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#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] 

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.
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.
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
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
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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