reversals and lawsuits, many doctors still defend Ampligen as the most effective drug for those patients who have acute viral onset, persistent herpesvirus infections, depressed natural killer cell function, and 2-5A synthesase/RNase L up-regulation. For those who have been bedridden for years, who are confined to wheelchairs, and whose lives have lost all semblance of normality,Ampligen may be a godsend, and the frustration of those who have experienced a return to a functional life during Ampligen trials, only to have it taken away again at the end of the trial, is more than justified.
Dr. Kenny DeMeirleir claims that close to 80% of his patients reported“complete clinical recovery” after taking an extended course of treatment. Patients report improvement in overall function, energy levels, cognitive performance, and some have been able to return to work. Dr. Lapp, who has been using Ampligen since 1998, reports significant improvement in 50% of his severely ill patients. It is important to note that while few doctors claim that Ampligen works for the majority of their patients, it seems to have a very positive effect on a subset of those who are the most seriously ill, and that, in and of itself, provides a good reason for Hemispherx to pursue Ampligen's final approval.
CONS. Although test results are encouraging, it is important to note that Ampligen is not a surefire cure. The percentage of patients who demonstrate substantial improvement with the drug has yet to be determined. Side effects are common. Although Hermispherx maintains that Ampligen is generally well tolerated, patients have reported diarrhea, constipation, flushing, temporary vision loss, muscle aches, depression, loss of libido, dizziness, chills, fever, malaise, anxiety, and loss of energy.
Dr. Peterson reported at the 1990 CFIDS Conference that some patients experienced an interferon-like reaction, with headaches, myalgias, and, rarely, hair loss. A puzzling effect noted by Dr. Paul Cheney was that although patients report overall lessening of symptoms, particularly cognitive symptoms, they do not necessarily equate this lessening of severity to “feeling good” (CFIDS Chronicle, Physicians Forum, 1991). Side effects usually subside after several months, but that may be too long for many patients to endure.
AVAILABILITY AND COST. As of 2011, Ampligen was available only at Dr. Lapp's Hunter-Hopkins clinic in Charlotte, NC, and Dr. Peterson’s Lake Tahoe clinic under an open-label trial. (An open-label trial is one in which all patients receive,and pay for, the drug.) Dr. Bateman’s Fatigue Consultation Clinic in Salt Lake City and Dr. Enlander's clinic in New York have also begun to seek recruits for an open-label trial. Hemispherx is planning to add several other sites around the U.S., as well as sites in Mexico and Argentina. In July 2012, Hemispherx announced that it had submitted a new drug application to ANMAT (Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica), the agency responsible for the national regulation of drugs, foods and medical technology in Argentina, under the ANMAT's Orphan Drug regulations.
Ampligen is quite expensive. A single infusion at the highest dosage costs $150. At two infusions a week, that amounts to $1200 per month. Additional costs, such as medical visits, lab work and the administration of the infusions, can amount to $1000 a month. Altogether, one year of treatment may cost over $24,000. The lower dosage, which is more commonly used for CFS/ME patients, is much less expensive, amounting to about $7,200 a year. Patients must pay for the cost of the treatment because Ampligen is available on a cost recovery basis only. Some insurers will reimburse for administration costs and lab work, which can save thousands of dollars. Medicare does not cover any expenses for investigational therapies.
MORE INFORMATION
The Hunter-Hopkins Center's report from the 9th Hemispherx Biopharma investigators meeting. Quite technical but very thorough:http://www.drlapp.net/meLetterMar2011.htm
NIH webpage on clinical trials. Shows current status of Ampligen trials.
http://www.clinicaltrials.gov/ct2/show/NCT00215813?term=00215813&rank=1
Informative thread on patient experiences with Ampligen.http://forums.phoenixrising.me/showthread.php?12999-Ampligen-Experiences
Dr. Lapp's Ampligen protocol:http://www.drlapp.net/ampligen.htm
Hemispherx Biopharma's page on Ampligen.http://www.hemispherx.net/content/rnd/drug_candidates.htm
A fascinating blog written by a New Zealand journalist who moved to the U.S. to participate in an open-label Ampligen trial:http://ampligen-treatment.blogspot.com/
San Francisco Ampligen trial (with prices):http://phoenixrising.me/forums/showthread.php?12305-Ampligen-Treatment-Study-(AMP-511)-starting-in-San-Francisco-Bay-Area
ProHealth's history of Ampligen:
http://aboutmecfs.org.violet.arvixe.com/Trt/AmpHist.aspx
Dr. Lapp on XMRV & Ampligen - Information that may “change the field of medicine forever”
http://www.prohealth.com/library/showarticle.cfm?libid=16037
Cort Johnson's up-to-date news on the status of Ampligen:http://phoenixrising.me/archives/8819?utm_source=newsletter+subscribers&utm_campaign=9dd3ad21ce-April_Newsletter4_28_2012&utm_medium=email
Susan Vernon's article, Rintatolimod, aka Ampligen, on Trial. March 21, 2012.
http://www.research1st.com/2012/03/21/ampligen-on-trial/
"Ampligen On the Clock: Hemispherx’s ‘Complete Response’ Means Ball is Now in FDA’s Court Now" Cort Johnson again brings us up to date on Ampligen's status: http://phoenixrising.me/archives/12914
"Panel rejects experimental chronic fatigue syndrome drug." 21 Dec 2012 by Heidi Ledford http://blogs.nature.com/news/2012/12/panel-rejects-experimental-chronic-fatigue-syndrome-drug.html
"Hemispherx Biopharma Receives Complete Response Letter from FDA on Ampligen New Drug Application for Chronic Fatigue Syndrome." Feb 5, 2013. Press Release.
http://www.marketwatch.com/story/hemispherx-biopharma-receives-complete-response-letter-from-fda-on-ampligenr-new-drug-application-for-chronic-fatigue-syndrome-2013-02-04
BACKGROUND. In the early 1980s, a molecule called Poly(I)-Poly(C) was found to inhibit tumor growth and stimulate interferon production. As a result, it was used in a number of cancer trials. However, it was discovered that the substance made patients quite ill with serious side effects. Although Poly(I)-Poly(C) was extremely toxic, the toxicity decreased significantly when the structure of the RNA was altered. Fortunately, the effectiveness of the new substance (Ampligen) was not diminished, despite the change in structure.
In 1987 Ampligen was used experimentally in a small group of patients with AIDS (acquired immunodeficiency syndrome). The positive results of this trial seemed to confirm the claim that Ampligen works by enhancing natural killer cell function and influencing the 2-5A synthetase pathway. This pathway is vital in the defense against viral infections. According to Dr. Robert Suhadolnick of Temple University in Philadelphia, there are defects in key components in the antiviral system in some CFS/ME patients, the most notable of which are low latent 2-5A synthetase and upregulated RNase (ribonuclease) L activity (Journal of Interferon and Cytokine Research, 1997). Ampligen is believed to correct both of these defects.
USES IN CFS/ME. In August 1988, Dr. Daniel Peterson, a pioneer in CFS/ME treatment, was the first physician to use Ampligen on an extremely ill patient with CFS/ME. Because of the severity of the patient's illness, Dr. Peterson was able to obtain permission from the FDA to use Ampligen under compassionate care status. The results were impressive and encouraging. One year into therapy the patient had recovered near-normal function in some areas and demonstrated a 46-point increase in IQ. This justified the next pilot study by Dr. Peterson, as well as several other formal studies conducted independently.
At the 1990 CFIDS Conference in Charlotte, North Carolina, and at the Cambridge Symposium, Dr. Peterson reported positive results after treating 15 patients with Ampligen. At the end of 24 weeks, most of the patients demonstrated increased performance status (using Karnofsky scores) and exercise tolerance (as measured by treadmill testing). Cognitive improvement was demonstrated by improved memory and increased IQ scores. No significant toxicity was reported. Ampligen's antiviral properties were confirmed by evidence that human herpesvirus 6 (HHV-6) reactivation was absent after treatment and abnormal components of the 2-5A pathway returned to normal range. It is of interest that of the two or three patients who did not respond to Ampligen therapy, the only significant pretreatment distinction was measurable differences in 2-5A synthetase pathways.
The encouraging results of Dr. Peterson's study paved the way for a larger FDA-approved double-blind study in 1991 involving 92 patients in four U.S. cities. Again the results were encouraging. Many of the participants had been severely disabled before treatment and required assistance for simple daily activities. More than half of those in the study who received Ampligen demonstrated improvement and many were able to carry out daily activities with minimal assistance.
A study performed in Brussels, Belgium (presented at the 1996 American Association for Chronic Fatigue Syndrome
(AACFS) Conference) to evaluate the safety and efficacy of intravenously administered Ampligen also showed encouraging results. Eleven patients with myalgic encephalomyelitis (ME) were given intravenous Ampligen twice a week for 24 weeks. The Belgian physicians reported that at the end of 24 weeks, all 11 experienced some improvement. In addition, no adverse effects to treatment were noted. These positive results paved the way for expanded trials. It was hoped that with an expansion of clinical trials to Canada and Belgium, and Ampligen's
subsequent approval for Canada's Emergency Drug Release Program, that the drug would soon be approved for use in the U.S.
Unfortunately, since 1996 little progress has been made in obtaining FDA approval of the drug. A seemingly endless series of lawsuits, missed deadlines and administrative setbacks effectively quashed the widespread support the drug had enjoyed in the 90s. To cap the matter, in 2009, after the completion of Phase III of Ampligen's drug trials, the FDA refused to grant Ampligen “new drug,” status which, in effect, relegated Ampligen once more to clinical trials.
Recently,the results of a multi-center Phase III Ampligen trial were reported in the medical journal, PLoS ONE. (This Phase III trial took place between 1998 and 2004.) Much like previous studies, the trial found that Ampligen was of marginal benefit to some, but not all, severely ill patients. Notwithstanding these less than impressive results, Hemispherx Biopharma again filed for approval of the drug with the FDA.
On December 20, 2012 a committee of advisers to the US Food and Drug Administration (FDA) voted 9–4 against approving the drug. The committee determined that the drug had not been shown to be effective or safe. The committee's decision was undoubtedly taken into consideration on February 4th, 2013 when the FDA formally announced that it would not approve Ampligen. The FDA recommended that Hemispherx conduct at least one additional clinical trial, complete various nonclinical studies and perform a number of data analyses. Given the expense of the additional requirements, there is some question as to whether Hemispherx can afford to continue seeking FDA approval for the drug.
PROTOCOL. Because this drug is still, after more than twenty years, in the trial phase, treatment protocols are still evolving. Ampligen is quite fragile, which makes administration difficult (it must be given intravenously). Two intravenous infusions a week of between 10 mg - 400 mg are given over a 6- to 12-month period, though some doctors recommend a course of treatment up to 18 months for more severely ill patients. Longer courses of treatment seem to produce longer lasting results.
PROS. No other drug has received more attention from the CFS/ME community than Ampligen. But even in the wake of delays, reversals and lawsuits, many doctors still defend Ampligen as the most effective drug for those patients who have acute viral onset, persistent herpesvirus infections, depressed natural killer cell function, and 2-5A synthesase/RNase L up-regulation. For those who have been bedridden for years, who are confined to wheelchairs, and whose lives have lost all semblance of normality,Ampligen may be a godsend, and the frustration of those who have experienced a return to a functional life during Ampligen trials, only to have it taken away again at the end of the trial, is more than justified.
Dr. Kenny DeMeirleir claims that close to 80% of his patients reported“complete clinical recovery” after taking an extended course of treatment. Patients report improvement in overall function, energy levels, cognitive performance, and some have been able to return to work. Dr. Lapp, who has been using Ampligen since 1998, reports significant improvement in 50% of his severely ill patients. It is important to note that while few doctors claim that Ampligen works for the majority of their patients, it seems to have a very positive effect on a subset of those who are the most seriously ill, and that, in and of itself, provides a good reason for Hemispherx to pursue Ampligen's final approval.
CONS. Although test results are encouraging, it is important to note that Ampligen is not a surefire cure. The percentage of patients who demonstrate substantial improvement with the drug has yet to be determined. Side effects are common. Although Hermispherx maintains that Ampligen is generally well tolerated, patients have reported diarrhea, constipation, flushing, temporary vision loss, muscle aches, depression, loss of libido, dizziness, chills, fever, malaise, anxiety, and loss of energy.
Dr. Peterson reported at the 1990 CFIDS Conference that some patients experienced an interferon-like reaction, with headaches, myalgias, and, rarely, hair loss. A puzzling effect noted by Dr. Paul Cheney was that although patients report overall lessening of symptoms, particularly cognitive symptoms, they do not necessarily equate this lessening of severity to “feeling good” (CFIDS Chronicle, Physicians Forum, 1991). Side effects usually subside after several months, but that may be too long for many patients to endure.
AVAILABILITY AND COST. As of 2011, Ampligen was available only at Dr. Lapp's Hunter-Hopkins clinic in Charlotte, NC, and Dr. Peterson’s Lake Tahoe clinic under an open-label trial. (An open-label trial is one in which all patients receive,and pay for, the drug.) Dr. Bateman’s Fatigue Consultation Clinic in Salt Lake City and Dr. Enlander's clinic in New York have also begun to seek recruits for an open-label trial. Hemispherx is planning to add several other sites around the U.S., as well as sites in Mexico and Argentina. In July 2012, Hemispherx announced that it had submitted a new drug application to ANMAT (Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica), the agency responsible for the national regulation of drugs, foods and medical technology in Argentina, under the ANMAT's Orphan Drug regulations.
Ampligen is quite expensive. A single infusion at the highest dosage costs $150. At two infusions a week, that amounts to $1200 per month. Additional costs, such as medical visits, lab work and the administration of the infusions, can amount to $1000 a month. Altogether, one year of treatment may cost over $24,000. The lower dosage, which is more commonly used for CFS/ME patients, is much less expensive, amounting to about $7,200 a year. Patients must pay for the cost of the treatment because Ampligen is available on a cost recovery basis only. Some insurers will reimburse for administration costs and lab work, which can save thousands of dollars. Medicare does not cover any expenses for investigational therapies.
MORE INFORMATION
The Hunter-Hopkins Center's report from the 9th Hemispherx Biopharma investigators meeting. Quite technical but very thorough:http://www.drlapp.net/meLetterMar2011.htm
NIH webpage on clinical trials. Shows current status of Ampligen trials.
http://www.clinicaltrials.gov/ct2/show/NCT00215813?term=00215813&rank=1
Informative thread on patient experiences with Ampligen.http://forums.phoenixrising.me/showthread.php?12999-Ampligen-Experiences
Dr. Lapp's Ampligen protocol:http://www.drlapp.net/ampligen.htm
Hemispherx Biopharma's page on Ampligen.http://www.hemispherx.net/content/rnd/drug_candidates.htm
A fascinating blog written by a New Zealand journalist who moved to the U.S. to participate in an open-label Ampligen trial:http://ampligen-treatment.blogspot.com/
San Francisco Ampligen trial (with prices):http://phoenixrising.me/forums/showthread.php?12305-Ampligen-Treatment-Study-(AMP-511)-starting-in-San-Francisco-Bay-Area
ProHealth's history of Ampligen:
http://aboutmecfs.org.violet.arvixe.com/Trt/AmpHist.aspx
Dr. Lapp on XMRV & Ampligen - Information that may “change the field of medicine forever”
http://www.prohealth.com/library/showarticle.cfm?libid=16037
Cort Johnson's up-to-date news on the status of Ampligen:http://phoenixrising.me/archives/8819?utm_source=newsletter+subscribers&utm_campaign=9dd3ad21ce-April_Newsletter4_28_2012&utm_medium=email
Susan Vernon's article, Rintatolimod, aka Ampligen, on Trial. March 21, 2012.
http://www.research1st.com/2012/03/21/ampligen-on-trial/
"Ampligen On the Clock: Hemispherx’s ‘Complete Response’ Means Ball is Now in FDA’s Court Now" Cort Johnson again brings us up to date on Ampligen's status: http://phoenixrising.me/archives/12914
"Panel rejects experimental chronic fatigue syndrome drug." 21 Dec 2012 by Heidi Ledford http://blogs.nature.com/news/2012/12/panel-rejects-experimental-chronic-fatigue-syndrome-drug.html
"Hemispherx Biopharma Receives Complete Response Letter from FDA on Ampligen New Drug Application for Chronic Fatigue Syndrome." Feb 5, 2013. Press Release.
http://www.marketwatch.com/story/hemispherx-biopharma-receives-complete-response-letter-from-fda-on-ampligenr-new-drug-application-for-chronic-fatigue-syndrome-2013-02-04
