#6 Mt. Sinai Standard Therapys for Fibromyalgia

Medications for Fibromyalgia

by Michelle Badash, MS

The information provided here is meant to give you a general idea about each of the medications listed below. Only the most general side effects are included, so ask your healthcare provider if you need to take any special precautions. Use each of these medications only as recommended by your healthcare provider, and according to the instructions  provided. If you have further questions about usage or side effects, contact your  healthcare provider.  Your doctor may  prescribe one or more of the following medications to help treat your fibromyalgia symptoms

Read More... #6 Mt. Sinai Standard Therapys for Fibromyalgia

#5 GHB gamma-hydroxy butyrate & Fibromyalgia

GHB gamma-hydroxy butyrate & Fibromyalgia

The Effects of Sodium Oxybate on Clinical Symptoms and Sleep Patterns in Patients with Fibromyalgia

Scharf MB, Baumann M, Berkowitz DV
Journal of Rheumatology. 2003;30(5):1070-1074

Scharf and colleagues report a double-blind, randomized, placebo-controlled cross-over trial of sodium oxybate in patients with fibromyalgia (FM). They evaluated the effects of sodium oxybate, a commercial form of gamma-hydroxybutyrate (GHB), on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic sleep variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in patients with FM. They studied 24 female patients of which 18 completed the trial. The patients who dropped out were in the active medication portion of the study, and none of the side effects were considered serious events (transient episodes of headache, anxiety attack, or paresthesia).
In the intention-to-treat analysis of all patients who entered the protocol, tender-point index was decreased from baseline by 8.5, compared with an increase of 0.4 for the placebo (P = .0079) portion of the cross-over trial. Sodium oxybate was associated with relief of 29% to 33% of 6 of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end-of-day fatigue, overall fatigue, and morning fatigue), compared with relief of 6% to 10% with placebo (P < .005). Slow-wave (stage 3/4) sleep was significantly increased while alpha intrusion, sleep latency, and rapid eye movement (REM) sleep were significantly decreased compared with placebo (P < .005). Two of the 5 subjective sleep-related variables were significantly different from placebo: morning alertness (improved by 18% with sodium oxybate, compared with 2% for placebo; P = .0033) and quality of sleep (improved by 33% and 10%, respectively; P = .0003). The investigators conclude that sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, dramatically reduced the sleep abnormalities of alpha intrusion, and decreased slow-wave sleep associated with the characteristic nonrestorative sleep. This study is important for rheumatologists, because fatigue and fibromyalgia are common problems in our patients and a new effective class of drugs may improve functional outcome in FM patients.
FM is associated with alpha intrusion during sleep[^1] and low growth hormone secretion.^[2] Moldofsky and coworkers have demonstrated that alpha intrusion on the electroencephalogram (EEG) is a normal part of wakefulness; however, when it occurs too frequently in sleep, it is accompanied by daytime complaints of musculoskeletal pain, fatigue, and altered mood.[2,3] Although the mechanisms of sleep induction maintenance in normal individuals are poorly understood,[4] they are even more complex and multifactorial in patients with FM[2] and in patients with inflammatory processes associated with proinflammatory cytokines such as tumor necrosis factor.^[5] In normal subjects, patients with FM or inflammatory conditions, and animal models, evidence for an increasingly important role for GHB has been accumulating.[6,7]

GHB is a naturally occurring metabolite of the human nervous system, with the highest concentration in the hypothalamus and basal ganglia. A commercial form of GHB has been developed as sodium oxybate. In healthy human volunteers, sodium oxybate has been shown to promote a normal sequence of non-REM and REM sleep for 2 to 3 hours. However, it is also important to recognize that GHB has gained wide recognition in the popular press as a "recreational drug" used for date rape^[8,9] as it is tasteless and creates a sense of amnesia when taken with alcohol. Thus, GHB is both a therapeutic agent and a recreational drug. It has sedative, anxiolytic, and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral gamma-aminobutyric acid-ergic and dopaminergic activities, and recent studies suggest the serotonergic system might also be involved.^[10] As the serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the stimulation of this system may be involved in certain neuropharmacologic events induced by GHB administration.^[10]
The biology of GHB may shed light on the important abnormality in sleep and the associated hypothalamic diurnal variations found in FM.[2,11] The potential importance of the study by Sharf and coworkers is that no medication has previously been shown to improve the EEG sleep arousal disorders that include phasic (alpha-delta), tonic alpha non-REM sleep disorders, or the periodic alpha cycling alternating pattern disorder.[12] Traditional hypnotic agents, while helpful in initiating and maintaining sleep and reducing daytime tiredness, do not provide restorative sleep or reduce pain. Tricyclic drugs, such as amitriptyline and cyclobenzaprine, may provide long-term benefit for improving sleep but may not have a continuing benefit beyond 1 month for reducing pain.
The basic balance between sleep and wakefulness has been an area of active interest in neurochemistry in recent years. There have been significant advances in understanding the molecular biology involved, largely based on studies of patients with narcolepsy and cataplexy. One emerging area of importance is the neuro-hormone hypocretin (orexin), whose deficiency (< 40 pg/mL) is highly associated with narcolepsy and cataplexy (89.5%).[13] In animal models of narcolepsy, the absence of hypothalamic orexin (hypocretin) neuropeptides leads to inability to maintain wakefulness and intrusion of REM sleep into wakefulness.[14] Absence of oxyrexen-2 receptor eliminates orexin-evoked excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset.
In summary, the article by Scharf and colleagues demonstrates that sodium oxybate improves functional status in fibromyalgia patients. This benefit may result from a significant reduction in the sleep abnormalities (alpha intrusion and diminished slow wave sleep) associated with the nonrestorative sleep that is a critical feature of FM. According to the authors, no other compound has been reported to reduce the alpha sleep abnormality. Although this abnormality is not specific to FM and its presence has not been distinguished as a cause or effect in FM, reducing alpha intrusion appears to correlate with clinical improvement.

References

Roizenblatt S, Moldofsky H, Benedito-Silva AA, Tufik S. Alpha sleep characteristics in fibromyalgia. Arthritis Rheum. 2001;44:222-230.
Moldofsky HK. Disordered sleep in fibromyalgia and related myofascial facial pain conditions. Dent Clin North Am. 2001;45:701-713.
Moldofsky H, Lue FA, Shahal B, Jiang CG, Gorczynski RM. Diurnal sleep/wake-related immune functions during the menstrual cycle of healthy young women. J Sleep Res. 1995;4:150-159.
Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci. 2001;24:429-458.
Dickstein JB, Moldofsky H, Hay JB. Brain-blood permeability: TNF-alpha promotes escape of protein tracer from CSF to blood. Am J Physiol Regul Integr Comp Physiol. 2000;279:R148-R151.
Gamma hydroxybutyrate (Xyrem) for narcolepsy. Med Lett Drugs Ther. 2002;44:103-105.
Xyrem approved for muscle problems in narcolepsy. FDA Consum. 2002;36:7.
Tellier PP. Club drugs: is it all ecstasy? Pediatr Ann. 2002;31:550-556.
Smalley S. The perfect crime. Newsweek. February 3, 2003:141:52.
Gobaille S, Schleef C, Hechler V, Viry S, Aunis D, Maitre M. Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain. Life Sci. 2002;70:2101-2112.
Scharf MB, Hauck M, Stover R, McDannold M, Berkowitz D. Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report. J Rheumatol. 1998;25:1986-1990.
Brooks S, Black J. Novel therapies for narcolepsy. Expert Opin Investig Drugs. 2002;11:1821-1827.
Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status. Sleep. 2002;25:733-736.
Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron. 2003;38:715-730.

Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia.

Preliminary report.

Scharf MB, Hauck M, Stover R, McDannold M, Berkowitz D Center for Research in Sleep Disorders, Cincinnati, Ohio, USA. 

OBJECTIVE: To evaluate the effects of using a gamma-hydroxybutyrate (GHB) administered in divided doses at night in 11 patients previously diagnosed with fibromyalgia (FM). 

METHODS: Subjects completed daily diaries assessing their pain and fatigue levels and slept in the sleep laboratory before and one month after initiating GHB treatment. Polysomnographic recordings were evaluated for sleep stages, sleep efficiency and the presence of the alpha anomaly in non-REM sleep. 

RESULTS: There was a significant improvement in both fatigue and pain, with an increase in slow wave sleep and a decrease in the severity of the alpha anomaly. 

CONCLUSION: Further controlled studies are needed to characterize the clinical improvement and the polysomnographic changes we observed.
 

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GHB Report - Summary

Medical Uses

GHB is being used in other countries for many medical purposes. One of the purposes that deserves special mention is its use in France and Italy as an aid to childbirth. Its ability to calm maternal anxiety, protect against hypoxic injury to the baby, and accelerate dilation of the cervix (termed "spectacular" in one report) provide a graphic contraposition to allegations of toxicity, addiction and lethality.

It is rare to find a substance with as many applications to such a host of human maladies. Few medicines have as many beneficial actions upon the body as GHB for the prevention and treatment of debility and disease. Even fewer medicines have less side effects. The scientific and medical consensus on GHB established by conscientious laboratory and clinical investigation of the applications of GHB to enhance health and decrease suffering can only be sensationalized to a limited degree before all pretense at accuracy and honesty must be abandoned. It is unfortunate, but absolutely necessary, that we assess the rationale for SB3, SB54, and AB6 in light of this research.

Toxicity
GHB is fundamentally non-toxic.

Unlike alcohol, GHB has no general toxicity or organ toxicity. It is cleanly and quickly metabolized by the liver to carbon dioxide and water. Unlike alcohol, it does not kill brain cells and it does not cause cross-linking damage (an aging effect) to either tissues or skin (i.e., wrinkling). It does not cause cirrhosis of the liver. In 30 years of research, no long-term adverse effect has yet been identified.

These properties make GHB an excellent relaxation and sleep aid for pilots, truck drivers, factory workers and military personnel because of the rapidity at which it is cleared from the system and the complete lack of any lasting pharmacological effects. This can not be said for other sleep-aid drugs which are presently widely prescribed in the US.

What Effects Does GHB Cause?
In low doses (less than a gram), GHB is a mild relaxant. It causes a subtle drop in muscle tone and a mild relaxation of inhibitions (making people more sociable), very much like drinking a beer or glass of wine. This effect lasts for 1 or 2 hours.

In moderate doses (1-2 grams), GHB causes strong relaxation (mental and physical). This effect happens in 5-10 minutes on an empty stomach and 15-30 minutes on a full stomach (like with alcohol, food dramatically decreases the strength of the effect). GHB slows and deepens respiration (causing no net effect on blood gasses) and it slows heart rate, makes people passive, calm and possibly sleepy. There may be noticeable interference with articulation, motor coordination and balance. At this dose, the effects can last 2-3 hours.

In stronger doses (2-4 grams), interference with motor control and speech is more pronounced. The relaxation effect is quite strong, often causing sleepiness or sleep. The sleep induced by GHB is very deep, making it more difficult than would usually be expected to wake somebody. This state has been inappropriately labeled "coma" by some medical authorities with minimal concern for the popular perception of such an inflammatory term. Comas are technically defined as unarrousability, but the dangerous aspects of coma have to do with hypometabolism (inadequate production of biological energy) that interferes with normal mental function. During GHB-induced sleep, all the normal physiological sleep functions of the brain (stages 1, 2, 3 and 4, and REM) take place in a normal sequence.

The sleep-enhancing properties of GHB are potentially of immense value to society. GHB selectively deepens stage 3 and 4 sleep, which are most frequently impaired in the elderly. This is probably the mechanism by which GHB treats narcolepsy. This may also be the mechanism by which GHB increases growth hormone output (which normally takes place during the deepest stages of sleep). Not all people fall asleep on GHB. At the 2-4 gram dose range, GHB's effects last about 3-4 hours. At high doses (4-8 grams), powerful deep sleep is usually induced within 5-15 minutes on an empty stomach. The effect will sometimes last up to 4 hours. At extremely high doses (10-30 grams), the deep-sleep effects last for much longer periods. The highest reported GHB dose (termed a "poisoning" by the authors) involved a man who took an estimated 15 tablespoons of GHB! He woke up 24 hours later feeling groggy with a mild headache. He had no lasting effects.

GHB: Is it Lethal?
No. Everybody reported to have been "poisoned" with GHB has "fully recovered," even the man who took 15 tablespoons (50-75 grams?). There have been no long-term consequences identified in any of these cases despite close observation by attending physicians.

Although it is possible that somebody could ingest the 50-150 grams (2-5 ounces, 5 heaping tablespoons?) that might be expected to be life threatening, it is exceedingly difficult to do so. In high doses, GHB causes nausea and vomiting, which strongly limits the maximum amount that a person can consume. It is possible that a dedicated person wishing to commit suicide might be able to take a sleep-inducing dose of GHB and then, just before falling asleep, gulp down a huge amount of GHB, but this is not something which can be done accidentally. The sodium content alone (NaGHB is 17% sodium by weight) is enough to make somebody gag. It is the equivalent of trying to swallow 2 heaping tablespoons of pure table salt.

Can GHB Contribute to Death by other Causes?
We don't know. It is possible. But there is no supporting data with which to answer this question definitively. Like alcohol, GHB is contraindicated with CNS depressants. GHB should not be taken with alcohol, tranquilizers (benzodiazepines), sedatives (barbituates), or opiates (morphine, heroin, etc.). While GHB does not seriously suppress respiration by itself, CNS depressants do. Although it has not been measured, it is possible that GHB increases that respiratory suppression when combined with these drugs.  Interestingly, GHB is being used clinically to treat drug addiction and drug withdrawal symptoms for CNS depressants and opiates. It is reported to be outstandingly effective for this use.

Depression
Regarding the effect of increased levels of happiness, some US psychiatrists now prescribe GHB as an anti-depressant agent used during the day in several small doses. The reports have been noteworthy. Several report increased levels of happiness are sustained even when the person no longer has GHB in their system. Claude Rifat, a French biologist, reported, "GHB may be the first authentic anti-depressant. GHB suppresses depressed ideation with amazing rapidity.... (GHB) strongly stimulates the desire to be and remain alive despite unfavorable circumstances. Despair disappears, replaced by a feeling that life is worth living. GHB can suppress depression within hours. No conventional so called anti-depressant does that. Conventional antidepressants can takes weeks or months to alleviate suffering. GHB treatment is also very short; less than a month of treatment is usually effective, as opposed to months or years with other treatments." Increased levels of happiness may also be the result of the extended periods of deeper sleep and a more rested body.  

Mental Enhancement
Mental clarity, perception and judgment all appear to improve with low dose use. Rapid eye movement sleep and protein synthesis - processes which may be linked, and both of which are facilitated by GHB - have been correlated with periods of intensive learning [Laborit, 1972]. GHB has also been shown to stimulate the release of acetylcholine, one of the brain's own intelligence and alertness boosting chemicals [Gallimberti, 1989]. Preliminary testing suggests improved reaction times and perceptual and cognitive reflexes with low dose use of GHB. These findings of increased alertness are surprising to those accustomed to expecting GHB to act solely as a sedative. Perhaps the answer lies in the fact that nature designed this molecule.

Full report prepared by  Steven Wm Fowkes, Executive Director  Cognitive Enhancement Research Institute Post Office Box 4029, Menlo Park, CA 94026 USA 650-321-CERI Fax: 650-323-3864
Email: fowkes@ceri.win.net Web: http://www.ceri.com/    http://www.win.net/ceri

 

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GHB A GREAT HORMONE AT BEDTIME

Category: Neurochemistry Term Paper Code: 536

GHB is a natural metabolite manufactured by the human body and by many mammalian tissues in which it functions to increase dopamine levels in the body (Mamelak 1989). GHB can be found in many organs in the body such as the kidney, heart, skeletal muscles, and fat (Chin and Kreutzer 1992). Hypothalamus and basal ganglia in the brain are found to have the highest amount of GHB (Gallimberti 1989). GHB is believed to acts as a depressant to the central nervous system (WWW1) and a neurotransmitter or neuromodulator, and high affinity brain receptor that does not act on GABA receptor sites directly (Mamelak 1989; Chin and Kreutzer 1992).
The Action of GHB In sleeping situation, GHB can facilitate non rapid eye movement (NREM) and rapid eye movement (REM) sleep, the stage of sleep at which there is an increased release of growth hormone (Vickers 1969; Laborit 1972; Mamelak 1989). Mamelak (1989) has provided studies that "indicate GHB reduces energy substrate consumption in both the brain and the peripheral tissues, protects these tissues from the damaging effects of anoxia or excessive metabolic demand." "GHB may function naturally in the induction and maintenance of physiological states, like sleep and hibernation, in which energy utilization is depressed. GHB may also function naturally as an endogenous protective agent when tissue energy supplies are limited" (Mamelak 1989).
Vickers (1969) states that GHB sleep is characterized by increased levels of carbon dioxide in the arteries similar to normal sleep whereas the central nervous system continues to be responsive to stimuli such as pain and other irritations. Even though not everyone can be put to sleep by GHB, "sleep is deeper and more restful during the influence of GHB, and people tend to wake up after the GHB has worn off. There was speculation that this is related to the release of stored-up dopamine" (Laborit, 1972).
GHB temporarily inhibits the dopamine release in the brain, causing an increase in dopamine storage, and later increased release of dopamine when the GHB influence wears off (Chin and Kreutzer 1992). This could explain for the feelings of increased well-being, alertness and arousal afterward or the next day which are common with the use of higher GHB dosage. Dopamine activity in the hypothalamus is known to stimulate pituitary release of growth hormone (GH), but GHB inhibits dopamine release while stimulating GH release. This might be due to the fact that GHB's GH-releasing effect takes place through an entirely different mechanism (Takahara 1977). While GH is being released, the level of prolactin also rises. GHB decreases anxiety, achieves greater intensity and frequency of uterine contractions, increases sensitivity to oxytocic drugs (used to induce contractions), preserves reflexes, prevents the lack of respiratory depression in the fetus, and protects against fetal cardiac anoxia (Vickers 1969; Laborit 1964).
GHB activates a metabolic process referred to as the "pentose pathway" which plays an important role in protein synthesis within the body (Laborit 1972). It also causes a "protein sparing" effect (Laborit 1964) which reduces the rate at which proteins in the body is broken down. Respiration would become slower and deeper. GHB also stimulates the release of acetylcholine in the brain (Gallimberti 1989). Additionally, "GHB seems to act through the endogenous opioid system, in which dynorphin levels are raised by GHB in the brain, and its metabolic and pharmacological effects can be inhibited by naloxone" (Mamelak 1989).
Benefits and Applications  GHB was found to be able to boost energy, cause pleasant and relax feelings, desire to socialize, enhance sexual experience, rejuvenate muscle and sleep, stimulate growth hormones (a steroid alternative) release (Steele and Watson 1995), relieve depression, and treat addiction. Research has been done to conclude that GHB was also primarily used to relieve and suppress withdrawal symptoms, cravings, and anxiety among alcoholics (Fadda 1989; Gallimberti 1989). "Most people experience relaxation and deep sleep within 45 minutes in response to 3.5g or less of GHB"

References

 Artru, A. A., Steen, P. A. and Michenfelder, J. D. Gamma-Hydroxybutyrate: Cerebral Metabolic, Vascular, and Protective Effects. Journal of Neurochemistry. 35(5): 1114-1119 (1980). Chin, M. Y., Kreutzer, R. A. and Dyer, J. E. Acute poisoning from gamma-hydroxybutyrate in California. West Journal of Medicine (United States) 156(4): 380-384 (1992). Chin, R. L. et al. Clinical course of gamma-hydroxybutyrate overdose. Annals of Emergency Medicine 31(6): 716-722 (1998). Fadda, F. et al. Suppression by gamma-hydroxybutyric acid of ethanol withdrawal syndrome in rats. Alcohol and Alcoholism (Great Britain) 24(5): 447-451 (1989). Ferrara, S. D. et al. Fatality due to gamma-hydroxybutyric acid (GHB) and heroin intoxication. Journal of Forensic Science 40(3): 501-504 (1995). Gallimberti, L. et al. Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. The Lancet, 787-789 (1989). Kam, P. C. & Yoong, F. F. Gamma-hydroxybutyric acid: an emerging recreational drug. Anaesthesia 53(12): 1195-1198 (1998). Laborit, H. Correlations between protein and serotonin synthesis during various activities of the central nervous system (slow and desynchronized sleep, learning and memory, sexual activity, morphine tolerance, aggressiveness, and pharmacological action of sodium gamma-hydroxybutyrate). Research Communications in Chemical Pathology and Pharmacology 3(1) (1972). Laborit, H. Sodium 4-Hydroxybutyrate. Int Journal of Neuropharmacology (Great Britain) 3: 433-452 (1964). Mamelak, M. Gammahydroxybutyrate: an endogenous regulator of energy metabolism. Neuroscience Biobehav Rev 13(4): 187-198 (1989).
Park, S. et al. GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes. The Rancho Bernardo Study. Diabetes Care 19(5): 450-456 (1996). Steele, M. T. & Watson, W. A. Acute poisoning from gamma hydroxybutyrate (GHB). Mo Medicine 92(7): 354-357 (1995). Takahara, J. et al. Stimulatory effects of gamma-hydroxybutyric acid on growth hormone and prolactin release in humans. Journal of Clinical Endocrinalogical Metabolism 44: 1014 (1977). Vickers, M.D. Gamma-hydroxybutyric Acid. Int Anaesthesia Clinic 7: 75-89 (1969).
Viera, A. J. & Yates, S. W. Toxic ingestion of gamma-hydroxybutyric acid. South Medical Journal 92(4): 404-405 (1999).

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Data on Xyrem® (sodium oxybate) presented at the American College of Rheumatology

Orange, CA - November 17, 2005

 

The National Fibromyalgia Association (NFA) today announced that a recent study on the narcolepsy drug Xyrem® (sodium oxybate), significantly reduces pain and improves sleep in people with fibromyalgia.
The data from an eight-week study will be presented today at the annual meeting of the American College of Rheumatology in San Diego.
"These results are very exciting because - for the first time - we have results that provide evidence that a product which improves the quality of sleep during the night also has a dramatic effect on reducing pain," said the study's lead researcher, I. Jon Russell, M.D., Ph.D. associate professor of medicine at the University of Texas Health Science Center in San Antonio and a member of the NFA's Medical Advisory Board.  "Both pain and losses of sleep are significant issues faced by patients suffering from fibromyalgia syndrome."
Fibromyalgia (FM) is a complex chronic pain illness that can lead to significant patient disability. The fact that there is no known cause or cure for fibromyalgia challenges patients and healthcare professionals alike. It is estimated that FM affects approximately six to eight million Americans and 5% of the world's population. Patients with fibromyalgia suffer from a variety of symptoms ranging from stiffness, muscle spasms and body wide pain, fatigue and severe sleep disturbances.
"This study will provide significant hope for patients searching for ways to effectively manage the chronic pain of this severe disorder," said Lynne Matallana, president and founder of the National Fibromyalgia Association. "The NFA is very excited to support research that examines new treatment options for fibromyalgia." 
Xyrem, marketed by Orphan Medical, Inc., a subsidiary of Jazz Pharmaceuticals, was approved by the U.S. Food and Drug Administration (FDA) in October 2002 as the first and only treatment for cataplexy (sudden loss of muscle tone) in patients with narcolepsy. 

The Study

• Significant benefit in the primary outcome variable (POV) was seen with both doses of sodium oxybate compared with placebo [illustrated by 4.5g, p=0.005].
• Sleep quality [SLP] was improved with both dosages of oxybate [4.5g, p=0.004].
• A significant correlation was seen between change in pain and change in sleep quality [r=0.55, p<0.001].
• In this study, sodium oxybate was shown to be well tolerated, as illustrated by the high rate of study completion.
• In the study, the most commonly reported adverse events included nausea and dizziness and were dose-related [4.5g, 15% and 6.7%, respectively; placebo, 9.2% and 1.5%].

Methodology 

Dr. Russell and his colleagues, Drs. Robert M. Bennett in Portland and Joel E. Michalek in San Antonio, conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial. The centers initially recruited 188 patients [placebo, n=64; oxybate 4.5g, n=58; oxybate 6g, n=66], of whom 147 [78%] completed the trial. One group took 4.5 grams of sodium oxybate per day, while a second group took 6 grams per day. The sodium oxybate was administered orally twice a day. The POV was a composite of changes from baseline in three co-primary, self-report measures: Pain Visual Analog Scale [PVAS], captured with electronic diaries; Fibromyalgia Impact Questionnaire [FIQ]; and Patient Global Assessment [PGA].  Secondary outcome measures included changes in sleep quality [SLP]. The trial lasted eight weeks.

"These results show significant improvements when compared to placebo in the patient's sleep quality as well as the reduction of the patient's pain," stated Dr. Russell.

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10/03/2006 XYREM® LICENSE AGREEMENT TO INCLUDE FIBROMYALGIA SYNDROME 

UCB also adds new marketing territories under expanded agreement --
Brussels, Belgium and Palo Alto, California – October 3rd 2006 – UCB (Euronext Brussels: UCB) and Jazz Pharmaceuticals, Inc. today announced the signing of an expanded product license agreement for Xyrem^® (sodium oxybate).
Under the agreement, UCB obtains the right to commercialize Xyrem for the treatment of fibromyalgia syndrome, if and when the product is approved for this indication. On September 7, 2006, Jazz Pharmaceuticals announced the initiation of its Phase III clinical development program evaluating the use of Xyrem for the treatment of fibromyalgia syndrome.
In addition, the agreement doubles, from 27 to 54, the number of countries in which UCB has commercialization rights to Xyrem. Jazz Pharmaceuticals markets Xyrem in the United States. Commenting on the new agreement William Robinson, Executive Vice President, Global Operations, UCB said, “Fibromyalgia is an under-diagnosed, under-treated condition and we are encouraged on the initiation of the Phase III trial to evaluate Xyrem as a treatment for this chronic pain illness. Acquiring the rights to in-licence Xyrem for fibromyalgia syndrome demonstrates the ongoing commitment of UCB to satisfying unmet medical needs.” He continued, “We also look forward to making Xyrem available to narcolepsy patients in many more countries.”
Under the expanded agreement, UCB has made an upfront payment and will make milestone payments to Jazz Pharmaceuticals, subject to future clinical development and sales results. UCB will also pay royalties to Jazz Pharmaceuticals on Xyrem sales across the 54 agreed territories. “We are pleased to announce the significant expansion of our commercial partnership with UCB for Xyrem, which will bring this important therapy to patients in many more countries,” said Robert M. Myers, Chief Business Officer of Jazz Pharmaceuticals. “We look forward to continuing the investigation of the clinical utility of Xyrem for the treatment of fibromyalgia syndrome.”

About Fibromyalgia
Fibromyalgia is a chronic pain illness which is characterized by widespread musculoskeletal aches, pains and stiffness, soft tissue tenderness, general fatigue and sleep disturbances. The most common sites of pain include the neck, back, shoulders, pelvic girdle and hands, but any body part can be involved.

About Xyrem in Europe¹
In 2005, Xyrem became the first and only medication approved by the European Medicines Agency (EMEA) for the treatment of cataplexy in adult patients with narcolepsy, and the product has since been launched for this indication in Denmark, Germany, Norway and the UK. In April 2006, UCB filed an application with the EMEA seeking marketing approval for the use of Xyrem in the treatment of narcolepsy in adult patients. The application spans all symptoms of narcolepsy, including excessive daytime sleepiness and fragmented night-time sleep. The most commonly reported adverse drug reactions are dizziness, nausea, and headache, all occurring in 10 % to 20 % of patients. Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. Sodium oxybate is contraindicated in patients being treated with opioids or barbiturates.
Jazz Pharmaceuticals Mark Leonard 847-267-9660 markdleonard@comcast.net Jazz Pharmaceuticals, Inc. Matthew Fust Chief Financial Officer 650-496-3777 mediainfo@jazzpharma.com

Read More... #5 GHB gamma-hydroxy butyrate & Fibromyalgia

#4 The Endocannabinoid System

The Endocannabinoid System 

1. R E V I E W A R T I C L E
2. Migraine, Fibromyalgia and Irritable Bowel
3. Clinical Endocannabinoid Deficiency (CECD) 
4. Endocannabinoid mechanisms also regulate bronchial function
5. Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes
6. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract
7. Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression

Can this Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?

Read More... #4 The Endocannabinoid System

#3 THC & Fibromyalgia Cannabis and the Cannabinoids

THC & Fibromyalgia Cannabis and the Cannabinoids

1. IACM-Bulletin of 11 June 2006
2. Science: Cannabidiol inhibits tumour growth 
3. Delta-9-THC based monotherapy 
4. Medical Use of Cannabis and THC in Germany 
5. Clinical Trial: THC Reduces Pain  
6. Medical Uses of Cannabis 

Cannabis preparations have been used as remedies for thousands of years. The active ingredients of the hemp plant can currently also be put to use in a multitude of severe medical conditions. However, the potential medical applications of natural cannabis products or individual pharmacologically active ingredients are restricted by existing laws

IACM-Bulletin of 11 June 2006
* Science: THC reduces pain due to fibromyalgia in pilot study
* Science: Cannabidiol inhibits tumor growth in leukemia and breast cancer in animal studies
Science: THC reduces pain due to fibromyalgia in pilot study

The effect of oral THC was investigated in nine patients with fibromyalgia in a study at the Department of Anesthesiology and Intensive Care Medicine of the University Hospital in Mannheim. Fibromyalgia is a chronic pain syndrome of unknown origin. In the four participants who completed the three-month study pain was reduced by 67 per cent on average. All four experienced a pain reduction by more than 50 per cent.

All pain medication was stopped 3 weeks prior to the investigation. In the study, patients received a daily oral dose of 2.5–15 mg THC. Starting with 2.5 mg the dosage was increased weekly by 2.5 mg THC, as long as no severe side effects were reported. Once a week, 24 hours after the last THC medication and a day before any dose increase, an electrical induced pain was caused. Moreover, the pain intensity was daily recorded by means of a numeric pain scale with the endpoints 0 (no pain) and 10 (maximum pain imaginable).

Five of the nine participants terminated the study before reaching the maximum dose of 15 mg due to severe side effects, primarily sedation, dizziness, fatigue or continuous tiredness. The experimentally induced pain was significantly reduced by THC in a dose of 10 and 15 mg. Daily recorded pain intensity was reduced from 8.1 on average at the beginning of the study to 2.8 after three months.

(Source: Schley M, Legler A, Skopp G, Schmelz M, Konrad C, Rukwied R. Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Curr Med Res Opin 2006;22(7):1269-1276 [electronic publication ahead of print])

Science: Cannabidiol inhibits tumour growth in leukaemia and breast cancer in animal studies

Italian researchers investigated the anti-tumour effects of five natural cannabinoids of the cannabis plant (cannabidiol, cannabigerol, cannabichromene, cannabidiol-acid and THC-acid) in breast cancer. Cannabidiol (CBD) was the most potent cannabinoid in inhibiting the growth of human breast cancer cells that had been injected under the skin of mice. CBD also reduced lung metastases deriving from human breast cancer cells that had been injected into the paws of the animals.

Researchers found that the anti-tumour effects of CBD were caused by induction of apoptosis (programmed cell death). They concluded that their data "support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer."

These observations are supported by investigations of US scientists who found out that exposure of leukaemia cells to CBD led to a reduction in cell viability and induction of apoptosis. In living animals CBD caused a reduction in number of leukaemia cells. The scientists noted that CBD "may be a novel and highly selective treatment for leukemia."

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Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief
Authors: Schley, Marcus1; Legler, Andreas1; Skopp, Gisela2; Schmelz, Martin1; Konrad, Christoph1; Rukwied, Roman1 Source: Current Medical Research and Opinion, Volume 22, Number 7, July 2006, pp. 1269-1276(8)

Abstract: Objective:

Fibromyalgia (FM) is a chronic pain syndrome characterized by a distinct mechanical hyperalgesia and chronic pain. Recently, cannabinoids have been demonstrated as providing anti-nociceptive and anti-hyperalgesic effects in animal and human studies. Here, we explored in nine FM patients the efficacy of orally administered delta-9-tetrahydrocannabinol (THC) on electrically induced pain, axon reflex flare, and psychometric variables.

Research design and methods: Patients received a daily dose of 2.5-15 mg of delta-9-THC, with a weekly increase of 2.5 mg, as long as no side effects were reported. Psychometric variables were assessed each week by means of the West Haven-Yale Multidimensional Pain Inventory (MPI), Pittsburgh Sleep Quality Index (PSQI), Medical outcome survey-short form (MOS SF-36), the Pain Disability Index (PDI), and the Fibromyalgia Impact Questionnaire (FIQ). In addition, patients recorded daily, in a diary, their overall pain intensity on a numeric scale. Each week, pain and axon reflex flare was evoked experimentally by administration of high intensity constant current pulses (1 Hz, pulse width 0.2 ms, current increase stepwise from 2.5-12.5 mA every 3 minutes) delivered via small surface electrodes, attached to the volar forearm skin.

Main outcome measures: Daily pain recordings by the patient, experimentally induced pain, and axon reflex flare recorded by a laser Doppler scanner.

Results: Five of nine FM patients withdrew during the study due to adverse side effects. Delta-9-THC had no effect on the axon reflex flare, whereas electrically induced pain was significantly attenuated after doses of 10-15 mg delta-9-THC (p < 0.05). Daily-recorded pain of the FM patients was significantly reduced (p < 0.01).

Conclusions: This pilot study demonstrated that a generalized statement that delta-9-THC is an analgetic drug cannot be made. However, a sub-population of FM patients reported significant benefit from the delta-9-THC monotherapy. The unaffected electrically induced axon reflex flare, but decreased pain perception, suggests a central mode of action of the cannabinoid.

Document Type: Research article DOI: 10.1185/030079906X112651
Affiliations: 1: Department of Anaesthesiology and Intensive Care Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany 2: Institute of Forensic Toxicology, University of Heidelberg, Heidelberg, Germany

Survey on the Medical Use of Cannabis and THC in Germany

Page Range: 17 - 40
DOI: 10.1300/J175v03n02_03
Copyright Year: 2003

Abstract:
In recent years, a number of open patient interviews and standardized surveys have been conducted to gain more information concerning subjective experiences with the use of cannabis products in a multitude of medical conditions. After a first effort in 1999 (Schnelle et al. 1999), a second anonymous survey was conducted among patients in the German speech area of Europe concerning use of natural illegal cannabis products and THC, a natural cannabinoid that may be prescribed by German doctors since 1998, and that is also manufactured synthetically. Questionnaires were distributed to the members of the Association for Cannabid as Medicine (ACM) and additional persons interested in participating. One hundred eighty-two completed questionnaires were sent to the Institute for Oncological and Immunological Research and the ACM, of whom 17 were excluded because these participants apparently did not suffer from severe diseases. Of the 165 respondents included in the final analysis, 61.2% were male and 38.8% were female. Median age was 40.3 ± 12.4 years, with a range of 16 to 87 years. Twenty-two participants did not use cannabis products for therapeutic purposes. The main reasons were fear of criminal prosecution, the assumption that their doctor will not prescribe THC or a refusal of the doctor to do so. Among the 143 participants with cannabis or THC experience, the main diagnosis groups were neurological symptoms (28%) and painful conditions (25.3%), followed by diseases with mainly gastrointestinal symptoms, such as nausea and appetite loss (14%). The most frequent single diagnoses were multiple sclerosis (17.5%), Tourette syndrome (11.9%), HIV/AIDS (10.5%), migraine/headaches (4.9%), chronic pain that was not described more precisely (4.2%), hepatitis C (3.5%), depression, sleep disorders, spinal cord injury, and back pain (2.8% each), asthma, allergy, fibromyalgia, menstraul pain, and epilepsy (2.1% each). Average daily THC doses were 14.9 ± 9.5 mg, ranging from 4 to 35 mg. Doses of natural cannabis products (marijuana, hashish) were 1.3 ± 0.9 grams on average (range: 0.02-3.5g). The drugs were inhaled by 55.9%, employed orally by 16.8%, and 23.1% use both routes of administration. The cited conditions were much improved by cannabis or THC in 74.8%. An additional 13.3% of patients noted a small improvement, and 2.1% noted no improvement. Others were unsure whether it improved their condition (7.0%), or did not answer the question (2.8%). High satisfaction was reported in 54.4%, 28.0% were satisfied, 14.0% were partly satisfied and 2.1% were not satisfied, while 1.4% did not answer. No side effects were experienced in 73.4%, while 22.4% reported moderate side effects, and 4.2% did not respond. About three-quarters made statements to the consequences of discontinuation of use with regard to withdrawal symptoms. Of these, 67.6% reported no withdrawal symptoms; in 17.6% these symptoms were mild, and in 2.8% they were more severe, while 12.0% reported that they coould not evaluate the severity of withdrawal symptoms. Fifty-three participants noted that they had asked their doctor to prescribe THC. In 54.8% the doctor was willing to do so, but in more than half of the cases (45.9%), the health insurance companies refused to pay for the treatment. There was no association between the reaction of the doctor or of the health insurance and the diagnosis.

Most of the participants who reported a refusal by their doctor or the health insurance used cannabis products in the previous month. Experience with both the medical use of THC and natural cannabis products was reported by 16 participants. There were no clear differences between both drugs with regard to side effects and medicinal efficacy. In conclusion, this survey adds to an increasing number of patient reports of successful and well-tolerated medical uses of cannabis products in a multitude of conditions. Furthermore, it reflects the division of German doctors and health insurances on the issue.

Journal Title:Journal of Cannabis Therapeutics:
Studies in Endogenous, Herbal, and Synthetic Cannabinoids
official journal of the International Association for Cannabis as Medicine
Volume: 3 Issue: 2
ISSN: 1529-9775 Pub Date: 3/1/2003
Contributors:
Franjo Grotenhermen MD, affiliated with the nova-Institut, Goldenbergstraße 2, D-50354 Hürth, Germany, franjo.grotenhermen@nova-institut.de
Martin Schnelle MD, Affiliated with the Institute for Oncological and Immunological Research , Hardenbergstrasse 19, Berlin , Germany , martin.schnelle@eifoi.de


Clinical Trial: THC Reduces Pain In Fibromyalgia Patients
June 22, 2006 - Mannheim, Germany

Mannheim, Germany: Oral administration of THC significantly reduces both chronic and experimentally induced pain in patients with fibromyalgia, according to clinical trial data to be published in the forthcoming issue of the journal Current Medical Research and Opinion. The study is the first-ever clinical trial assessing the efficacy of cannabinoids in the treatment of fibromyalgia.

Investigators at Germany's University of Heidelberg assessed the analgesic effects of oral THC in nine patients with fibromyalgia over a 3-month period. Subjects in the trial were administered daily doses of 2.5 to 15 mg of THC, but received no other pain medication during the trial. Among those participants who completed the trial, all reported a significant reduction in daily recorded pain and electronically induced pain, investigators found.

"All patients who completed the delta-9-THC therapy ... experienced pain relief of more than 50 percent," authors concluded. Investigators recommended that follow up placebo-control trials be conducted assessing the use of cannabinoids on fibromyalgia. Previous trials have shown that both naturally occurring and endogenous cannabinoids hold analgesic qualities, particularly in the treatment of cancer pain and neuropathic pain, both of which are poorly treated by conventional opiates.

Fibromyalgia is a chronic pain syndrome characterized by widespread musculoskeletal pain, fatigue, and multiple tender points in the neck, spine, shoulders, and hips. An estimated 3 to 6 million Americans are afflicted by the disease, which is often poorly controlled by standard pain medications.

For more information, please contact Paul Armentanot (202) 483-5500. Full text of the study, "Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief," will be available in the forthcoming issue of Current Medical Research and Opinion.

(www.norml.org)

The disease is characterized by widespread musculoskeletal pain, fatigue, and multiple tender points in the neck, spine, shoulders, and hips. An estimated 3 to 6 million Americans are afflicted by fibromyalgia, which is often poorly controlled by standard pain medications.
Fibromyalgia patients frequently self-report using cannabis therapeutically to treat symptoms of the disease,[1-2] and physicians – where legal to do so – often recommend the use of cannabis to treat musculoskeletal disorders.[3-4] To date however, only one clinical trial is available in the scientific literature assessing the use of cannabinoids to treat the disease.

Writing in the July 2006 issue of the journal Current Medical Research and Opinion, investigators at Germanyʹs University of Heidelberg evaluated the analgesic effects of oral THC in nine patients with fibromyalgia over a 3-month period. Subjects in the trial were administered daily doses of 2.5 to 15 mg of THC, but received no other pain medication during the trial. Among those participants who completed the trial, all reported a significant reduction in daily recorded pain and electronically induced pain.[5]

Previous clinical and preclinical trials have shown that both naturally occurring and endogenous cannabinoids hold analgesic qualities,[6-7] particularly in the treatment of cancer pain [8] and neuropathic pain, [9] both of which are poorly treated by conventional opioids. As a result, some experts have suggested that cannabinoid agonists would be applicable for the treatment of chronic pain conditions unresponsive to opioid analgesics such as fibromyalgia, and they theorize that the disease may be associated with an underlying clinical deficiency of the endocannabinoid system.[10]

REFERENCES
[1] Swift et al. 2005. Survey of Australians using cannabis for medical purposes. Harm Reduction Journal 4: 2-18. [2] Ware et al. 2005. The medicinal use of cannabis in the UK: results of a nationwide survey. International
Journal of Clinical Practice 59: 291-295. [3] Dale Gieringer. 2001. Medical use of cannabis: experience in California. In: Grotenhermen and Russo (Eds).
Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. New York: Haworth Press: 153-
170. [4] Gorter et al. 2005. Medical use of cannabis in the Netherlands. Neurology 64: 917-919. [5] Schley et al. 2006. Delta-9-THC based monotherapy in fibromyalgia patients on experimentally inducedpain, axon reflex flare, and pain relief. Current Medical Research and Opinion 22: 1269-1276. [6] Burns and Ineck. 2006. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain.
The Annals of Pharmacotherapy 40: 251-260. [7] David Secko. 2005. Analgesia through endogenous cannabinoids. CMAJ 173: [8] Radbruch and Elsner. 2005. Emerging analgesics in cancer pain management. Expert Opinion on Emerging Drugs 10: 151171. [9] Notcutt et al. 2004. Initial experiences with medicinal extracts of cannabis for chronic pain: Results from 34 ʹN of 1ʹ studies. Anaesthesia 59: 440. [10] Ethan Russo. 2004. Clinical Endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome, and other treatment-resistant conditions? Neuroendocrinoogy Letters 25: 31-39.
http://www.schmoo.co.uk/thclub/thcuses.htm

Medical Uses of Cannabis
Ailments for which the medical use of cannabis may be beneficial include: Addiction, Arthritis, Appetite Loss, Nausea, Cancer Chemotherapy, AIDS Wasting Syndrome, Nausea From Cancer, Chemotherapy, Glaucoma, Multiple Sclerosis, Depression, Parkinson’s Disease, Movement Disorders, Dystonia, Asthma, Brain Injury/Stroke, Crohn's Disease, Ulcerative Depression, Mental Illness, Epilepsy, Fibromyalgia, High Blood Pressure/ Hypertension, Migraine, Nail Patella Syndrome, Schizophrenia, Tourette's Syndrome.

Below are notes on some of the most common medical uses of cannabis.

Arthritis: In 1994 the ‘Times’ reported; ‘The demand for Cannabis among British pensioners has stunned doctors, police and suppliers. The old people use the drug to ease the pain of such ailments as arthritis and rheumatism. Many are running afoul of the law for the first time in their lives as they try to obtain suppliers.’ Arthritis affects the joints and surrounding areas, including muscles, membrane linings and cartilage. It causes painful inflammation, heat, swelling, pain, redness of skin and tenderness in the affected areas. Cortisone-type drugs provide dramatic pain relief for short periods but decrease in effectiveness if used over time. The side effects of these drugs include nausea, restlessness, insomnia, dizziness, headache, depression and mood swings, irregular heartbeat and menstruation problems. Several cannabinoids have both analgesic (pain-relieving) and anti-inflammatory effects, a combination particularly helpful for arthritic people. Cannabidiol (CBD), one of the main active ingredients in cannabis is a very effective anti-inflammatory agent. Cannabis can be smoked or eaten to relieve the general pain, inflammation and discomfort of arthritis. Cannabis poultices can be applied topically to troubled areas. Cannabis in alcohol or as a cream can also be rubbed on the skin.

Appetite Loss, Nausea, Cancer Chemotherapy, AIDS Wasting Syndrome: One of the most outstanding medical values of cannabis is the role it can play in restoring a person’s relationship to food. Cannabis is remarkably powerful in combating nausea and vomiting, making it possible to consume food and hold it down. It is also an extraordinary stimulant of appetite itself; a condition known by cannabis users as ‘the munchies’. Conditions characterized by nausea, vomiting, appetite problems and severe weight loss include AIDS Wasting Syndrome, kidney failure, tuberculosis, hyperemesis gravidarum (magnified form of morning sickness) and anorexia and the side effects of chemotherapy.

Nausea From Cancer Chemotherapy: Nausea and vomiting, which can last for days after a single treatment and be so violent as to threaten to break bones and rupture the aesophagus, are common side effects of the chemotherapies used in treating cancer. Many patients develop such an aversion to the site or odor of food that they stop eating altogether and lose the will to live. Up to 40% of cancer patients undergoing chemotherapy do not respond to the standard treatment for preventing vomiting. These use expensive ‘antiemetics’ drugs such as ‘Zofran’ (which must be administered by intravenous drip and cost £250+ a treatment). ‘Marinol’ which uses THC was approved after much resistance in the USA in 1986. It is effective in many cases where other drugs have failed. Smoking or eating cannabis also seems to provide relief where standard treatments fail. The effectiveness of cannabis in treating nausea and vomiting from cancer chemotherapy is dose-related. The higher the blood levels of THC, the more complete the relief of vomiting. Lester Grinspoon, M.D. has calculated that using cannabis to treat chemotherapy nausea would cost about one percent as much as treatment with Zofran.

Glaucoma: The usual treatment is eye drops containing drugs called ‘beta-blockers’. While effective they can cause depression, exacerbate asthma, decrease heart rate and increase danger of heart failure. The most common form of glaucoma, ‘open angle glaucoma’ happens when the channels that carry fluid out of the eyeball gradually become narrower causing the intra ocular pressure to increase slowly over time, damaging the optic nerve that relays signals from the eye to the brain and resulting in blindness. Fortunately, it can be treated with cannabis. Cannabis relieves symptoms by reducing intra ocular pressure, thereby slowing down the progress of the condition, sometimes bringing it to a complete halt. The pressure relieving effects achieved by using cannabis last for four to five hours.

Multiple Sclerosis: Multiple Sclerosis destroys the sheathing that protects nerve fibres, interfering with the function of the nervous system. The victim suffers painful muscle spasms, loss of coordination, tremors, paralysis, insomnia, mood swings and depression, blurred vision, impotence, loss of bladder control and more. There are three types; fairly mild and does not get worse over time; one which gets worse slowly; and one which gets rapidly worse once it appears. Many suffers end up using wheelchairs. Modern medicine has failed to find an effective treatment for the overall condition although various drugs give short-term relief of different symptoms. Valium or similar tranquilizers are used to treat muscle spasms but have there associated side effect of addiction, and doses often have to be increased sharply over time (good for profits if nothing else). MS patients who use cannabis report a soothing of the painful muscle spasms and improved muscle coordination. Some are able to walk unaided when they were previously unable to do so. It also helps blurred vision, tremors, loss of bladder control, insomnia and depression.

Depression: Depression can be a very depressing state of mind to be in, and can include pessimism, hopelessness, despair, loss of interest in life, boredom and sadness. Symptoms include insomnia or excessive sleeping, loss of appetite or over eating, decreased sex drive, constipation, listlessness, chronic tiredness, difficulty with concentration and decision making, and irritability. About 30% of patients with depression respond badly to antidepressants or find the side effects intolerable. A significant difference between the two is that the mood lifting effects of cannabis occur within a few minutes of smoking or about an hour after ingesting while pharmaceutical antidepressants usually take several days or weeks to kick in - and the same or longer to safely get off them.

Movement Disorders: Diseases characterised by impaired motor function and difficulties with muscle control. Conventional drug treatments are not very effective and can have very bad side effects. Cannabis has proved to be surprisingly helpful. Research indicates that the reason may have something to do with the presence of receptors for cannabinoids in the ‘basal ganglia’, a part of the nervous system involved in the coordination of movement.

Parkinson’s Disease: A movement disorder closely associated with the aging process, thought to be caused by abnormalities in the ‘basal ganglia’ and deterioration of the brain systems associated with the brain chemical ‘dopamine’ which is involved in movement and motor control. Levels of dopamine decline with ageing. Conventional treatments include ‘Deprenyl’, ‘Bromocriptine’ and ‘L-dopa’, all drugs which increase levels of dopamine in the nervous system. ‘L-dopa’, the most frequently used of these treatments, may actually increase damage to parts of the brain involved in dopamine production. It does not slow down the progression of the disease or increase life expectancy. Its side effects include most of the symptoms of the disease it is intended to treat! These include nausea, loss of libido, vomiting, irritability, insomnia, loss of appetite, headache, dystonias, and muscle spasms. Cannabis has demonstrated a beneficial impact on all of them. However ‘Cannabidiol’ one of the active agents of cannabis may aggravate the ‘hypokinesia’, or overall lack of movement associated with Parkinson’s.

Dystonia: Dystonias are a group of movement disorders characterized by abnormal body movements and postures. Their causes can be a side effect of medicines used to treat psychotic conditions and Parkinson’s disease. Cannabis has been shown to be helpful for dystonia in studies with both humans and animals when conventional drugs are rarely effective and have dangerous side effects. Cannabis used in conjunction with standard medications can help achieve a more effective overall treatment.

Chronic Pain: One of the most difficult problems for health practitioners to treat. Conventional medicine uses opiate-type drugs such as codeine. Opiates are highly addictive and dosages have to be increased to remain effective, increasing the addiction. Much addiction has its roots in pain being self medication conscious or not. Non-addictive painkillers are also available, but they are often not strong enough to provide adequate pain relief! The painkilling properties of Cannabis (THC) are comparable to those of codeine and other commonly used painkillers without the side effects or risk of addiction. Studies have found that the dose of THC required to kill pain was far smaller than the amount of codeine required to give the same level of relief. Amazingly the same dosage of cannabis has a consistently stronger painkilling effect for experienced users of cannabis than for inexperienced users. This is the opposite of a development of tolerance! A single dose can relieve pain for several hours. Eating is often more effective than smoking and the effects last longer. However, the use of cannabis and opiates is not necessarily an either-or issue. If cannabis is used in an ongoing regime of medication, opiates could be added or substituted during periods when pain levels rise. Conversely, if opiates are used as the basis of the ongoing regime, cannabis could be added when pain levels rise , avoiding the need to increase the dosages of opiates being used and the associated dangers.

Diabetes: Insulin is excreted from the beta islet cells of the pancreas. Insulin, a natural body chemical, floods the body after a sugar-rich meal and causes various cell types to dramatically increase their uptake of glucose, a common sugar. The effect of insulin is to reduce the levels of glucose in the bloodstream. Diabetes can result from the body’s inability to produce sufficient quantities of insulin or from an inability to respond properly to the insulin that is produced. In either case, many of the clinical effects of diabetes stem from the deleterious effects of high blood sugar. There is some anecdotal evidence that cannabis lowers blood sugar. AIDS and cancer patients, among other cannabis users, often report an increase in appetite after consuming cannabis, and a few reports indicate that smoking cannabis can lower blood sugar in diabetics. A study (Tracy Blevins phd) was undertaken to determine whether this effect can be detected using an easily available over the counter blood glucose testing kit.

A morbidly obese man had a non-healing wound on his lower leg and was experiencing confusion and sleepiness after large meals. He suspected diabetes as the culprit, and, since smoking a large cannabis cigarette after large meals seemed to alleviate some of his symptoms, his blood sugar was tested before, immediately after and multiple times during the hour following a large meal rich in protein, fats and both complex and simple carbohydrates.

The results were dramatic and raised some interesting research questions. Before and immediately after the meal, the patient’s blood sugar was in the normal range, but within a few minutes increased by 80 mg/dl and remained at this high level for almost an hour. Then he smoked a 1 gram cannabis cigarette, and his blood sugar levels fell by 40 points almost instantly. This represents a full 50% of the abnormal increase in blood sugar. The drop of blood which was taken at the exact moment when he was self reporting a ‘high’ were the lowest in blood sugar, a good indication that the blood sugar lowering was caused by the ingestion of cannabis. Curiously, after a few minutes, his blood sugar started to increase again. It might be that smoking cannabis helped to reduce his blood sugar, but only transiently. Would a longer acting cannabinoid suppress blood sugar levels more efficiently?

Further studies are necessary to confirm this effect and to determine the parameters of the effect: the amount of cannabis needed, the time course of the effect, and also whether different types of cannabis show more or less blood sugar lowering. Also, in another non-diabetic patient, blood sugar was decreased by 11%, pointing to the possibility that cannabis can lower blood sugar in a non-disease state. Could it be that we have finally discovered the biological mechanism of “the munchies”?

Read More... #3 THC & Fibromyalgia Cannabis and the Cannabinoids

#2 Other Drug Therapy's and the Cannabinoid System

Other Drug Therapy's and the Cannabinoid System

1. Systemic low-dose ketamine to the pathophysiology of fibromyalgia
2. Cannabis and Pain and Inflammation
3. Patients Take Action
4. What is MARINOL and how does it work

Dextromethorphan is also being investigated as a possible treatment for pain associated with fibromyalgia, a chronic rheumatologic organic fatigue disorder

Dextromethorphan should not be taken with any of the following:

• • monoamine oxidase inhibitors (MAOIs)[4]
• • selective serotonin reuptake inhibitors (SSRIs)[4]
• • CNS depressant drugs and substances, including alcohol, antihistamines, and psychotropics, will have a cumulative CNS depressant effect if taken with dextromethorphan.[4]

Clinical pharmacology

Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood-brain barrier. The first-pass through the hepatic portal vein results in some of the drug being metabolized into an active metabolite of dextromethorphan, dextrorphan, the 3-hydroxy derivative of dextromethorphan. The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite. Dextromethorphan is metabolized by various liver enzymes and subsequently undergoes O-demethylation (producing dextrorphan), N-demethylation, and partial conjugation with glucuronic acid and sulfate ions. Hours after dextromethorphan therapy, (in humans) the metabolites (+)-3-hydroxy-N-methylmorphinan, (+)-3-morphinan, and traces of the unchanged drug are detectable in the urine.[4]

A major metabolic catalyst involved is the cytochrome P450 enzyme known as 2D6, or CYP2D6. A significant portion of the population has a functional deficiency in this enzyme and are known as poor CYP2D6 metabolizers. As CYP2D6 is a major metabolic pathway in the inactivation of dextromethorphan, the duration of action and effects of dextromethorphan can be increased by as much as three times in such poor metabolizers.[5]

A large number of medications (including antidepressants) are potent inhibitors of CYP2D6 (see CYP2D6 article). There exists, therefore, the potential of interactions between dextromethorphan and concomitant medications. There have been reports of fatal consequences arising from such interactions.[6]

Dextromethorphan crosses the blood-brain barrier, and the following pharmacological actions have been reported:

• NMDA glutamatergic receptor antagonist

• Dopamine reuptake inhibitor[4]

• σ1 and σ2 receptor agonist.[7]

• α3β4 nicotinic receptor antagonist[8]

• Serotonin reuptake inhibitor[9] 

 

Classification

At high doses, dextromethorphan is classified as a dissociative drug, a subclass of hallucinogenic drugs to which ketamine and phencyclidine (PCP) also belong.[11] It generally does not produce withdrawal symptoms characteristic of physically addictive substances, but psychological addiction has been reported by some users

Systemic low-dose ketamine to the pathophysiology of fibromyalgia

by Wood PB. Centre for Research on Pain, McGill University, Montreal, Quebec, Canada. J Pain. 2006 Sep;7(9):611-4.

ABSTRACT

Fibromyalgia is a common disorder characterized by chronic widespread pain that affects an estimated 2% of the general population. Recent advances have shed insight on this mysterious disorder, leading to the growing conclusion that disturbances of pain-related processes within the central nervous system, termed central sensitization, represent its most likely source. The phenomenon of central sensitization depends on plasticity in function of N-methyl-D-aspartate (NMDA) subtype glutamate receptors. Earlier studies implicated increased sensitivity of central NMDA receptors as playing a primary role in fibromyalgia, as evidenced by a significant reduction in symptoms among a large subset of patients in response to low doses of ketamine, a noncompetitive NMDA receptor antagonist. However, recent insights into the pharmacology of this drug cast doubt on a direct contribution of NMDA receptors and add credence to a model of the disorder that suggests that the primary pathology of fibromyalgia is a suppression of the normal activity of dopamine-releasing neurons within the limbic system. The implications for future therapies for fibromyalgia, and indeed many other chronic pain conditions, are discussed in light of these insights. 

PERSPECTIVE: The current lack of a demonstrable pathology underlying the pain of fibromyalgia has hampered progress toward adequate treatment of this mysterious disorder. Accumulating evidence suggests that fibromyalgia may represent a dysregulation of dopaminergic neurotransmission, which may provide insights to guide both rational clinical interventions as well as system-specific research models.

http://www.drugpolicy.org/marijuana/medical/challenges/litigators/medical/conditions/pain.cfm

Medicinal Uses of Marijuana: Pain

Many studies have found cannabinoids are integral to the body's pain mechanisms. Other studies suggest cannabinoids work with other pain medications like opiates to provide pain relief at lower dosages. In addition, patients with cancer, multiple sclerosis, and other ailments attest that marijuana helps ease their pain, often allowing them to cease or lessen the use of drugs with more profound side effects. The U.S. Society for Neuroscience has concluded that, "careful studies show that cannabinoids directlly interfere with pain signaling in the nervous system. The insights may lead to a new class of pain killers."

Joy, Janet E.; Stanley J. Watson, Jr.; John A. Benson, Jr., Eds. Marijuana and Medicine: Assessing the Science Base. Washington, DC: Division of Neuroscience and Behavioral Health, Institute of Medicine. 1999. 259 p. (Chapter 4 of this report contains sections on pain)

• "The available evidence from animal and human studies indicates that cannabinoids can have a substantial analgesic effect."

• The IOM report concluded that the following patient groups should be targeted for clinical studies of cannabinoids in the treatment of pain:

o Chemotherapy patients, especially those being treated for the mucositis, nausea, and anorexia.

o Postoperative pain patients (using cannabinoids as an opioid adjunct to determine whether nausea and vomiting from opioids are reduced).

o Patients with spinal cord injury, peripheral neuropathic pain, or central post-stroke pain.

o Patients with chronic pain and insomnia.

o AIDS patients with cachexia, AIDS neuropathy, or any significant pain problem.

The 1998 U.K. House of Lords report says, "There is scientific evidence that cannabinoids possess pain relieving properties, and some clinical evidence to support their medical use in this indication. Many of our witnesses consider that high priority should be given to further research in this area."

Excerpts from the American Public Health Association (APHA) amicus brief in Conant v. McCaffrey, (2001 filing):

Marijuana is an effective painkiller.

Patients with various pain syndromes claim significant relief from marijuana.(29) In fact, British researchers have recently reported that cannabis extract sprayed under the tongue was effective in reducing pain in 18 of 23 patients who were suffering from intractable pain.(30) The validity of their experiences is corroborated by studies in which cannabinoids have been shown to be effective analgesics in animal pain models.(31) This is particularly true for patients suffering from neuropathic pain.

Neuropathic pain is a symptom commonly associated with a variety of illnesses or conditions, including metastic cancer, HIV/AIDS, multiple sclerosis (MS), and diabetes, and it can also be a side effect of the recommended treatments for various conditions.(32) Over 30% of patients with HIV/AIDS suffer from excruciating pain in the nerve endings (polyneuropathies), many in response to the antiretroviral therapies that constitute the first line of treatment for HIV/AIDS.(33) But, there is no approved treatment for such pain that is satisfactory for a majority of patients.(34) As a result, some patients must reduce or discontinue their HIV/AIDS therapy because they can neither tolerate nor eliminate the debilitating side effects of the antiretroviral first-line medications.(35) (See complete APHA amicus brief for footnotes.)

GW Pharmaceuticals Medical Uses Index on: Pain

GW is a pharmaceutical company developing a variety of prescription medicines derived from cannabis to meet patient needs in a wide range of therapeutic indications.

Also see GW Pharmaceuticals on: phantom limb pain, spinal cord injury, and fibromyalgia. Also see phantom limb pain, spinal cord injury, fibromyalgia, etc. at GW Pharmaceuticals Research and Development Section

Legal Briefs Amicus brief of the American Pain Society and the American Academy of Pain Medicine in McFadden v. Mississippi State Board of Medical Licensure.

Doctors' Declarations on Pain

Books and Articles Grinspoon, Lester, M.D. Marijuana, the Forbidden Medicine (revised and expanded edition). New Haven, Conn.: Yale University Press. 1997. 312 p. Malfait, A. M., et al. "The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis." Proceedings of the National Academy of Sciences. 2001. 97: 9561-9566. Randall, Robert C., Ed. Muscle Spasm, Pain & Marijuana Therapy. Galen Press. 1991. 237 p. Richardson, Jennelle Durnet; Kilo, Sonja; Hargreaves, Kenneth M. "Cannabinoids Reduce Hyperalgesia and Inflammation via Interaction with Peripheral CB1 Receptors." Pain. 1998. 75(1): 111-119. Russo, Ethan. "Cannabis for migraine treatment: the once and future prescription? An historical and scientific review." Pain. 1998. 76:3-8. Russo, Ethan. "Editorial: Cannabinoids in pain management." British Medical Journal. 2001. 323: 1249. Russo, Ethan. "Hemp for Headache: An In-Depth Historical and Scientific Review of Cannabis in Migraine Treatment." Journal of Cannabis Therapeutics. 2001. 1(2): 21-92.

News Klarreich, Erica. "Cannabis spray blunts pain: Early trials suggest cannabis spritz may give relief to chronic pain sufferers." British Association for the Advancement of Science. 4 Sept., 2001. "Marijuana-Like Drugs May Be Effective Painkillers." Los Angeles Times. 26, Oct., 1997. Schmeltzer, Wendy. "Chronic Elderly Pain." National Public Radio. 12, April 1998. 11:40. (Note: Click this link to download an audio file maintained on the NPR Website.) Yi, Matthew. "Doctor found reckless for not relieving pain: $1.5 million jury verdict for family of cancer patient who went home to Hayward to die." San Francisco Chronicle. 14 June, 2001. 1(A).

Hundreds of Articles on Cannabis and Pain and Inflammation

http://www.druglibrary.org/crl/pain/

http://www.medscape.com/medscapetoday

Opioids for Soft Tissue Pain Syndromes

The soft tissue pain syndromes are poorly researched and controversial in and of themselves, but the use of opioids to manage them augments the controversy because these syndromes can be generated by certain medications. Joseph Audette, MD, from the Massachusetts General Hospital, Boston, reported on opioid use for soft tissue pain syndromes, primarily fibromyalgia and myofascial pain.

Fibromyalgia is a soft tissue pain syndrome that is symmetric, right and left, and includes the presence of tender points. In some patients, it may manifest as generalized hyperalgesia. Myofascial pain is more localized and is associated with trigger points. It appears to be stress-related and associated with syndromes such as chronic fatigue syndrome and pelvic pain syndrome. Many clinicians are reluctant to treat the soft tissue syndromes with opiates since we do not know what we are treating and have no evidence of benefit. Patients who are given opiates are those in whom other treatments -- physical therapy, invasive therapies, rehabilitation, and adequate trials of other analgesics -- have failed. The opioids are not to meant to ameliorate pain but to improve the function of life.

Dr. Audette noted that, thus far, these syndromes have not been found to be associated with pathologic changes in muscle. There is some evidence for central sensitization: serotonin deficiency and increased substance P (SP) in the cerebrospinal fluid,[8-10] and abnormal activation of NMDA receptors.[10] People with fibromyalgia have a high incidence of Arnold-Chiari malformations.[11] Nonsteroidal anti-inflammatory drugs are not effective for treatment of soft tissue pain syndromes

http://www.jaoa.org/cgi/reprint/104/2/73.pdf

Most other patients with chronic pain can be managed by osteopathic physicians, though many osteopathic physicians choose an approach that is too conservative, leaving patients with legitimate chronic pain without relief of symptoms. One may ask who should decide what is legitimate chronic pain? Legitimate chronic pain can be characterized as pain resulting from a known anatomic or physiologic dysfunction. Guidelines, charts, and questionnaires can be used to assess quality, quantity, duration, and location of pain.

Physicians’ expectations of a patient’s level of pain may also contribute to how aggressively that patient is treated.

Physicians expect extreme quantities of post trauma pain (eg, surgical procedures, motor vehicle accidents, visceral pain syndromes such as hepatic capsule disease, biliary disease, and gastrointestinal disorders). Acute pain is generally treated adequately because physicians have evidence that there is a cause for pain. However, after a certain window of time, physicians may determine that the pain the patient is having should be resolved and may then adopt a more conservative approach to pain management. Is it the physician’s ethical responsibility to gradually decrease the dose of medication for patients taking habit-forming medications regardless of resultant pain? Or is it the physician’s duty to ensure pain relief and the return of sufficient daily functioning?

Patients Take Action

Most physicians would agree that many patients will take matters into their own hands when they perceive that they are not receiving adequate care for pain from their physicians. In addition, if pain is not adequately controlled in elderly patients, families may pursue legal remedies. A family invoked the elder abuse law in the Bergman versus Eden Medical Center, resulting in a $1.5 million judgment. Although physicians have a responsibility to encourage their patients toward personal responsibility for their condition, they do not want patients to seek harmful or illegal means of pain relief. The under treatment of pain by physicians may have provoked the Compassionate Use Act of 1996 in California. The act was written “to ensure that seriously ill Californians have the right to obtain and use marijuana for medical purposes where that medical use is deemed appropriate and has been recommended by a physician who has determined that the person’s health would benefit from the use of marijuana in treatment of cancer, anorexia, acquired immunodeficiency syndrome, chronic pain, spasticity, glaucoma, arthritis, migraine, or any other illness for which marijuana provides relief.” The act also states that “no physician shall be punished or denied any right or privilege for having recommended marijuana to a patient for medical purposes.”

What is MARINOL and how does it work?

MARINOL is a type of medicine called a cannabinoid. MARINOL attaches to special receptors in the brain—much like a key fits in a lock. The US Food and Drug Administration (FDA) approved MARINOL to treat nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional treatments.The FDA also approved MARINOL to treat appetite loss associated with weight loss in people with acquired immunodeficiency syndrome (AIDS). If you have HIV/AIDS, your health care professional may prescribe MARINOL to help stimulate your appetite. Other important facts about MARINOL:

• The active ingredient in MARINOL is dronabinol

• Dronabinol is a synthetic version of a naturally occurring compound known as delta-9-THC (delta-9-tetrahydrocannabinol)

• Delta-9-THC stimulates appetite and reduces nausea and vomiting by binding to special receptors found in your nervous system

• Delta-9-THC is also one of many components in marijuana. In fact, delta-9-THC is the main ingredient responsible for most of marijuana’s effects

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