Medication
Last Update 04/17/2009

Printable Articles and Studies

Cheap Drug May Fight Fibromyalgia Pain

 

APA: Paroxetine Helps Relieve Fibromyalgia Symptoms

Bridging the primary care physician through the opioid contract

Consumer Reports Poll: 66% of Americans Blindsided by Cost of Drugs; Many Not Taking Needed Medications

FDA Approves Second Drug to Treat Fibromyalgia June, 2008

New Data Suggest Cymbalta® Reduced Pain In Fibromyalgia Patients With And Without Depression

Cymbalta (Duloxetine) shows efficacy in fibromyalgia with or    without concurrent major depression

Milnacipran as a Fibromyalgia Treatment January 2009

Pregabalin Improves Pain and Fatigue Symptoms

The Efficacy and Safety of Milnacipran

Cough Drug May Help Fibromyalgia Pain

Lyrica Reduced Fibromyalgia Pain In Patients Regardless Of Symptoms Of Anxiety Or Depression

Oxygenol on Chronic Fatigue and Fibromyalgia

Suicidal tendencies a possible problem when using anti-seizure drugs.

A generic version of the fentanyl Pain patch

Opioid Analgesics in Fibromyalgia

Atypical antipsychotics in the treatment of fibromyalgia

Opioids and Fibromyalgia

Off-label applications for SSRIs

Addiction? Tolerance? Dependency? New stance on using pain drugs.

Pharmacologic Management of Acute and Chronic Pain

Drug for Opioid Constipation Effective in Phase III Trial

Venlafaxine Alleviates Pain  with Fibromyalgia

Prescription Opioid Abuse, Addiction Less Common Than Many Believe

National Institute on Drug Abuse, NIDA on Addiction vs. Dependence

Oral Transmucosal Fentanyl Improves Quality of life

United Kingdom Expands Approval For Provigil (Modafinil)

A fatal drug interaction between oxycodone and clonazepam

Are antidepressant drugs efficacious in the treatment of fibromyalgia?

Just give me something for the pain

Fentanyl patches

Efficacy of Tramadol in Treatment of Pain in Fibromyalgia

Brain Scans Show Antidepressants At Work

Modafinil receives supplemental approval to improve wakefulness

Painkiller Users: Heartburn Pill a Day Keeps Ulcers Away

Duloxetine Reduces Fibromyalgia Pain: Presented at AAPM

Your meds can cause tooth decay by Ed Tate III

The effects of two single doses of tramadol on sleep

Gabapentin for the treatment of pain in guillain-barre syndrome:

Sodium Oxybate May Reduce Fibromyalgia Pain

Narcotic Actiq's use and abuse raise concern

Special Features

      

 

 

The Efficacy and Safety of Milnacipran

The Efficacy and Safety of Milnacipran for Treatment of Fibromyalgia. A Randomized, Double-blind, Placebo-controlled Trial.
J Rheumatol. 2008 Dec 15. [Epub ahead of print] Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH.

 From Seattle Rheumatology Associates and Swedish Medical Center, Seattle, Washington; University of Michigan, Ann Arbor, Michigan; Cypress Bioscience, Inc., San Diego, California; and Forest Research Institute, Jersey City, New Jersey, USA.

PMID: 19132781

OBJECTIVE: To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM).

METHODS: A 27-week, randomized, double-blind, multicenter study compared milnacipran 100 and 200 mg/day with placebo in the treatment of 888 patients with FM. Two composite responder definitions were used to classify each patient's individual response to therapy. "FM responders" concurrently satisfied response criteria for improvements in pain (visual analog scale 24-h morning recall), patient global impression of change (PGIC), and physical functioning (SF-36 Physical Component Summary); while "FM pain responders" concurrently satisfied response criteria for improvements in pain and PGIC.

RESULTS: At the primary endpoint, after 3-month stable dose treatment, a significantly higher percentage of milnacipran-treated
patients met criteria as FM responders versus placebo (milnacipran 200 mg/day, p = 0.017; milnacipran 100 mg/day, p = 0.028). A
significantly higher percentage of patients treated with milnacipran 200 mg/day also met criteria as FM pain responders versus placebo (p = 0.032). Significant pain reductions were observed after Week 1 with both milnacipran doses. At 15 weeks, milnacipran 200 mg/day led to significant improvements over placebo in pain (real-time, daily and weekly recall; all measures, p < 0.05), PGIC (p < 0.001), fatigue (p = 0.016), cognition (p = 0.025), and multiple SF-36 domains. Milnacipran was safe and well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events.

CONCLUSION: Milnacipran is safe and effective for the treatment of
multiple symptoms of FM.


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Cheap Drug May Fight Fibromyalgia Pain

Naltrexone Used For 30 Years For Addiction POSTED: 9:24 am EDT April 17, 2009

A mysterious condition that causes pains and chronic flu-like symptoms and exhaustion may be eased by a cheap drug that has been around for 30 years.

Researchers at Stanford University said that a small study showed that naltrexone, which has been used to treat drug addiction, reduced the pain of fibromyalgia 30 percent more than a placebo.

The results were based on a small study of 10 women who were studied for 14 weeks. They were given a placebo part of the time and the drug at other times, but they did not know which they were taking. "Patients' reactions were really quite profound," said author Dr. Sean Mackey. "Some people decided to come off other medications. Some people went back to work really improving their quality of life."

He emphasized that the early results were not enough to lead to a recommendation, but said he hopes larger studies would give more information.

There are few treatments for fibromyalgia, but this one would only cost about $40 a month, according to a news release on the work.

  While the diagnosis is still controversial because there is no definitive way to test for it, some say that 4 percent of people in the U.S. have the condition.

Jarren Younger, another author of the study, said the idea to test the drug came when people in support groups said it had worked for them.  The study will be published April 17 in the journal Pain Medicine.


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Consumer Reports Poll: 66% of Americans Blindsided by Cost of Drugs; Many Not Taking Needed Medications

New Consumer Reports Best Drugs For Less Magazine Rates 200 Medications
YONKERS, N.Y., March 17 /PRNewswire-USNewswire
Sticker shock is taking a toll on Americans when they fill their prescriptions: 66% of those polled by Consumer Reports said they found out the cost of a drug when they picked it up at the pharmacy counter, while just 4% said they had a conversation with their doctor about the cost of a drug. And 28% of Americans told Consumer Reports they'd taken potentially dangerous actions to save money, such as not filling prescriptions, skipping dosages, and cutting pills in half without the approval of their doctor.

Cutting Corners, Not Complying With Prescriptions

"We were surprised by the extent to which consumers are cutting corners and the risks they're taking as a result of belt-tightening. Most importantly, patients need to talk to their doctors about the cost of drugs and let them know when they have difficulty paying for prescriptions," said Dr. John Santa, director of the Consumer Reports Health Ratings Center. In a separate poll of Hispanic consumers, Consumer Reports found that half of Hispanic Americans are not following through on their doctors' prescriptions and nearly 3 in 10 had decided against filling a script for cost reasons.

New Magazine Identifies Proven, Cost-Effective Alternatives.The poll is being released in conjunction with Consumer Reports Best Drugs For Less, a 60-page magazine that rates more than 200 prescription drugs and over-the-counter medicines for more than 20 conditions including heart disease, asthma, diabetes, and depression. Best Drugs for Less can be purchased by visiting www.ConsumerReportsHealth.org, where the ratings can be accessed for free. The ratings are part of a larger initiative by the newly launched Consumer Reports Health Ratings Center to provide consumers with health ratings based on independent and unbiased review of the best scientific evidence available.

"By every measure, and certainly through our extensive polling, it is clear that our long term economic crisis will only be solved by also fixing our nation's health-care system," said Consumers Union President Jim Guest. According to Guest, Consumers Union has been a strong advocate of increased federal funding for comparative effectiveness -- the task of comparing different options for treating a medical condition -- which received $1.1 billion in stimulus funding and is being looked at by Congress for additional funding. "Comparative effectiveness research helps patients and doctors make better choices, and will help improve our broken health-care system," said Guest.

Misgivings About Generics
When generic versions of a brand name drug are available, they are as safe and effective as the original. For brand name drugs, where a generic version is not available, in many cases doctors or pharmacists can substitute the generic version of an older drug with equivalent effectiveness (and often a longer safety record).
• Nearly half of Americans polled (47%) had reservations or misconceptions about taking generic drugs.
• Forty-six percent of Americans polled by Consumer Reports said their physician never or sometimes recommended generics.
• Accurate information about generics is not reaching the consumers who could benefit the most, such as those spending more than $50/month on prescription drugs (52%).
• In a separate Consumer Reports poll of Hispanic consumers, 43% expressed misgivings about generics, saying they sometimes or never work.
Americans Heeding Direct-to-Consumer Drug Advertising
"The pharmaceutical industry undermines generic drugs very effectively through advertising and free samples of brand-name drugs, while using more subtle tactics to tell patients and doctors that generics are something to be afraid of," said Dr. Santa.
• One fifth of people who regularly take a prescription medication have requested a drug from their doctor that they had seen in a drug ad and the majority (67%) said their doctor wrote the prescription.
• Eighty percent of the same group said they had received free drug samples from their doctors.
Americans Perceive Undue Influence of Pharmaceutical Industry
• Consumers perceive the undue influence of pharmaceutical companies on their doctors. Those practices raising the greatest concern among consumers were rewarding doctors who write a lot of prescriptions (82%); receiving fully paid trips (77%) or gifts worth more than $50 (76%); and paying for doctors' attendance at meetings (67%).
Washington, D. C., Campaign For Comparative Effectiveness

To underscore the point that some pills work better than others -- and hence the need for rigorous comparisons -- Consumer Reports is staging a display at Union Station in Washington, D.C., from Tuesday, March 17th to Thursday, March 19th. The display at the station's main hall will be easy to spot: Just look for the giant pills running on treadmills. Copies of Consumer Reports Best Drugs For Less will be distributed at Union Station, in addition to four key metro stops, as part of a weeklong Washington D.C. campaign to raise awareness about comparative effectiveness.

Poll Methodology
The Consumer Reports National Research Center conducted a telephone survey of a nationally representative probability sample of telephone households. A total of 2,004 interviews were completed among adults ages 18+ and interviewing took place January 15-19, 2009. The margin of error is +/-3.4% points at a 95% confidence level.
The material above is intended for legitimate news entities only; it may not be used for commercial or promotional purposes. Consumer Reports(R) is published by Consumers Union, an expert, independent nonprofit organization whose mission is to work for a fair, just, and safe marketplace for all consumers and to empower consumers to protect themselves. To achieve this mission, we test, inform, and protect. To maintain our independence and impartiality, Consumers Union accepts no outside advertising, no free test samples, and has no agenda other than the interests of consumers. Consumers Union supports itself through the sale of our information products and services, individual contributions, and a few noncommercial grants.

SOURCE Consumer Reports

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The abuse and addiction potentials of opioid analgesics prescribed for patients with chronic pain have been of great concern. However, current research indicates that these problems are not as common or widespread as many seem to believe.

In an evidence-based review for Pain Treatment Topics (Pain-Topics.org), editor Stewart B. Leavitt, MA, PhD, summarizes the
findings of major research investigations of these problems. "The research is extensive, but requires careful examination," he notes.
"Unfortunately, news media, government agencies, and others have portrayed abuse and addiction associated with prescribed opioids as problems of much larger proportions than seems warranted by the evidence." Several comprehensive investigations support this
assertion:

In an extensive review, combining results from 24 clinical studies, the overall rate of prescribed opioid analgesic abuse or addiction in patients with pain was about 3.3%. However, fewer than 2 out of 1,000 (0.19%) patients without a current or past substance-use disorder experienced problems with opioids prescribed for pain.

Similarly, a clinical investigation of patients receiving daily opioid therapy for chronic noncancer pain prescribed by primary-care physicians found that only 3.7% of patients had a confirmed opioid-use disorder. However, whether or not any of these patients also had prior substance-use problems was not examined.

A systematic review, encompassing 17 studies of patients with moderate-to-severe chronic noncancer pain who were treated with
opioid analgesics for at least 6 months, found opioid abuse in only 0.4% of patients. Signs of opioid addiction were evident in only 1
case out of 2042 subjects evaluated (0.05%). Whether these extremely low rates were in the overall patient population or solely in those patients without prior substance-use problems is unknown.

Estimates of substance-use disorders among the general public range from 5% to as high as 67%, depending on the population examined;although, the exact percentages of those disorders involving solely opioids has been poorly defined. At the least, it seems fairly certain that the rate of opioid-use problems in patients prescribed those drugs for pain would be no greater than in the population at large, according to Leavitt's review. And, according to other experts, the data suggest that news media accusations of increased opioid abuse being associated with greater numbers of patients being prescribed opioids for chronic pain management are unfounded.

This topic is worthy of further investigation and debate; however, the preponderance of available evidence suggests that establishing
medical policies or practices in pain management on a presumption of high rates of prescribed opioid-analgesic abuse or addiction could be misguided, resulting in added costs for healthcare delivery and the undertreatment of pain. Healthcare providers can be reasonably assured that only a very small percentage of their patients with chronic pain, if any, will exhibit abuse/addiction when receiving long-term opioid analgesics. And, this would be especially so in those patients who have not experienced substance-misuse problems in the past.

The complete article -- titled "Opioid-Analgesic Abuse & Addiction Prevalence Still Uncertain" -- with references, can be freely
accessed at:
http://pain-topics.org/pdf/e-Briefing-Vol3-No1-2008.pdf#opioidabuse

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Final Patient Completes Phase III Trial for Fibromyalgia Treatment

The first Phase III pivotal clinical trial from Jazz Pharmaceuticals in studying JZP-6 for the treatment of fibromyalgia has been completed. The program includes two randomized, double-blind, placebo-controlled studies. The first one enrolled 550 patients at 65 centers in the U.S.; the second study is enrolling patients at sites in the U.S. and Europe. The primary endpoint for both studies is change in pain. The company said it remains blinded to the trial results but will release its primary efficacy and safety data in the fourth quarter of the year. It plans to submit an NDA to the FDA by the end of 2009.

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Milnacipran as a Fibromyalgia Treatment January 2009

As of early 2009, the U.S. FDA was reviewing the New Drug Application1 (NDA) for milnacipran as a fibromyalgia treatment. The administration missed its October 2008 deadline for making a decision, saying only that it needed more time to review data.

Forest Laboratories, Inc. and Cypress Bioscience, Inc. submitted the NDA for milnacipran based on findings that people with fibromyalgia who took milnacipran had less pain, more physical function and a positive impression of being better overall. Further studies have supported these results.

Milnacipran is an antidepressant similar to Cymbalta (duloxetine), as both drugs raise levels of the neurotransmitters serotonin and norepinephrine. Milnacipran, however, is the only drug in its class that raises norepinephrine more than serotonin. Outside the U.S., it's been on the market for about a decade and is available in more than 50 countries. It's currently not approved for any use in the U.S.

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Suicidal tendencies a possible problem when using anti-seizure drugs.

FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from
placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In
the FDA's analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%)
compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one
week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs.
The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the
class for psychiatric or other conditions.

Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable
changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

The drugs included in the analyses include (some of these drugs are also available in generic form):

Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Levetiracetam (marketed as Keppra)
Oxcarbazepine (marketed as Trileptal)
Pregabalin (marketed as Lyrica)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
Zonisamide (marketed as Zonegran)

Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is
shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly.

Read the complete 2008 MedWatch Safety Summary including a link to the Healthcare Professional Sheet regarding this issue at:

http://www.fda.gov/medwatch/safety/2008/safety08.htm#Antiepileptic

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FDA Approves Second Drug to Treat Fibromyalgia June, 2008

The U.S. Food and Drug Administration (FDA) approved Cymbalta (duloxetine) on June 16 for treating fibromyalgia. Cymbalta is the first serotonin-norepinephrine reuptake inhibitor (SNRI) that has been proven to reduce pain in fibromyalgia patients. This is the second FDA-approved medication to treat the disease, while the first was Lyrica (pregabalin) in June 2007.

The Fibromyalgia Network has been reporting on the progress of Cymbalta through clinical trials since the spring of 2004.

SNRI drugs, such as Cymbalta, are thought to relieve pain by increasing the availability of serotonin and norepinephrine (NE) in the central nervous system. These two neurotransmitters help filter out pain signals in the spinal cord so that fewer make it up to the brain. When serotonin and NE are released at the nerve endings, SNRIs latch onto these two neurotransmitters and carry them back across the nerve junction so that both can be reused to fight pain. In a way, SNRIs "recycle" the two neurotransmitters that are low in many patients with fibromyalgia.

In the most recent double-blind, randomized, phase III clinical trial of 520 men and women with fibromyalgia, researchers compared Cymbalta at 20 mg, 60 mg, and 120 mg doses taken once daily for six months versus placebo. People taking the two higher doses (but not 20 mg/day) reported pain reduction after the first week. After three and six months, patients taking either 60 or 120 mg daily reported a significant reduction in pain compared to patients taking the placebo. Aside from measures of pain, the two higher doses of Cymbalta also reduced mental fatigue, which might possibly relate to improvements in mental clarity.

Cymbalta was shown to be equally effective in men and women with and without mood disorders. Even people over 65 years of age reaped similar improvements in pain as those in the younger age groups.

Nausea, dry mouth, constipation, and sleepiness were the most common side effects of the medication. The side effects increased at the higher dose. Weight gain or blood pressure elevations may occur in a subgroup of patients taking Cymbalta.

Details on overcoming side effects, monitoring blood pressure and making adjustments for daytime sleepiness were reported in the January 2008 issue of the Fibromyalgia Network Journal. "The key message is to not give up too soon: try different doses and try taking it at different times during the day. Patients usually find the right approach for them," said Lesley Arnold, M.D. of the University of Cincinnati College of Medicine, in Ohio, and lead investigator for the clinical trials on Cymbalta.

Cymbalta has already been FDA-approved to treat diabetic peripheral neuropathic pain (DPNP), major depressive disorder, and generalized anxiety disorder, all in adults older than 18 years of age.

The FDA also added important warnings and precautions to the Cymbalta prescription information including who should not take this medication.

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Lyrica Reduced Fibromyalgia Pain In Patients Regardless Of Symptoms Of Anxiety Or Depression

17 Apr 2008   

Pfizer's Lyrica reduced pain of fibromyalgia in patients regardless of whether they experienced symptoms of anxiety or depression at the beginning of the study, according to a pooled analysis presented today at the American Academy of Neurology annual meeting. The analysis, which looked at data pooled from previous clinical trials, also showed that patients' self-reported improvements were more closely associated with improvements in pain and sleep than fatigue or symptoms of anxiety or depression.

Fibromyalgia is the most common, chronic widespread pain condition in the United States and is thought to result from neurological changes in how patients perceive pain. Fibromyalgia is usually accompanied by poor sleep, stiffness and fatigue.

"The data showed that Lyrica reduced fibromyalgia pain, and alleviating that pain was associated with patients' overall feeling of well-being," said Dr. Lesley Arnold, one of the study's authors and associate professor in the department of psychiatry at the University of Cincinnati Medical Center. "Understandably, many patients with a chronic pain condition such as fibromyalgia also experience depression and anxiety, and importantly we found that Lyrica helped reduce pain in patients regardless of the presence of symptoms of these co-morbid conditions."

About the Analysis

The results are from a retrospective, pooled analysis of data from three placebo-controlled clinical trials (8 weeks, 13 weeks and 14 weeks long) of Lyrica in over 2,000 fibromyalgia patients. These studies randomized patients to receive Lyrica 150 mg, 300 mg, 450 mg or 600 mg or placebo dosed twice daily. Patients were asked to measure their pain on a scale of zero to 10; the baseline score for study participants was 6.9 (150 mg, 450 mg, 600 mg) or 7.0 (300 mg). A score of 4.0 to 6.9 is considered moderate pain and a score of greater than 7.0 is considered moderate to severe pain on this 10- point scale.

In the studies, 38 percent of fibromyalgia patients had moderate to severe anxiety symptoms, while 27 percent had moderate to severe depressive symptoms, as assessed using the Hospital Anxiety and Depression Scales (HADS-A or HADS-D). Patients with severe depression or unstable psychiatric conditions were excluded from the studies.

The new analysis confirmed that Lyrica was significantly more effective than placebo in reducing pain in patients with fibromyalgia. Patients receiving 600 mg a day of Lyrica had a pain reduction of 2.08 on the pain scale; 450 mg a day had a reduction of 2.01; 300 mg a day had a reduction of 1.76; 150 mg a day had a reduction of 1.37, and placebo had a reduction of 1.25.

Additionally, Lyrica was found to reduce pain in patients regardless of whether they had symptoms of anxiety or depression.

The analysis also examined the relationship between improvements in pain, sleep, fatigue, anxiety and depressive symptoms with patients reporting feeling "much improved" or "very much improved" as measured by the Patient Global Impression of Change (PGIC). The PGIC is a standardized, self-reported tool that measures the change in a patient's overall status ranging from "very much improved" to "very much worse."

Pain reduction was found to have the greatest association on patients reporting improvement as measured by PGIC. The relationships between feeling much or very much improved were strongest for pain and sleep, and less pronounced for fatigue and symptoms of anxiety or depression, but statistically significant for all variables.

The most common side effects in the pooled analysis versus placebo of these three studies were dizziness and somnolence, followed by weight gain, blurred vision and dry mouth.

About Lyrica

In the United States, Lyrica® (pregabalin) capsules, CV, is approved for the management of fibromyalgia. Lyrica is also indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia (pain after shingles), and as adjunctive therapy for adults with partial onset seizures. The 600 mg/day is not an approved dosage for Lyrica in the management of fibromyalgia.


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Opioids and Fibromyalgia

Jane Kohler. FMS Community.org 2007

If you suffer with fibromyalgia pain, chances are that you have already tried a variety of medications and therapies. For many who suffer with Fibro pain the mainstream therapies can change their life, treatments like antidepressants, muscle relaxers, stretching, water exercise, anti-seizure drugs or heat and massage may lessen the pain and allow you to work and take care of your family.

There is a subset of Fibro sufferers who do not respond to these types of treatments, and others who may have overlapping conditions such as Diabetes, CMP, TMJ, Arthritis, Degenerative Disc Disease and other conditions, for them the only answer may be Opiods.

This is where controversy enters your life as the use of opioids to treat chronic pain is a subject of great debate. Many of the physicians in the U.S. are reluctant to prescribe opioids as they were trained to fear addiction. They were taught that anyone who was prescribed opiods for pain relief would develop a tolerance for the drug or become addicted to the drug. All this keeps you from pain relief despite the studies that prove that chronic pain patients do not feel high, or euphoric when taking opiods. They do not exhibit the usual benefits that someone who takes a drug for fun will experience; they simply experience less pain and are able to function within society.

This brings up the dependency issue, if you are not addicted, but dependent on a drug it is just as bad. Wrong again! You can be dependent on your glasses, you are not addicted to them, but you sure lead a better life when you can see where you are going. Is a diabetic addicted to insulin? No, but they are dependent on it, they need it to survive and have a quality life. You can depend on a drug to insure a better quality of life; this does not mean you are addicted.

Why are doctors reluctant to prescribe? Let’s toss our government into the mix; their stand on the issue has caused the majority of care providers to back away from the issue. Many doctors have been under investigation, or arrested for prescribing opioids to pain patients. As a result fibromyalgia patients and others who suffer with chronic pain will be left without appropriate pain relief.

If you are interested in using opioids for pain relief, do the research so you can understand the controversy and present your case to your care provider in an educated manner.

What are Opioids?

    Opioids are more commonly known as narcotics. They stem from opium, a natural element that is found in the opium plant. Natural opium has been in use for hundreds of years, and synthetic opium is now available. Opioids are most widely prescribed for acute pain, such as having surgery, or having a tooth removed. They can be used to treat chronic pain if prescribed, and used carefully.

The most common forms of prescribed opiods:

  • oxycodone
  • morphine
  • fentanyl

    Why the Controversy?

        There is much debate about both the usefulness and safety over the use of opioids to treat fibromyalgia pain. The main reason most care providers will not prescribe opioids is the lack of documented research to show that opioids actually provide pain relief for fibro patients. Others cite concerns about tolerance and addiction issues associated with long-term opioid use. Antidotal evidence from fibromyalgia patients show that opioids can be highly-effective in treating widespread pain and muscle stiffness. Thanks to the lack of scientific study and the fear of legal repercussions the majority of doctors shy away from prescribing opiods and fibromyalgia sufferers find it difficult to get help.


    Do Opioids Relieve Fibromyalgia Pain?
     
        The effectiveness of opioids in fibromyalgia pain relief is one of the key components to the controversy, many patients claim that opioids have given them significant pain relief, some doctors disagree. However, there is research that shows that opioids are effective in relieving fibromyalgia pain. A recent study showed that fibromyalgia sufferers experienced pain relief and a better quality of life from the use of opioids. It was reported that 38% of the subjects a noticeable reduction in pain, the subjects also reported less anxiety and depression, less sleep disturbance, increased mobility and an over all better quality of life.


    Do Opioids Cause Addiction?

        If we tackle this issue with facts, less than 0.5% of people who are given opioids for pain become addicted. Is there a risk? Of course some people will become addicted; it is a sad fact that there are drug users in the world who seek these drugs to get high, feel good, and to avoid dealing with life’s stressors. Heredity and mental health issues also play a part in addiction, in these cases opioids help them to feel high, get away from life. Chronic pain patients will not feel the “high”, they will only feel a lessening of symptoms and they will be able to work, care for their family and themselves. We may become dependent on the drug to keep moving, but we will not become addicted.


    How do you ask for Opioids?

    Asking your doctor for pain relief can be stressful, you feel like some kind of trash asking for drugs thanks to media hype, but you can do it in a calm and professional way.

    It is important to provide your doctor with as much information as possible about your symptoms and their severity. Provide a list of things you have already tried to get rid of the symptoms, list drugs and therapies tried such as massage, stretching or water aerobics. Keep a daily log, journal or chart that records your symptoms and their severity, rate the pain level for each day from 1 to 10, with 10 being the most severe pain. If you go shopping and carry the bags into the house and then are unable to put the items away, say so. If taking a shower and washing your hair leaves you in so much pain you can not go to work, tell them. Make sure they are aware of overlapping conditions you may be dealing with such as disc disease, diabetic pain, arthritis etc.

    Always include a paragraph about your life before the disease infiltrated your life. If you worked full time, played tennis and rode bikes, say so. Let them know the pain is keeping you from making a living or leading a decent quality of life with your family.

    My Doctor will not Prescribe Opioids.

    Some doctors will not prescribe opioids unless it is an end of life circumstance, nothing you say will change their mind. The best thing you can do is change care providers if your insurance allows. You may have used the same doctor for years, you trust and respect them, but you may have to cut them loose to find a caring doctor who will help, if your insurance allows. Your quality of life must come first.

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Pain Patients Should Not be Punished for Opioid Medication Abuse or Addiction

Practitioners prescribing opioids for pain should be prepared to deal with patients' problems in using the medicines, according to a
special report from Pain-Topics.org. Patients should not be discharged from treatment if opioid abuse or addiction occurs. Report
explains how opioids can be continued while medication-misuse problems are addressed.


Newswise - "Any practitioner prescribing opioids for chronic use should be accountable for having a strategy in place if medication
abuse or addiction occurs," says Peggy Compton, RN, PhD. "Providing daily opioid pain relievers without suitable addiction expertise or
support in place puts both the pain-management practitioner and patient at risk for poor outcomes."

Unfortunately, the common practice of discharging patients from opioid therapy when there are concerns about substance abuse or
addiction can do significant harm; not just to patients, but also affecting their families, the healthcare system, and society at
large. Such practice should be avoided, Compton urges.

Compton is an Associate Professor of Nursing at the UCLA School of Nursing, Los Angeles. Her report, exclusively for Pain Treatment
Topics and published at the Pain-Topics.org website - "Should Opioid Abusers Be Discharged From Opioid-Analgesic Therapy?" - can be
accessed atS http://pain-topics.org/clinical_concepts/comments.php#Compton

In her report, Compton stresses that instead of denying patients their pain-relieving opioids, working partnerships between addiction
and pain specialists should be developed, with the pain practitioner continuing treatment for pain while also playing a role in addiction
treatment. This does not require the pain-management practitioner to become an addiction specialist; however, pain practitioners should be
involved in, rather than draw away from, addiction treatment for their patients with chronic pain who have need for such services.

Important suggestions in the report include:

# It is very difficult to identify true addiction in patients with chronic pain.

# Patients taking opioids every day should be monitored for signs of drug abuse or addiction.

# If opioid-use problems arise, and are accurately assessed, substance-abuse treatment strategies should become part of the pain
treatment plan.

# Pain practitioners should stay involved, since there is a lack of special services for treating patients with both pain and addiction.

# Pain practitioners can support a patient's addiction recovery by encouraging attendance at 12-step programs, limiting the patient's
access to opioid medicines, and monitoring the patient's mental health status.

Such participation by pain practitioners not only enhances therapy for chronic pain but provides them a unique opportunity to help stem
the significant public health problem of opioid abuse and addiction. In this report, Compton outlines specific steps for any healthcare
provider to follow.

Pain Treatment Topics and the associated Pain-Topics.org website provide open and free access to noncommercial, evidence-based
clinical news, information, research, and education on the causes and effective treatment of the many types of pain conditions. It is
independently produced and currently supported by an unrestricted educational grant from Covidien/Mallinckrodt Inc., St. Louis, MO, a
leading manufacturer of generic opioid analgesic products.

© 2008 Newswise.  All Rights Reserved.


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Cymbalta (Duloxetine) shows efficacy in fibromyalgia with or without concurrent major depression
By Janis Kelly

Cymbalta is a drug that inhibits both norepinephrine and serotinin reuptake. It is currently marketed for depression and has showns a significant improvement in fibromyalgia symtpoms. This effect was independent of whether or not the patient had major depression.

This was a double-blind, placebo-controlled trial involving 207 patients, and it was sponsored by the manufacturer.

I would say the weight of the evidence shows that duloxetine leads to sustained relief of pain, especially in the female subjects, who improved on all pain outcomes," said principal investigator Dr Lesley M Arnold (University of Cincinnati College of Medicine, OH) .

"Are we on the brink of a new era of fibromyalgia syndrome management?" According to Dr. Geoffrey Littlejohn  "The future does seem positive in regard to significant improvement in FMS symptoms with these new potential therapies. However, it is wise to continue to reflect on the FMS process and to recognize that social and psychological factors, even everyday life stressors, can dramatically affect FMS neurobiology."

The duloxetine study is part of an effort to improve on results with tricyclic antidepressants, which are widely used in FM in doses lower than those typically used in mood disorders, Arnold et al explain. The tricyclics produce some improvement in FM-related fatigue and in sleep, overall well-being, and pain severity but have less effect on tenderness. These drugs reduce both NE and 5-HT reuptake but also have varied effects on choloinergic and histamine activities and on other mechanisms that modulate pain.

Separating out the effect on reuptake inhibition has not been useful. Targeted inhibition of NE reuptake with venlafaxine (Efexor, Wyeth) and selective inhibition of 5-HT reuptake with fluoxetine (Prozac, Eli & Lilly Co) have both been relatively ineffective in FM   The duloxetine study combines both approaches by using a combination reuptake inhibitor to elevate levels of both NE and 5-HT, but without the other effects of the tricyclics.

The multicenter study enrolled 207 subjects meeting the American College of Rheumatology (ACR) criteria for primary fibromyalgia. Patients were randomized to placebo (n=103, including 92 women) or to duloxetine 60 mg bid (n=104, including 92 women). In the placebo group, 42/103 patients had major depressive disorder. In the duloxetine group, 37/104 patients had major depressive disorder.

The double-blind treatment phase continued for 12 weeks and included weekly visits for the first 2 weeks, then visits every 2 weeks.

Significant improvement on most FM symptoms

I would say the weight of the evidence shows that duloxetine leads to sustained relief of pain, especially in the female subjects, who improved on all pain outcomes.

The 2 primary outcome measures were pain severity as measured by the Fibromyalgia Impact Questionnaire (FIQ) pain item and the FIQ total score, reflecting the overall impact of FM. Secondary end points included the FIQ items for fatigue, morning tiredness, and stiffness, and tender point assessment.

Other secondary end points were the Clinical Global Impressions of Severity scale, the Patient Global Impression of Improvement scale, the Brief Pain Inventory (short form), the Beck Depression Inventory, the Beck Anxiety Inventory, the Medical Outcomes Study Short Form 36 (SF-36), the Quality of Life in Depression Scale, and the Sheehan Disability Scale. All of them were assessed on an intention-to-treat analysis.

"The FIQ score was improved at week 12. Only the FIQ pain score was not significantly improved at week 12, although it was improved at week 4. Another pain score, the Brief Pain Inventory, was significantly improved at week 12, as was the SF-36 bodily pain score. Furthermore, the female subjects improved on all pain outcomes (including the FIQ pain score) at week 12," Arnold tells rheumawire.

There was a striking improvement in the FIQ total score for the entire duloxetine group, which became significant at week 4 and continued through week 12 (p=0.027). The group difference in the other primary end point, the FIQ pain score, became significant at week 4 but was not significant at week 12 (p=0.130). Response rates, defined as a <50% decrease in FIQ pain score, were 27.7% for duloxetine vs 16.7% for placebo at week 12 (p=0.06).

Arnold points out that the improvement in tender point measures was particularly important, since previous studies using tricyclic antidepressants found little improvement in tender points.

The duloxetine-treated patients also had significant improvements in general activity, mood, walking ability, normal work, sleep, and enjoyment of life, as measured on the Brief Pain Inventory.

Equally effective in patients without depression

Duloxetine was equally effective in patients with or without major depressive disorder, Arnold notes. "I was not surprised that the improvement in fibromyalgia symptoms with duloxetine was independent of the presence or absence of depression. Duloxetine may have an effect on the descending pain pathways that involve serotonin and norepinephrine that is independent of its effect on mood."

Although the numbers are small, the data also suggest that there may be a sex difference in response to duloxetine for FM. The investigators found that duloxetine-treated women improved significantly more than placebo-treated women on both the primary and secondary end points, while male subjects treated with duloxetine did not have significantly better responses than the placebo-treated men on either primary or secondary efficacy measures.

"I was surprised by the lack of effect in men. I think the power was not great enough to show an effect in men. We need to study a larger group of men before coming to any firm conclusion about duloxetine in the treatment of men with fibromyalgia," Arnold says.

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Merck to Enter a Venture for Pain Drugs

By ANDREW POLLACK

Merck & Company, stung by the withdrawal of Vioxx from the market, will enter a collaboration to develop new painkilling drugs with Neuromed
Pharmaceuticals, a privately held biotechnology company.

In a deal that is expected to be announced today, Merck will pay an initial $25 million to gain the exclusive rights to Neuromed's family of drugs for
chronic pain. The most advanced of the drugs, NMED-160, has entered midstage clinical trials. Merck would pay Neuromed an additional $202 million if NMED-160 wins approval worldwide. If NMED-160 is approved for a second use, and another drug is approved for two uses, payments would reach $450 million. Janet Skidmore, a spokeswoman for Merck, said the deal was not an attempt to replace Vioxx, which was withdrawn from the market after it was found to raise the risk of heart attacks.

Rather, she said, Merck has identified pain as one of the nine medical treatment areas in which it is focusing. The company already has two other
pain drugs in Phase 2 trials, and one in Phase 1. Neuromed's drugs are made to interfere with the transmission of pain signals by blocking the influx of calcium ions into nerve cells. "We think these have the potential to become very powerful agents for chronic pain, on the level of morphine,"
Christopher Gallen, the chief executive of Neuromed, said in an interview.

The first drug that works by that mechanism, Prialt from the Elan Corporation, won Food and Drug Administration approval in December 2004 for
use by patients who do not get relief from other analgesics. But because Prialt can cause severe side effects including heart problems and
hallucinations, it must be delivered directly into the fluid surrounding the spinal cord by a catheter and implanted pump. Sales in 2005 were only $6.3
million.

NMED-160, by contrast, is taken orally. Dr. Gallen said animal studies suggested the drug did not share Prialt's problems and could have fewer side
effects than morphine. But more extensive testing is required, so the drug is not likely to reach the market until early next decade, he said. Neuromed has offices in Vancouver, British Columbia, and Conshohocken, Pa.
Copyright 2006 The New York Times Company

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Sodium Oxybate May Reduce Fibromyalgia Pain New

SAN DIEGO, CA -- February 24, 2006 -- The sleep aid sodium oxybate (Zyrem) may also help reduce pain, tenderness, and chronic fatigue
from fibromyalgia, according to a preliminary study presented here February 23rd at the 22nd Annual Meeting of the American Academy of
Pain Management (AAPM). No drugs are currently approved by the U.S. FDA for the treatment of fibromyalgia.

"Fibromyalgia is notoriously refractory to treatment," said lead investigator Patrick B. Wood, MD, assistant professor of family
medicine at the Louisiana State University Health Sciences Center in Shreveport, Louisiana.

The researchers hypothesized that sodium oxybate would regulate neurotransmitter levels required for normal sleep cycles, which are
frequently disrupted during stage III and IV sleep in people with fibromyalgia.

"This study demonstrates a pretty novel application of this drug," said Dr. Wood, but he acknowledged that some clinicians have used the
drug off label for fibromyalgia.

In the double-blind, multicenter study, 150 fibromyalgia patients were randomized to receive 4.5 g or 6 g of sodium oxybate or placebo.
They filled out a daily electronic diary reporting pain and fatigue visual analog scale scores as well as rescue medication use. Other
measures of sleepiness, function, and global impression were recorded at office visits throughout the 27-day study.

Both doses of the drug resulted in significant reductions in pain, fibromyalgia impact scores, and patient-reported change in global
impression scores compared to placebo.

There was a strong trend toward significant reductions in tender point count and tender point index. The sodium oxybate group reported
1.5 fewer tender points on average and about a 3-point reduction in tender point index score compared with the placebo group. Sleep
scores were about 2 points lower on average for the active treatment arm.

There was a dose-dependent increase in nausea, vomiting, headache, and dizziness for patients receiving
sodium oxybate compared with those who received placebo.

The authors cautioned that this is preliminary, proof-of-concept data. They are currently designing further studies to determine
sodium oxybate's efficacy in treating fibromyalgia.

Orphan Medical, a subsidiary of Jazz Pharmaceuticals, sponsored this study.

[Presentation title: A Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group, Multi-Center Trial Comparing the Effects of Orally
Administered Xyrem (Sodium Oxybate) With Placebo for the Treatment of
Fibromyalgia.

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Duloxetine Reduces Fibromyalgia Pain: Presented at AAPM 

By Crystal Phend SAN DIEGO, CA -- February 27, 2006 -- The antidepressant duloxetine (Cymbalta) appears effective in treating
pain and improving quality of life compared to placebo in women with fibromyalgia, researchers said here February 23rd at the 22nd Annual
Meeting of the American Academy of Pain Management (AAPM).

"There are no approved drugs for fibromyalgia," said presenting author Michael J. Detke, MD, PhD, medical director for Cymbalta at
Lilly Research Laboratories, Indianapolis, Indiana. "It's a significant medical problem."

Although the same serotonin and norepinephrine systems responsible for depression are dysfunctional in patients with fibromyalgia, Dr.
Detke said duloxetine's pain-relieving effect appears independent from its effect on mood.

The researchers presented two randomized, placebo-controlled, double-blind studies of women with fibromyalgia according to the
American College of Rheumatology criteria and significant pain (an intensity of at least 4 on the Fibromyalgia Impact Questionnaire or
Brief Pain Inventory). Twenty-five to 40% of the patients had a current major depressive disorder and all baseline characteristics
were similar between treatment arms.

In the first study, 92 women received 60 mg of duloxetine twice daily while another 92 received placebo. In the second study, 118 were
randomized to 60 mg of duloxetine once daily, 116 to a dose of 60 mg twice daily, and another 120 to placebo.

Average pain scores were significantly lower by about 1 point in both studies for the duloxetine groups compared with placebo, but there
was no difference between once and twice daily dosing groups in the second study. Both studies showed significantly greater percentages
of patients achieving a 50% reduction in pain on duloxetine versus placebo, which Dr. Detke called a "pretty robust" finding.

Fatigue and rest scores showed similar significant reductions in the second study for duloxetine versus placebo. The reductions were not
significant in the first study.

Patients with and without major depressive disorder experienced the same significant reduction in pain compared to placebo. No
significant interaction between pain alleviation and depression was found in either study.

The authors concluded that duloxetine was safe and effective in treating fibromyalgia pain.

[Presentation title: Duloxetine in the Treatment of Fibromyalgia in
Women -- Results from Two Clinical Trials.

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Cough Drug May Help Fibromyalgia Pain

Findings Could Affect Other Chronic Pain Conditions By Salynn Boyles WebMD Medical News Reviewed By Brunilda  Nazario, MD on Monday, May 23, 2005

May 23, 2005 -- An ingredient found in over-the-counter cough medicines may help ease the pain of fibromyalgia, according to new research from the University of Florida.

Fibromyalgia patients who took dextromethorphan experienced temporary reductions in the intensity of pain associated with minor repetitive physical contact -- a common characteristic of the poorly understood disease.

Researchers say the findings may have broader implications for the treatment of a host of chronic pain conditions. But they added that patients should definitely not self-medicate with over-the-counter drugs containing dextromethorphan.

"We are not telling people to try cough medicine to relieve their fibromyalgia pain," researcher Roland Staud, MD, tells WebMD.

Staud characterized the pain-relieving impact of the drug as "moderate." But he added that dextromethorphan or similarly acting medications may prove to be important additions to current treatments for fibromyalgia and other conditions involving heightened pain sensitivity.

Constant, Chronic Pain

It is estimated that as many as 10 million Americans have fibromyalgia -- a baffling disease that strikes mostly women and is characterized by pervasive pain, stiffness, fatigue, and muscle tenderness.

While the cause of fibromyalgia remains unknown, it is now thought that a mechanism known as central sensitization plays a major role in the disease. The theory is that the brain and spinal cord magnify pain signals to abnormally high levels.

Fibromyalgia patients often experience pain to stimuli that are not normally perceived as painful, such as a pat on the back. The pain can get worse with repeated contact.

Dextromethorphan has been shown to block the action of chemicals that relay pain to the spinal cord. It works by blocking a receptor known as N-methyl-D-aspartate or NMDA, which responds to these pain-transmitting chemicals. For this reason, Staud and colleagues evaluated the drug for pain control in fibromyalgia.

They found that people with fibromyalgia treated with dextromethorphan experienced moderate improvement in pain associated with repeated physical contact compared with those who got placebo treatments.

Better Drugs Needed

Staud tells WebMD that pharmaceutical researchers are working to develop more effective drugs that target the NMDA receptor with fewer side effects than the medications that are now available.

He estimates that these drugs could be commercially available within three to five years and could eventually be major players in pain control.

NMDA-receptor blockers like dextromethorphan have already been shown to improve pain control when given with morphine and other widely used opium-based medications. The hope is that combining the two drugs will allow a lower dose of the opioids to be used to control pain.

Fibromyalgia expert Laurence Bradley, PhD, agrees that more research is needed before doctors or their patients turn to dextromethorphan for pain control.

"It would be a disservice to start to recommend that either patients or physicians begin experimenting right away with dextromethorphan, because I think there are some important questions about how to minimize the side effects [of the drug]," he says.

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There is finally a generic version of the fentanyl Pain patch. Just approved.

LOS ANGELES (Reuters) - U.S. regulators approved the first generic rival to Johnson & Johnson's Duragesic pain relief skin patch, the U.S. Food and Drug Administration said on Friday.
Mylan Laboratories Inc. said it will produce several different strengths of the patch, known generically as the fentanyl transdermal system, and launch the product immediately.
Johnson & Johnson's annual sales of the patch total about $1.63 billion. Mylan, the biggest U.S. maker of generic drugs, had hoped to launch its copycat version last year, but the FDA (news - web sites) granted J&J an additional six months of market exclusivity in return for testing the drug's safety and effectiveness in children. Shares of Mylan, which fell 4 cents to close at $16.60 on the New York Stock Exchange (news - web sites), were higher at $17 after hours. Shares of J&J, which rose 40 cents to close at $64.62, were little changed after hours. (Additional reporting by Deena Beasley in Los Angeles)

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Oxygenol on Chronic Fatigue and Fibromyalgia

RENO, Nev., May 12, 2005 (PRIMEZONE) -- Martin Nutraceuticals Inc.'s (Pink Sheets:MTNU) Director of Research and Development, Dr. A. W. Martin, is pleased to announce results of recent clinical trials of Oxygenol(tm) in the aid of Chronic Fatigue Syndrome and Fibromyalgia.

Oxygenol(tm) is a proprietary blend of antioxidants with many health benefits. In the study, Oxygenol(tm) was given to patients suffering from Chronic Fatigue Syndrome and Fibromyalgia. These two conditions are characterized by extreme fatigue and cognitive symptoms which include sleep disorder, short term memory loss, concentration difficulties, widespread musculoskeletal aches, pain and stiffness and soft tissue tenderness.

Dr. Martin states, "Fibromyalgia is a symptom of the greater complex of Chronic Fatigue Syndrome -- one that perhaps should be considered a sister ailment."

The test patients were given 200 mg daily of Oxygenol(tm) in a 6-week period. In this amount of time, over 3/4 of the patients showed that 85% of all cognitive symptoms were decreased and remarkably 1/4 of these cases showed over 95% improvement of all cognitive symptoms with the use of Martin Nutraceuticals Oxygenol(tm). The tests that were used included Short Term Memory Testing using recall and concentration, as well as Cognitive Testing.

Dr. Martin attributes these findings to Oxygenol's ability to cross the blood brain barrier and increase micro circulation to the brain. "Oxygenol's efficacy is what makes it a fantastic product, one that we anticipate will prosper in a market that does more than $1 billion in annual sales," concurs Dr. Martin.

Dr. Martin is a Canadian nutritional researcher and author of several books including "Chronic Fatigue Syndrome: the Modern Women's Curse."

Martin Nutraceuticals' Oxygenol(tm) will be available in exclusive retail outlets by the third quarter of this year.

Forward-Looking Statements

The management of the company, who take full responsibility for its content, prepared this press release. Statements in this news release concerning the company's business outlook or future economic performance, anticipated profitability, revenues, expenses, or other financial items, and statements concerning assumptions made or expectations as to any future events, conditions, performance or other matters, are "forward-looking statements" as that term is defined under the Federal Securities Laws. Forward-looking statements are subject to risks, uncertainties and other factors which could cause actual results to differ materially from those contained in such statements. Such risks, uncertainties and factors include, but are not limited to, future capital needs, changes and delays in product development plans and schedules, customer acceptance of new products, changes in pricing or other actions by competitors, and general economic conditions.

CONTACT:  Martin Nutraceuticals Inc.
          Harvey Panesar, President
          (780) 707-0587
          www.martinnutra.com

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Atypical antipsychotics in the treatment of fibromyalgia: a case series with olanzapine

Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jan;29(1):161-4.Rico-Villademoros F, Hidalgo J, Dominguez I, Garcia-Leiva JM, Calandre EP.
Biometrica, Departamento Medico, Eloy Gonzalo 27, 28010 Madrid, Spain.

Fibromyalgia is a common and disabling chronic pain syndrome. Although a wide array of symptomatic pharmacological treatments has been used to treat this condition, only modest results have been obtained. Olanzapine has been proven effective in some chronic pain conditions. The authors present a case series of patients suffering from fibromyalgia who received olanzapine as add-on therapy during a 3-month period. Olanzapine (2.5-20.0 mg/day) was administered to 25 consecutive patients (24 females, 1 male) meeting the American College of Rheumatology diagnostic criteria for fibromyalgia, and who were receiving nonsteroidal anti-inflammatory drugs (NSAIDs; 68%), benzodiazepines/zolpidem
(48%), antidepressants (32%), and cyclobenzaprine (4%), either alone or in combination. Overall, 6 of the 14 patients (43%) who completed the 12-week trial reported to be much or very much improved ('responders'), according to the Clinical Global Impression (CGI) scale and 7 of them (50%) reported a good or very good sense of well-being. Olanzapine's modal dose among responders was
10.0 mg/day. It was discontinued in 11 patients (44%) due to adverse reactions, most commonly weight gain (n=5, 20%). Our preliminary findings suggest a possible role for olanzapine in treating fibromyalgia. Unfortunately, the beneficial
outcome of olanzapine was largely obscured by its poor tolerability, which could be explained by the greater propensity of patients with fibromyalgia toadverse drug reactions, and the greater risk of antipsychotic-induced weight gain among women. Whether other atypical antipsychotics will provide similar symptomatic relief, while showing a better tolerability profile than olanzapine in patients with fibromyalgia, should be further investigated.

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A fatal drug interaction between oxycodone and clonazepam.

Burrows DL, Hagardorn AN, Harlan GC, Wallen ED, Ferslew KE.

Section of Toxicology, Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City,TN 37614, USA. toxdoc2b@yahoo.com

A case is presented of a fatal drug interaction caused by ingestion of oxycodone (Oxycontin) and clonazepam (Klonapin). Oxycodone is an
opium alkaloid used in long-term pain management therapy. Clonazepam is a benzodiazepine used for the treatment of seizures and panic
disorders. The Drug Abuse Warning Network (DAWN) has reported an increase of 108% in the last two years of emergency department
episodes related to Oxycontin. Six billion prescriptions were written for Oxycontin in the year 2000, an 18-fold increase from
four years previous (1). Oxycontin has recently gained enormous notoriety at the local and national levels; however, there are very
few previously documented cases of lethal drug interactions between oxycodone and clonazepam. Synergistic effects between these two
drugs are postulated to arise from different agonistic mechanisms producing similar physiological changes. It is also theorized that
clonazepam may inhibit the metabolism of oxycodone. A 38-year-old white female was found dead in Jefferson County, Tennessee in March
of 2001. The deceased had physical evidence of previous drug abuse and positive serological findings of hepatitis B and C. Prescription
pill bottles filled under the name of the deceased, as well as another name, were found with the body. Serum, urine and gastric
contents from the deceased were screened for numerous drugs and metabolites using a combination of thin layer chromatography and
immunoassay techniques (EMIT and FPIA).

Analysis of biological specimens from the deceased revealed the presence of: benzodiazepines, opiates (oxycodone), and trazodone metabolites in
the serum; cannabinoids, benzodiazepines, opiates (oxycodone), trazodone, trazodone metabolites, nicotine, and nicotine metabolite
in the urine; and benzodiazepines, opiates (oxycodone), nicotine, and nicotine metabolite in the gastric contents. Quantitative
analyses for clonazepam was performed by high performance liquid chromatography (HPLC) and revealed a plasma concentration of 1.41
microg/mL. Plasma oxycodone and urine 11-nor-carboxy-delta-9-tetrahydrocannabinol concentrations were
determined by gas chromatography/mass spectrometry and revealed concentrations of 0.60 microg/mL and 27.9 ng/mL, respectively. The
deceased had pathologies consistent with severe central nervous system (CNS) and respiratory depression produced by high
concentrations of clonazepam and oxycodone including collapsed lungs, aspirated mucus, and heart failure. The pathologies were
sufficient to cause death, which was officially attributed to a drug overdose; however, the manner of death was unknown.

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Painkiller Users: Heartburn Pill a Day Keeps Ulcers Away

ANN ARBOR, MI - For those who take certain painkiller drugs regularly to help ease arthritis pain or other chronic aches, the relief comes with a tradeoff: a quadrupled chance of developing painful ulcers over the long term, as their digestive systems brim with acid that erodes the lining of their stomachs and upper intestinal tract.

But a new study may offer a promising way to prevent this unwelcome effect.

In an international, multicenter, randomized, placebo-controlled study, a prescription heartburn drug called esomeprazole effectively prevented ulcers among 573 long-term painkiller users. And, it produced few side effects.

“This is a very encouraging result, especially since the participants represented the ‘real world’ population that faces this ulcer risk,” says James Scheiman, M.D., a University of Michigan Health System gastroenterologist who will present the results Tuesday in Baltimore at the 68th Annual Scientific Meeting of the American College of Gastroenterology. “The effect was strong in participants taking over-the-counter painkillers, as well as in those taking prescription Cox-II inhibitor drugs.”

Esomeprazole, which is marketed as Nexium® (esomeprazole magnesium) by Astra Zeneca Pharmaceuticals LP, is a member of the class of acid-reducing drugs known as proton pump inhibitors. It blocks the production and secretion of gastric acid.

Astra Zeneca funded the study, and Scheiman is a paid member of the panel that advised the company on the study, as well as presenter of the ACG presentation. Scheiman is also a paid consultant to Astra Zeneca on other research, on which he serves as principal investigator.

The study results show that ulcers and other effects can be prevented by countering the acid that increases the injury to the gastrointestinal tract that can be caused by use of non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs include ibuprofen, naproxen, and Cox II inhibitors, all commonly used to treat chronic pain.

The study participants were three-quarters women, and more than 80 percent were taking NSAIDs for some form of arthritis. Although all had screened negative at the study’s outset for the bacteria Helicobacter pylori that causes ulcers, they were all at an increased risk of developing ulcers because of their regular painkiller use combined with a history of previous ulcers (about 26 percent), an age over 60 years (about 64 percent), or both (about 10 percent).

The study was done in this group of patients to represent more accurately the “real world” mix of drugs, medical histories and risk factors seen in millions of patients worldwide, says Scheiman, a professor of internal medicine in the U-M Medical School.

All of the participants were taking NSAIDs at least five days a week, either one drug alone or in combination. Around 15 percent were taking Cox II inhibitors (such as celecoxib, marketed as Celebrex, or rofecoxib, marketed as Vioxx). Some were also taking aspirin at doses designed to protect their cardiovascular systems.

Previous studies have shown that about 10 percent to 30 percent of such patients might develop ulcers in a given year. And in fact, among those in the study who received a placebo instead of esomeprazole, 12.3 percent developed either a gastric ulcer or duodenal ulcer in the six months of the study.

But the ulcer rate was 5.2 and 4.4 percent, respectively, for non-Cox II inhibitor NSAID users who received either 20 milligrams or 40 milligrams of esomeprazole daily.

In the small subgroup of patients who were using Cox II inhibitors, 17 percent taking placebo pills developed ulcers. And although the group was not large enough to achieve statistical significance, none of those patients on either dose of esomeprazole developed ulcers during the study.

This last result intrigues Scheiman, who notes that clinicians may want to take note even before further studies are conducted to evaluate whether a Cox II inhibitor-proton pump inhibitor combination might be the best option for such patients.

In addition to being effective at preventing ulcers and other effects, esomeprazole was safe and well-tolerated. Only 6 percent of patients receiving it stopped taking the drug during the study because of any adverse event, compared with 13 percent of placebo patients.

In all, Scheiman notes, the results should give hope to any patient who needs to take painkillers regularly. “With these data, and results from other studies, we can say that we have a way to prevent ulcers and other gastrointestinal effects, in long-term NSAID users,” he says. “There doesn’t have to be a tradeoff between one kind of pain and another.”

The study’s main authors include Neville Yeomans of the University of Melbourne, Australia; Christopher J. Hawkey of the University of Nottingham, United Kingdom; Nicholas Talley of the Mayo Clinic, Rochester, Minnesota; Joseph Sung of the Chinese University of Hong Kong; Roger Jones, London, and Lena Gothe and Jorgen Naesdal, Astra Zeneca, Molndal, Sweden. Written by: Kara Gavin

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The trilateral opioid contract. Bridging the pain clinic and the primary care physician through the opioid contract.

Fishman SM, Mahajan G, Jung SW, Wilsey BL. Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, USA

We have extended the traditional use of opioid contracts to involve the primary care physician (PCP). The PCP was asked to collaborate with the
pain specialist's decision to use opioids by cosigning an opioid contract. Explicit in the agreement was the understanding that the
primary care physician would assume prescribing the refills for these medications once the opioid regimen had become stabilized. The present
study was a retrospective chart review of the first 81 patients with non-malignant chronic pain who received an opioid agreement requiring
the participation of the primary care physician. Sixty-nine of the 81 patients (85%) agreed to the terms of the contract
initially, but only 50 of these 69 individuals (72%) successfully obtained their PCP's written agreement for the prescribing of opioids
for chronic pain management.

Despite expecting reluctance on the part of the PCP to enter into this agreement, the low compliance rate was due to
lack of commitment on the part of the patient, who either refused to sign the contract outright or, after initially agreeing to sign the
contract, did not have it signed by the PCP. If the PCP did not agree to sign the opioid contract, the patient was tapered off the medication. If
the contract was approved and signed by the PCP, there were no subsequent reversals by this physician in terms of agreeing to continue
to prescribe opioids. In all cases in which a contract was completed, the patient was successfully stabilized on an appropriate opioid regimen
and then discharged back to the care of the PCP for long-term opioid treatment. The opioid contract may be an effective tool for networking
specialty and primary care services in the delivery of chronic opioid therapy.

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Off-label applications for SSRIs.

Am Fam Physician. 2003 Aug 1;68(3):498-504. Stone KJ, Viera AJ, Parman CL. Naval Hospital Jacksonville, Florida 32214, USA. PMID: 12924832

Selective serotonin reuptake inhibitors (SSRIs) are widely used because of their safety, tolerability, and demonstrated efficacy across a broad range of clinical conditions. Medical literature supports the use of SSRIs for the treatment of many conditions outside of the indications approved by theU.S. Food and Drug Administration.

SSRIs offer a reasonable alternative to traditional therapy for generalized anxiety disorder. A side effect of SSRIs coincidentally provides therapy
for premature ejaculation. SSRIs may reduce the frequency and severity of migraine headaches and are possibly effective in reducing the pain of
diabetic neuropathy.

When taken in combination with tricyclic antidepressants, SSRis offer more potent therapy for fibromyalgia than either agent alone. SSRIs appear to be effective in some patients with neurocardiogenic syncope that is refractory to standard therapies.

Clinical experience supported by ongoing research continues to expand on the broad array of therapeutic applications for this class of medication.

[The full text of this article can be found at
http://www.aafp.org/afp/20030801/498.html

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United Kingdom Expands Approval For Provigil (Modafinil) To Include Sleep Apnea/ Hypopnea Syndrome, Narcolepsy

WEST CHESTER, Pa., Dec. 3 /PRNewswire-FirstCall/ -- Cephalon, Inc. (Nasdaq: CEPH) today announced that it has received marketing approval from the Medicines Control Agency (MCA) in the United Kingdom to expand the label of Provigil® (modafinil) to treat excessive daytime sleepiness in patients with obstructive sleep apnea/hypopnea syndrome. The 200 mg tablet of Provigil was also approved, in addition to the 100 mg dosage currently available in this territory. Cephalon UK Limited will officially launch the new indication at a symposium during the British Thoracic Society meeting being held December 4-6 in London.

"We are pleased that the data used to support this label expansion was accepted by the UK regulatory authority," said Paul Blake, MB, FRCP, Senior Vice President of Clinical Research and Regulatory Affairs at Cephalon. "Achievement of this milestone will enable us to grow the market for modafinil in the United Kingdom and sets the stage for regulatory submissions in other European countries over the next year."

The UK approval is the first of two regulatory milestones that Cephalon expects to achieve this year for Provigil. Cephalon intends to file an application with the U.S. Food and Drug Administration at year-end seeking to expand the label of Provigil to include treatment of excessive sleepiness associated with sleep disorders beyond narcolepsy.

Provigil
Modafinil is the first in a new class of wake-promoting agents and is currently approved in more than 20 countries for the treatment of excessive daytime sleepiness associated with narcolepsy. Provigil was initially launched in the UK in 1998 for the treatment of narcolepsy.

In controlled clinical trials, Provigil has been found to be generally well tolerated with a low incidence of adverse events relative to placebo. The most commonly observed adverse events associated with the use of Provigil were headache, infection, nausea, nervousness, anxiety and insomnia.

Obstructive Sleep Apnea Hypopnea Syndrome
Obstructive sleep apnea/hypopnea syndrome is a serious and potentially life-threatening sleep disorder affecting four percent of middle-aged men and two percent of middle-aged women. Individuals with obstructive sleep apnea hypopnea syndrome experience frequent awakenings throughout the night as a result of blockage of the airway during sleep. This disruption of sleep leads to excessive daytime sleepiness causing many people to doze off repeatedly throughout the day -- at their jobs and at home.

The most commonly used standard treatment is continuous positive airway pressure (CPAP). A nasal CPAP device can prevent airway closure while in use, but despite this treatment many patients continue to experience residual excessive sleepiness.

Cephalon, Inc.
Founded in 1987, Cephalon, Inc., is an international biopharmaceutical company dedicated to the discovery, development and marketing of innovative products to treat sleep and neurological disorders, cancer and pain. Cephalon employs 1,200 people in the United States and Europe. The company markets three proprietary products in the United States and 22 products internationally. Full prescribing information on Cephalon's US products is available by calling 1-800-896-5855.

Cephalon's biotechnology pipeline is focused on the identification of novel molecules that affect cell survival and death. Additional information about Cephalon and its subsidiaries can be obtained by visiting the company's Website at http://www.cephalon.com .

Cephalon UK Limited has headquarters in Guildford and markets drugs to treat a number of central nervous system disorders. In collaboration with Novartis, Cephalon UK markets Tegretol® (carbamazepine), Ritalin® (methylphenidate), Anafranil® (clomipramine) and Lioresal® (baclofen). Also included in this collaboration is Provigil (modafinil) for the UK. In addition, Cephalon UK also markets Gabitril® (tiagabine monohydrate) and Actiq ® (fentanyl -- as citrate) in the UK and Ireland.

In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Cephalon's current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs, development of potential pharmaceutical products, interpretation of clinical results, prospects for regulatory approval, manufacturing development and capabilities, market prospects for its products, sales and earnings projections, and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as "anticipate," "estimate," "expect," "project," "intend," "plan," "believe" or other words and terms of similar meaning. Cephalon's performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, regulatory and political conditions affecting the biotechnology and pharmaceutical industries as well as more specific risks and uncertainties such as those set forth below and in its reports on Form 8-K, 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Cephalon does not intend to update publicly any forward-looking statement, except as required by law. The Private Securities Litigation Reform Act of 1995 permits this discussion.
SOURCE: Cephalon, Inc.

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Gabapentin for the treatment of pain in guillain-barre syndrome: a double-blinded, placebo-controlled, crossover study.  


Pandey CK, Bose N, Garg G, Singh N, Baronia A, Agarwal A, Singh PK, Singh U.
Departments of Anaesthesiology and Critical Care Medicine and Bio-statistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Pain syndromes of Guillain-Barre are neuropathic as well as nociceptive in origin. We aimed to evaluate the therapeutic efficacy of gabapentin in relieving the bimodal nature of pain in Guillain-Barre syndrome in a randomized, double-blinded, placebo-controlled, crossover study in 18 patients admitted to the intensive care unit for ventilatory support. Patients were assigned to receive either gabapentin (15 mg. kg(-1). d(-1) in 3 divided doses) or matching placebo as initial medication for 7 days. After a 2-day washout period, those who previously received gabapentin received placebo, and those previously receiving placebo received gabapentin as in the initial phase. Fentanyl 2 micro g/kg was used as a rescue analgesic on patient demand or when the pain score was >5 on a numeric rating scale of 0-10. The numeric rating score, sedation score, consumption of fentanyl, and adverse effects were noted, and these observed variables were compared. The numeric pain score decreased from 7.22 +/- 0.83 to 2.33 +/- 1.67 on the second day after initiation of gabapentin therapy and remained low during the period of gabapentin therapy (2.06 +/- 0.63) (P < 0.001). There was a significant decrease in the need for fentanyl from Day 1 to Day 7 during the gabapentin therapy period (211.11 +/- 21.39 to 65.53 +/- 16.17 [ micro g]) in comparison to the placebo therapy period (319.44 +/- 25.08 to 316.67 +/- 24.25 [ micro g]) (P < 0.001). IMPLICATIONS: Gabapentin, an antiepileptic drug, has been used effectively for different types of pain management. This study demonstrates that gabapentin has minimal side effects and is an alternative to opioids and nonsteroidal antiinflammatory drugs for management of the bimodal nature of pain of Guillain-Barre Syndrome patients.

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EFFICACY OF TRAMADOL IN TREATMENT OF PAIN IN FIBROMYALGIA.
I. Jon Russell, Marc Kamin, Robert Bennett, Thomas Schnitzer, Jerry Green, Warren Katz.

An outpatient, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the efficacy and safety of tramadol in the treatment of the pain of fibromyalgia syndrome.
    One hundred patients with fibromyalgia syndrome, (1990 American College of Rheumatology criteria) were enrolled into an open-label phase and treated with tramadol 50-400 mg/day.
   Patients who tolerated tramadol and perceived benefit were randomized to treatment with tramadol or placebo in the double-blind phase. The primary efficacy outcome measurement was the time (days) to exit from the double-blind phase because of inadequate pain relief, which was reported as the cumulative probability of discontinuing treatment because of inadequate pain relief. 
   One hundred patients entered the open-label phase; 69% tolerated and achieved benefit with tramadol. These patients were then randomized to continue tramadol (n=35) or convert to a placebo (n=34) during a 6-week, double-blind treatment period.
    The Kaplan-Meier estimate of cumulative probability of discontinuing the double blind period because of inadequate pain relief was significantly lower in the tramadol group compared with the placebo (p=0.0001). Twenty (57.1%) patients in the tramadol group successfully completed the entire double-blind phase compared with nine (27%) in the placebo group (p=0.15).
   These results support the efficacy of tramadol over a period of 6-weeks in a double blind study for
the treatment of pain of fibromyalgia in a group of patients who had been determined to tolerate it and perceive benefit. Reference: Journal of Clinical Rheumatology 2000;6:250-257

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OPIOID ANALGESICS IN FIBROMYALGIA-FOLLOW-UP STUDY OF THERAPY SELECTION,
EFFICACY AND PREDICTORS OF OUTCOMES.


Kip L. Kemple, Northwest Rehabilitation Network; Gregory T. Smith, Progressive Rehabilitation Association; Julia Wong-Ngan, Oregon Health Sciences University.

Theme: Arthritis and Rheumatic Pain While opioid analgesics have gained acceptance in the management of non-cancer pain, indications for their use in Fibromyalgia (FM) have not been defined.     We have completed baseline and 12-24 month follow-up evaluations of 43 patients with FM enrolled in an opioid treatment protocol. Our goal was to study therapy selection patterns, efficacy and to evaluate whether specific pain or psychological profiles predict outcome.

Methods: All patients met ACR criteria for FM. Most patients were on low (#22) or moderate (#13) dose opioids at enrollment. They were allowed to adjust Rx according to pain severity, balanced with review of risks.

Evaluations included: pain scores (VAS), FIQ, MMPI, Beck or Zung Depression Index, McGill Pain Questionnaire, SF-36 and diagnostic interview including review of abuse history.

Results: Initial FM morbidity levels were high (SF-36 scores low and FIQs high). Opioid doses increased in 31 patients, decreased in 3 and were unchanged in 9. Mean dose at FU was 52 mg Morphine equiv/24 hr with mean increase of 26 mg Meq/24. Benefit was rated as "good" by 26 patients; "fair" by 16; and "poor" by 1. Measures of pain, fatigue, function and depression all improved modestly but changes were not significant. Since outcome changes were small, correlations with other predictive measures were difficult to assess. MMPI profiles did not correlate with pain or function, but improvement in function (FIQ) was significant (p<.05) in patients with abuse history. Affective and sensory pain descriptors (McGill) correlated with greater pain severity, higher FIQs, higher opioid doses and with less benefit (p<.05).

Conclusion: Pain in FM is complex. Response to opioids is variable. Evaluation of affective and sensory pain domains may help predict outcome. Disclosure: This project was supported in part by Purdue Pharma.

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Addiction? Tolerance? Dependency? New stance on using pain drugs.

Three major medical societies, The American Academy of Pain Medicine (AAPM), the American Pain Society (APS), and the American Society of
Addiction Medicine (ASAM) have issued a joint consensus paper which clearly defines the frequently misunderstood terms addiction, tolerance,and physical dependence, and discusses their definitions in the context of opioid use in the treatment of pain.

"The addiction community was concerned because of inaccurate diagnosis. The pain community was concerned about over-diagnosis of addiction when it didn't exist, and how this misdiagnosis interfered with treatment with opioids," said Edward Covington, MD, Director of the Chronic Pain
Rehabilitation Program at the Cleveland Clinic and past president of AAPM, who was one of the paper's authors. "Also we needed agreement about what is and what is not an addictive disorder."

Dr. Covington noted that addiction a primary, chronic, neurobiologicdisease can be identified by the three "Cs" Craving or Compulsive use,loss of Control, and use despite adverse Consequences.

Other behaviors that signal addiction include "drug seeking" behavior, taking multiple doses of medications, and an inability to take them on
schedule, "doctor shopping," frequent reports of lost or stolen prescriptions, isolation from friends and family members, and taking pain
medications for sedation, increased energy, or to get "high."

Physical dependence and tolerance are often confused with addiction.

According to the consensus paper definitions, both of these are normalresponses to regular use of some prescribed medications, including opioids,and are not in themselves evidence of an addictive disorder.

"Unlike tolerance and physical dependence, addiction is not a predictable effect of [taking] a drug but an adverse reaction in biologically and psychosocially vulnerable individuals."

It is also important for healthcare professionals to recognize the difference between true addiction and "pseudoaddiction," notes Albert Ray, MD, President of AAPM.

With pseudoaddiction, patients whose pain is undertreated appear to behave "like addicts" to get the pain relief they need. They may focus on getting more medication, for example, and appear to be engaging in drug-seeking behavior. But unlike a person with a true addictive disorder, however, once their pain is properly managed, these behaviors stop immediately." (The Pain Connection. Spring 2001; 1-4.)

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New Data Suggest Cymbalta® Reduced Pain In Fibromyalgia Patients With And Without Depression

New data suggest that patients with fibromyalgia treated with 60mg or 120mg of Cymbalta® (duloxetine HCl) experienced greater reduction in pain severity beginning one week after starting duloxetine than those taking placebo (sugar pill), as measured by the Brief Pain Inventory Average Pain Score (BPI). The study, which included patients with and without depression, also showed greater improvements in patients taking duloxetine than in those taking placebo in scores on the Patient's Global Impression of Improvement questionnaire (PGI I), which measures how the patient has felt overall since beginning to take the medication. The data were presented today at the 2007 Congress of the International MYOPAIN Society in Washington, D.C.

At three months, patients treated with 60mg per day or 120mg per day of duloxetine showed significantly greater reduction in pain and improvement in PGI-I scores compared with patients taking placebo. At three months, more patients treated with either 60mg or 120mg of duloxetine showed significantly greater reduction in pain as measured by a 30 percent improvement in baseline BPI scores (50.7 percent and 52.1 percent, respectively) compared with patients taking placebo (36 percent).

"Fibromyalgia is a chronic illness, characterized by widespread pain, tenderness and fatigue. It can also affect the patient's overall emotional health and well-being," said I. Jon Russell, M.D., Ph.D., associate professor of medicine at the University of Texas Health Science Center in San Antonio. "Between 34 percent(1) and 62 percent(2) of those living with fibromyalgia will experience depression at some point in their lives. In this study, which included patients with and without depression, duloxetine reduced the pain associated with fibromyalgia."

Fibromyalgia is estimated to affect 2 percent to 4 percent of the U.S. population(3), the majority being women. In addition to chronic pain, fibromyalgia patients often have complaints about cloudy thinking, morning stiffness and overall inability to function in their everyday lives.

Additional Study Highlights

-- At six months, patients taking duloxetine 60mg or 120mg maintained reduced BPI scores and patients taking 120mg had improved PGI-I scores compared with those taking placebo.

-- At the end of the six-month trial, more patients treated with both 60mg or 120mg of duloxetine showed a response to treatment, defined as a 50 percent reduction of baseline BPI scores (32.6 percent and 35.9 percent of patients, respectively), compared with patients taking placebo (21.6 percent).

-- Discontinuation rates over six months were similar among the groups (45.3 percent and 46.3 percent for duloxetine 60mg and 120mg patients, compared with 50 percent for placebo).

Adverse event-related discontinuation was significantly higher in patients taking 120mg (26.5 percent) but not in the 60mg (15.3 percent) group as compared with placebo (13.2 percent). Discontinuations due to lack of efficacy were not statistically different among treatment groups.

Adverse events were similar to those seen in prior duloxetine studies. In this study, the most common adverse events (occurred at a rate of greater than or equal to 5 percent and at least twice the rate of placebo) included nausea, dry mouth, constipation, somnolence (sleepiness), fatigue, insomnia, decreased appetite, hyperhydrosis, cough, tremor, rash and weight increase.

Fibromyalgia sNDA Submitted to FDA

Eli Lilly and Company (NYSE: LLY) also announced today that it recently submitted a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration (FDA) for Cymbalta for the management of fibromyalgia. The sNDA submission is based on data from approximately 1,400 patients in five clinical trials.

"Lack of awareness of fibromyalgia can lead to frustration as patients often see multiple physicians over a number of years before receiving a formal diagnosis," said Alan Breier, M.D., vice president for medical and chief medical officer, Eli Lilly and Company. "This research may help increase recognition of fibromyalgia and offer hope to those living with this debilitating condition."

About Cymbalta

Serotonin and norepinephrine in the brain and spinal cord are believed to both mediate core mood symptoms and help regulate the perception of pain. Based on pre-clinical studies, duloxetine is a balanced and potent reuptake inhibitor of serotonin and norepinephrine that is believed to potentiate the activity of these chemicals in the central nervous system (brain and spinal cord). While the mechanism of action of duloxetine is not fully known, scientists believe its effects on depression and anxiety symptoms, as well as its effect on pain perception, may be due to increasing the activity of serotonin and norepinephrine in the central nervous system.

Cymbalta is approved in the United States for the treatment of major depressive disorder (MDD), the management of diabetic peripheral neuropathic pain (DPNP) and the treatment of generalized anxiety disorder (GAD), all in adults (age 18+). Cymbalta is not approved for use in pediatric patients.

Important Safety Information

Cymbalta is approved to treat major depressive disorder and generalized anxiety disorder and manage diabetic peripheral neuropathic pain. Antidepressants can increase suicidal thoughts and behaviors in children, adolescents and young adults. Patients should call their doctor right away if they experience worsening depression symptoms, unusual changes in behavior or thoughts of suicide. Be especially observant within the first few months of treatment or after a change in dose. Cymbalta is approved only for adults 18 and over.

Cymbalta is not for everyone. Patients should not take Cymbalta if they have recently taken a type of antidepressant called a monoamine oxidase inhibitor (MAOI), are taking Mellaril® (thioridazine) or have uncontrolled glaucoma. Patients should speak with their doctor about all medicines they are taking, including those for migraine, to avoid a potentially life threatening condition. Patients should tell their doctor about their alcohol consumption, if they have liver disease, and about all of their medical conditions.

Patients taking Cymbalta may experience dizziness or fainting upon standing. The most common side effects of Cymbalta include:

-- For MDD: Nausea, dry mouth and constipation

-- For DPNP: Nausea, somnolence (sleepiness), dizziness and constipation

-- For GAD: Nausea, fatigue, dry mouth, somnolence (sleepiness) and constipation

This is not a complete list of side effects. For full Patient Information, visit http://www.cymbalta.com. For full Prescribing Information, including Boxed Warning, visit http://www.cymbalta.com. About Eli Lilly and Company  Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first in class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers - through medicines and information - for some of the world's most urgent medical needs. Additional information about Lilly is available at http://www.lilly.com.

P-LLY

This press release contains forward-looking statements about the potential of Cymbalta for the treatment of fibromyalgia, and reflects Lilly's current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. There is no guarantee that the product will continue to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

References

(1) Ahles TA, et al. "Psychiatric status of patients with primary fibromyalgia, patients with rheumatoid arthritis, and subjects without pain: a blind comparison of DSM-III diagnoses." American Journal of Psychiatry 1991; 148:1721-1726.

(2) Arnold LM, et al. "Comorbidity of fibromyalgia and psychiatric disorders." Journal of Clinical Psychiatry 2006; 67:1219-1225.

(3) American College of Rheumatology Web site - http://www.rheumatology.org/public/factsheets/fibromya_new.asp; visited Aug. 3, 2007.

Article URL: http://www.medicalnewstoday.com/articles/80629.php

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Just give me something for the pain

While physicians with experience in prescribing opioids for chronic pain are sometimes outspoken about their efficacy, many physicians continue to
approach this class of analgesics with trepidation due to concerns that opioids "inevitably cause addiction or intolerable side effects."  Still
others, who do see the benefits of opioids, avoid prescribing them based on fears of regulatory scrutiny.  Within the swirl of this controversy, remains the question of how effective opioids may be in treating some types of chronic pain.  The one certainty among the questions and opinions is that 40 million Americans each year visit a doctor for chronic pain due to nonmalignant conditions ranging from back trouble and arthritis to headaches and fibromyalgia.  Moreover, a recent survey revealed that more than 40% of people with chronic pain are not receiving adequate pain relief.

As a result, specialists in pain medicine and their professional associations are working to clarify misconceptions and to educate both
colleagues and patients on the benefits of opioid therapy for treating chronic, noncancer pain.

Russell Portenoy, M.D., Chairman of Pain Medicine and Palliative Care at Beth Israel Medical Center in New York and James Campell, M.D., Director of the Johns Hopkins Blaustein Pain Treatment Center, are among the leading pain specialists working to promote the use of opioids for chronic,
noncancer pain.  They are working against a significant history of negative attitudes and long-held beliefs regarding both the therapeutic and side
effects of opioids.  Twenty years ago, recalls Campbell, many physicians opposed using opioids even in patients with terminal illness.  In general,
concerns focused on opioids causing depression, social withdrawal, and impaired thinking as well as tolerance and unmanageable side effects.

In the 1970s, when oncologists found morphine offered effective pain relief for their cancer patients and experienced little or no apparent evidence of addiction, sentiments about opioids for treating pain began to shift. Pharmaceutical companies soon began marketing timed-release morphine
preparations that delivered the drug slowly rather than in the short bursts of relief provided by short-acting drugs.  The effects of the latter would
wear off in three to four hours and leave patients "counting minutes until the next dose."

Campbell and Portenoy focus significant attention on educating referring physicians, particularly primary care physicians.  An important topic is the
difference between addiction and physical dependence.  Addiction is a psychological phenomenon manifested as a compulsion to use a drug, despite
adverse and even dangerous consequences.  Studies show that, in the absence of a history of substance abuse, very few pain patients become addicted to their opioid pain relievers.  Physical dependence is the physiological response of the body to long-term use of a drug.  People treated with opioids do become dependent and will experience withdrawal symptoms if they stop taking the drug abruptly.  While uncomfortable, the symptoms are not life-threatening.

Tolerance - the need for increasingly larger doses of medication to achieve the same level of pain relief - is a physiological phenomenon that is well
understood.  A joint consensus statement  issued by the American Pain Society and the American Academy of Pain Medicine states that "Tolerance .
has not proven to be a prevalent limitation to long-term opioid use."  In cancer patients, it is often found that what appears at first to be
tolerance is actually progression of the underlying disease.  Tolerance to some opioid side effects can be expected.  Side effects can largely be
minimized by titrating opioids carefully, starting with a low dose and increasing the amount gradually until pain relief is achieved and side
effects are tolerable.

The thought leaders in pain medicine are careful to point out that opioids may not be perfect for every patient with chronic pain.  Nathan Rudin,
another Hopkins specialist, from the Division of Physical Medicine and Rehabilitation, believes that opioids "can be useful tools if you carefully
pick your patients."  He adds that criteria for that selection process is still a matter for discussion.  It is also the opinion of pain specialists
that the most effective pain management is a multidisciplinary effort and does not rely on a single modality or form of treatment.  Often pain
medication is combined with physical therapy, psychological counseling, perhaps even nerve blocks or surgery.  The net effect of an
interdisciplinary approach should be to "steer patients back into the normal flow of life, in addition to reducing their pain."

But despite professional reticence, there are signs of change.  Growing numbers of state medical boards and professional organizations are issuing
guidelines and policies that clarify the use of opioids and reassure physicians that they can prescribe opioids for pain relief without fearing
sanctions.  (Hendricks M. Johns Hopkins Magazine.  June, 1999.  Available at Johns Hopkins Magazine website, http://www.jhu.edu/%7Ejhumag/
0699web/pain.html.  Accessed on May 19, 2000.)

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Pharmacologic Management of Acute and Chronic Pain: Focus on Drug
Interactions and Patient-Specific Pharmacotherapeutic Selection


[South Med J 94(8):756-812, 2001. © 2001 Southern Medical Association]

Robert L. Barkin, MBA, PharmD, Diana Barkin, Departments of Anesthesiology, Family Medicine, Pharmacology, and Psychiatry, Rush Medical College and The Rush Pain Center at Rush Presbyterian St. Luke's Medical Center, Chicago, Ill; and The Pain Center of Rush North Shore, Skokie, Ill

Introduction
Pain is among the most common reasons patients seek medical care. Acute and chronic pain is debilitating. Recovery is slow, interference with daily
activities occurs, and pain manifests as a decremental change in the patient's quality of life. This is compounded by societal costs.[1-5]
Acute pain is often associated with an identifiable injury or trauma as a known antecedent, responds to therapeutic options, and resolves in less than 1 to 3 months. Chronic pain is more of a treatment challenge because the pathogenesis may be unclear, with less opportunity to predict the course of recovery. For patients already under great psychologic and financial stress, such an ambiguous prognosis is devastating. The goal of the clinician is to provide an opportunity for patients to regain some sense of control over their lives by providing the most effective pain treatment regimen possible.[1-5]

Pain usually defined as chronic lasts longer than 1 to 3 months or exceeds the typical recovery time for an initial injury. Chronic pain may be
continuous or episodic or a combination of both. Overall, chronic pain is commonly accompanied by emotional stress, increased irritability,
depression, social withdrawal, financial distress, loss of libido, disturbed sleep patterns, diminished appetite, and/or weight loss. Chronic pain can
have a wide-ranging impact; its management must therefore focus on multiple aspects of a patient's life. A multidisciplinary, comprehensive treatment plan is optimal, including (1) individual psychosocial counseling in conjunction with patient/family education; (2) noninvasive or minimally
invasive procedures, such as massage therapy, physical therapy, transdermal or transcutaneous electrical nerve stimulation (TENS), or acupuncture; (3) up-to-date pharmacologic and/or anesthetic therapies; and (4) if necessary, surgical intervention and physical medicine with rehabilitation focused to enhance the patient's functional status. Health care practitioners must consider uniting these various options in tailoring a patient-specific treatment plan, addressing both physiologic and psychologic symptoms.[1-8]

A pharmacotherapeutic plan begins with a thorough pain and pain medication history to identify the nature of the patient's pain (eg, acute versus
chronic, acute and chronic, nociceptive versus neuropathic). The patient interview should focus on patient-reported pain descriptors (eg,
exacerbation/modulation of pain; pain quality and intensity; pain sites as local, disseminated, or regional; characteristics and temporal relationships
of pain), current pharmacotherapies (prescription, over-the-counter, phytopharmaceutical, and/or social/recreational agents), and past treatments
(including successes and/or failures, adverse effects, and allergic reactions). A complete blood chemistry profile should be considered to
determine if dosage changes are warranted. Health care practitioners should familiarize themselves with the pharmacodynamics, pharmacokinetics, and potential drug-drug or drug-food interactions and contraindications of any pharmacotherapy used by the patient.[1-3,7,9]

Decisions about a polypharmaceutical or other complex regimen may be made jointly. Depending on the nature of the specific pain in a given patient, combinations of antidepressants, anxiolytics, anticonvulsants, sedative/hypnotics, centrally acting agents, opiates/opioids, muscle
relaxants, nonsteroidal anti-inflammatory drugs (NSAIDs), or other analgesics may be considered. Health care practitioners should also consider
any factors that affect the likelihood of compliance (eg, patient age, frequency and/or complexity of the regimen, route of administration,
tolerance of the regimen).[1-3,9]

Pharmacologic Agents


Nonopioid Analgesics
An extensive review of these agents has been published elsewhere. Aspirin (acetylsalicylic acid [ASA]) is used to reduce inflammation, pain, and
fever. It inhibits prostaglandin synthesis and acts on the hypothalamus to reduce fever, to prevent the formation of the platelet aggregation substance thromboxane, and to inhibit vitamin K-dependent and independent clotting factors. Renal elimination of ASA is primarily as free salicylic acids and conjugated metabolites. Aspirin use should be avoided in end-stage renal disease. The dose should be modified when aspirin is used for long-term therapy in the presence of hepatic compromise. Side effects of aspirin include gastrointestinal (GI) irritation, nausea, vomiting, tinnitus,
metabolic acidosis, acute respiratory distress syndrome, and occult GI blood loss.


Both aspirin and salicylic acid enter the central nervous system (CNS), and effects such as dizziness, vertigo, fatigue, insomnia, lethargy,
confusion, depression, and headache may occur.[1-3,8,10,11] Caution should also be taken in treating patients with platelet or bleeding
disorders or renal dysfunction. All patients receiving ASA for transient ischemic attacks or myocardial infarction who are prescribed a
cyclooxygenase-2 (COX-2) agent must continue taking the ASA (80 mg to 325 mg). Patients with a history of nasal polyps, asthma, or rhinitis may have aspirin intolerance, leading to severe exacerbation of allergic symptoms, including potentially fatal bronchospasms.

Acetaminophen (APAP) is an analgesic and antipyretic agent that lacks anti-inflammatory properties. The APAP central mechanism may be mediated
through central COX-2 mechanism. Metabolism occurs in the liver, primarily by cytochrome P-450 (CYP-450) 1A2, 3A4, and 2E1. A slight increase in the dosing interval may be needed when renal dysfunction is present. Prolonged use of APAP in patients with severe liver disease is not recommended. Hepatotoxicity may occur with daily long-term doses of more than 3,000 mg/day and short-term doses of 7 to 8 g and is exacerbated in patients with a history of alcohol abuse. No more than 3 to 4 g of APAP daily is currently recommended.[1-3]

Nonsteroidal anti-inflammatory drugs are antipyretic, anti-inflammatory, and analgesic agents that decrease prostaglandin production through their
variable inhibition of cyclooxygenase-1 (COX-1) and COX-2. All NSAIDs carry the risk of GI, hepatic, hematologic, and renal adverse effects, which
should be considered when contemplating their use long-term for pain. Drug monitoring should include complete blood count, creatinine clearance,
urinalysis, potassium level, liver function tests, occult fecal blood testing, and blood and urine testing for hematuria and proteinuria.
Gastrointestinal ulceration, bleeding, and perforation occur, often without warning symptoms.[1-3,11,12]

Other adverse effects associated with NSAID use include reduced renal blood flow and glomerular filtration, interstitial nephritis, acute tubular
necrosis, papillary necrosis, nephrotic syndrome, sodium and water retention (edema), acute renal failure, hyperkalemia, and hypertension; NSAIDs also decrease the efficacy of diuretics, ß-blockers, and angiotensin-converting enzyme (ACE) inhibitors. Elderly patients, patients with diabetes mellitus, or those with mild to moderate renal insufficiency may be predisposed to hyperkalemia, as may patients receiving concomitant therapy with other hyperkalemia-inducing agents (ACE-inhibitors, potassium-sparing diuretics, salt substitutes). Local as well as systemic injury is caused by
prostaglandin synthesis inhibition of gastric mucosa defense and platelet function, respectively. Inhibition of platelet aggregation can lead to
enhanced bleeding.[1-3,11,12]

Two isoenzymes of oral cyclooxygenase -- COX-1 and COX-2 -- have been identified. Only two COX-2 specific agents are currently available in the
United States. A comparison of these two agents is seen in the Table. The distribution, regulation, and function of cyclooxygenase, along with a
complete review of COX-1 and COX-2 agents, has been fully described elsewhere.[11,12]

Acute sodium retention is COX-2 inhibitor-mediated and clinically resolves with continuation of therapy. Glomerular filtration rate (GFR) is influenced due to inhibition of COX-1; COX-2 specific agents spare the GFR, which decrementally deteriorates in the elderly. Both hypertension and edema are of minor clinical occurrence with COX-2 specific agents. As with all NSAIDs, COX-2 agents should be used with caution in patients with fluid retention, hypertension, or heart failure. Rofecoxib has been found to be opioid-sparing in postoperative treatment of pain. Rofecoxib has prominent pharmacologic, pharmacokinetic, pharmacodynamic, and pharmacotherapeutic advantages over the available COX-2
specific agents.[3,11,12]

Centrally Acting Analgesic
Tramadol is an atypical analgesic with a binary mechanism of action. The mechanism of action combines centrally acting opioid (µ) activity with a
secondary spinal mechanism of monoamine reuptake inhibition. With its weak affinity for µ-opioid receptors, in conjunction with serotonin and
norepinephrine reuptake blockade, tramadol interferes with pathways that mediate pain. Spinally and supraspinally, tramadol is associated with a
lower degree of respiratory depression than opioids. It has a low potential for tachyphylaxis and abuse and is used for the long-term management of
moderate to moderately severe pain and for acute pain. The concomitant use of tramadol and NSAIDs (eg, rofecoxib) may offer the therapeutic benefits of both central and peripheral analgesia, though the requisite studies have not yet been concluded. Tramadol represents an option for patients who are at risk for the side effects of NSAIDs but are reluctant to take opioid analgesics. Only 20% is bound to plasma proteins. The active metabolite M1 and the parent exhibit linear pharmacokinetics, utilize the CYP-450 3A4 and 2D6 hepatic enzyme substrate, respectively. Dialysis removes less than 10% of a given dose.


Tramadol has been additionally studied in elderly populations and for a variety of conditions. It has been well tolerated overall and has proven to
be effective in fibromyalgia, acute or chronic pain, osteoarthritis, back pain, and neuropathic pain. In the near future, tramadol will be available
in combination with APAP (37.5 mg tramadol and 325 mg APAP), in a sustained-action dosage form, and in an oral liquid form.[1-3,6,13-18]

Opiates and Opioids
Probably the best-known class of medications used to treat pain is that of the opiates and opioids. When opiates are used for management of chronic pain, both chemical and psychologic dependence may ensue with chronic administration. Both practitioners and patients can have "opiophobia" (the patient's fear of opiate use, the physician's concern of "opiate addiction," and the pharmacist's cautions about dispensing the prescription), which leads to unnecessary underutilization of opiates in pain management. Opiates/opioids each uniquely produce a wide spectrum of pharmacologic effects, including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished GI motility, altered circulatory dynamics, urinary retention, histamine release, and physical dependence.[1-5,7,11,19-23]

The analgesic effects appear to be a function of several factors, including affinity for specific receptor binding sites, intrinsic activity at
respective receptors, and the pharmacokinetics and pharmacodynamics of the specific agents. The binding of µ receptors (µ1 and µ2) produces euphoria and is associated with morphine-like analgesia, respiratory depression, miosis, and inhibited GI motility. The µ2 receptor has been associated with effects on GI motility, euphoria, respiratory depression, bradycardia, and psychologic aspects of chemical dependence.

Codeine is metabolized to morphine, and hydrocodone is metabolized to hydromorphone. This hepatic metabolism occurs through the CYP-450 2D6
pathway. (A brief comment on each frequently prescribed opiate/opioid follows.) Hydrocodone, a phenanthrene derivative, is a dehydrogenated ketone codeine derivative. Fixed hydrocodone analgesic combinations include APAP and ibuprofen. Most opioids have side effects, including sedation, nausea, vomiting, pruritus, and urinary retention. Constipation is an adverse effect to which tolerance does not develop, so a laxative and/or stool softener may be added to opiate/opioid therapy.

Morphine dosage should be administered according to the patient's characteristics. Elderly patients are more sensitive to morphine. Dose
adjustments are not necessary in mild hepatic disease, but excessive sedation occurs in cirrhotic patients. This is a function of the
accumulation of the active analgesic metabolite, morphine-6-glucuronide (M-6-G), which is renally eliminated. Oxycodone is an analgesic metabolized by the CYP-450 2D6 isoenzyme and is excreted renally. Oxymorphone is a minor active metabolite of oxycodone created through hepatic CYP-450 metabolism.

Morphine acts as a pure agonist, binding with and activating opioid receptors at sites in the periaqueductal and periventricular grey matter,
ventromedulla, and spinal cord to produce analgesia. The principal therapeutic actions of morphine on the CNS are analgesia, sedation, and
alterations of mood. The pharmacologic activity is primarily due to the parent compound morphine. One metabolite, M-6-G, has been shown to have
analgesic activity, but it crosses the blood-brain barrier poorly and may accumulate during renal dysfunction or excessive administration. Elimination
of morphine is primarily via hepatic metabolism by phase II process to glucuronide metabolites (55% to 56%), which are then renally excreted. The
terminal half-life of morphine is 2 to 4 hours and up to 15 hours with linear pharmacokinetics over the dosage range of 30 to 100 mg. After the
administration of oral morphine, approximately 50% of the morphine is not used, because of presystemic (CYP-450 metabolism, first pass) elimination; only about 20% to 40% of the administered dose reaches the systemic
circulation.

Morphine is 30% to 35% reversibly bound to plasma proteins. The major pathway of the detoxification of morphine is conjugation. Virtually all
morphine is converted to glucuronide metabolites, including morphine-3-glucuronide (M-3-G) (about 50%) and M-6-G (about 5% to 15%).
While M-3-G has no significant analgesic activity, M-6-G has been shown to have opioid agonist and analgesic activity in humans.

Meperidine is a synthetic opioid. Normeperidine is an active nonopioid metabolite that is clinically important in that it is not
naloxone-reversible. The half-life of normeperidine is 15 to 30 hours, depending on the patient's renal function. After repeated dosing,
normeperidine accumulates, and the concentration exceeds that of meperidine in the plasma. Resultant effects of normeperidine include respiratory arrest and excitatory neurotoxicity (hyperreflexia, myoclonus, grand mal seizures, and agitation). These effects have been reported after less than 24 hours of dosing in patients at all ages and in those with normal renal function as well as in those with impaired renal function. Anticholinergic effects of meperidine are serious enough that the patient may have urinary retention and need catheterization; other effects include ventricular response to atrial flutter and supraventricular tachycardia.

Meperidine also blocks the neuronal reuptake of serotonin with a serotonin syndrome produced by monoamine oxidase inhibitor (MAOI) drug interactions. Deaths related to meperidine-MAOI interactions have been reported. Serotonin syndrome has also been reported with concomitant use of meperidine and fluoxetine. Meperidine use may aggravate preexisting seizure disorders. Use of meperidine in chronic pain and acute pain is falling into disuse.*


Propoxyphene is a synthetic opiate analgesic with chemical similarity to methadone. It is metabolized in the liver to norpropoxyphene, which is
eliminated in urine. Norpropoxyphene is not an opioid but has proarrhythmic lidocaine-like effects and cardiac anesthetic effects similar to those of
amitriptyline. Because of its long half-life, norpropoxyphene accumulates if the parent drug is given repeatedly. Norpropoxyphene accumulation is
associated with arrhythmias and pulmonary edema, and it is poorly dialyzed. There have also been reports of apnea, cardiac arrest, and death. Naloxone does not reverse the effects of norpropoxyphene. Long-term use of this agent is highly discouraged, and use in elderly patients is not recommended. The US General Accounting Office has listed propoxyphene among drugs "inappropriate for the elderly" and has emphasized that alternative analgesics are both more effective and safer. Propoxyphene use is generally discouraged.[1-4,7,8,10,11,19,25]

Fentanyl is a highly lipophilic opioid analgesic with agonist activity at the µ-opioid receptor in the brain, spinal cord, and smooth muscle. The
transdermal patch is applied to the skin on alternating sites and is replaced every 3 days. One week should be allowed before altering the dose,
and equilibration is not reached until 6 days after a dosage change. The transdermal delivery system offers continuous fentanyl administration.
Increased fat stores, muscle wasting, or altered clearance should be a prescribing caution, and initial dosage should not be greater than 25 µg/hr.
A transmucosal (oral cavity) dosage form of fentanyl is also available.

Pentazocine, nalbuphine, and butorphanol are the mixed opioid agonist-antagonists. Nalbuphine and pentazocine must be used with caution in
patients receiving opioids, to avoid precipitating withdrawal and increasing pain. Pentazocine is an agonist at both  and  receptors. Dysphoria,
nightmares, depersonalization, and visual hallucinations are other adverse effects caused by pentazocine. Pentazocine use is discouraged.[1-3,7,11]

Butorphanol is an antagonist-agonist at the µ receptor. Therapeutic effects also may occur via agonist effects on the  receptor. Opiate abstinence may occur with coadministration of propoxyphene and methadone. Negative side effects can be minimized with administration in small doses, and a nasal delivery form is available. Nalbuphine has both agonist and antagonist properties. The most common adverse reaction is sedation. Buprenorphine is a partial agonist at the µ receptors and an antagonist at the  receptors. It may also have some antagonist activity at the  receptor but lacks dysphoric effects. Buprenorphine is anticipated to be available for oral administration. Buprenorphine has been used for analgesia without producing hemodynamic instability in the management of pain resulting from myocardial infarction. It has a lower incidence of nausea and vomiting than other opioids. Opiate abstinence has not been a clinical event with any coadministered opiates in our clinical practice.?

* References 1-3,5,7,8,10,11,19-22,24.
? References 1-4,7,10,11,18-20,22,25,26.

Antidepressants
Selective serotonin reuptake inhibitors (SSRIs) have a limited side-effect profile. Adverse effects most commonly reported include headache, insomnia, anxiety, dizziness, tremors, drowsiness, nausea, vomiting, diarrhea, dyspepsia, xerostomia, sexual dysfunction, anorexia, and diaphoresis. Serotonin syndrome can occur when using SSRIs in combination with other medications, ie, MAOIs, dihydroergotamine, tryptophan, dextromethorphan, lithium, nefazodone, or "tryptans" that block the reuptake of serotonin. Selective serotonin reuptake inhibitors inhibit the CYP-450 enzyme system and cause delayed clearance of certain medications, especially those medications that use CYP-450 1A2, 2D6, and 3A4 enzymes as a substrate for their metabolism. All SSRIs can increase serum levels and decrease clearance of other substrate agents by way of these hepatic enzyme systems. The SSRIs are less effective than other antidepressants for the management of pain. A complete list of drug interactions involving the CYP-450 system and substrate drugs that may be used in the management of pain is provided in the Appendix.[1-3,5,7-10,25,27-29]
Among the tricyclic antidepressants (TCAs) is amitriptyline, which is hepatically converted to an active metabolite, nortriptyline. Imipramine is
transformed by the liver to desipramine. Trazodone (not a TCA) is hepatically converted to meta-chlorophenyl piperazine (mCPP), a serotonin
agonist, and is generally given at bedtime due to its sedative properties.

Generally, the adverse effects of TCAs result mostly from cholinergic/muscarinic receptor blockade, 2-adrenergic blockade,
histaminergic (H1, H2) blockade, and dopaminergic blockade. Receptor blockade of cholinergic/ muscarinic receptors can produce blurry vision,
xerostomia, sinus tachycardia, constipation, urinary retention, and memory dysfunction. Blockage of H1 and H2 receptors produces sedation, dizziness, weight gain, and hypotension and potentiates CNS depressant agents. 1-Adrenergic blockade is often associated with postural hypotension and dizziness. Dopamine-receptor blockade has been associated with extrapyramidal syndrome, dystonia, akathisia, rigidity, tremor, akinesia,
neuroleptic malignant syndrome, tardive dyskinesia, and endocrine changes. Tachycardia and prolonged PR and QRS intervals with membrane stabilization occur. Orthostatic hypotension and, in patients who have impaired left ventricular function, congestive heart failure may occur. Bupropion (not a TCA) blocks reuptake of both norepinephrine and dopamine and also has relatively few cardiac side effects, minimal (if any) effects on cardiac conduction, and no production of orthostatic hypotension.[1-4,7,28-30]

Other receptor-specific antidepressants, such as venlafaxine, nefazodone, and mirtazapine, do not currently fit into any broad antidepressant
classification. Venlafaxine (serotonin and norepinephrine reuptake inhibitor), has a complex mechanism of action. It blocks the reuptake of
serotonin at low doses, blocks the reuptake of norepinephrine at medium doses, and blocks the reuptake of dopamine at higher doses. Venlafaxine is
in effect three drugs in one because of such dose-related, receptor-mediated events. Venlafaxine provides the therapeutic benefits of tertiary and
secondary amine antidepressants without the TCA side-effect profile. Venlafaxine also is beneficial in chronic pain, since it lacks clinically
relevant CYP-450 interactions and is available in an extended release dosage form.[1-3,30,31]

Nefazodone is another antidepressant that acts dually on serotonin. Reuptake inhibition for 5-hydroxytryptamine (5-HT) and norepinephrine occurs, coupled with 5-HT2 receptor blockade. Some 1-adrenergic inhibition produces orthostatic hypotension. This agent produces two active metabolites: the OH-nefazodone metabolite, which has activity similar to that of nefazodone, and the mCPP metabolite, which is the same metabolite found with trazodone. The mechanism of action of mCPP is that of a 5-HT agonist coupled with mild 5-HT2 and 5-HT3 antagonism. This agent shows zero-order kinetics. There is also relevant CYP-450 3A4 inhibition.[1-3,7]

Mirtazapine is an atypical antidepressant described as a noradrenergic serotonin-specific antagonist. This agent produces therapeutic antagonism at
both 2 autoreceptors and heteroreceptors, thus facilitating enhanced noradrenergic and serotonin discharge. Mirtazapine's therapeutic benefits
include a lack of sexual dysfunction, a decrease in migraine headache, and a decrease in anxiety, agitation, depression and insomnia. Further antagonism occurs at 5-HT2 receptors (decreasing anxiety and agitation) and at 5-HT3 receptors (decreasing nausea and GI distress). H1-receptor antagonism at low doses (</=30 mg) produces drowsiness, facilitating sleep and improving appetite. No clinically significant interactions are revealed in the CYP-450 system. A unique dissolve-in-mouth dosage form is available. Mirtazapine is a useful adjuvant agent in the management of chronic pain.[10,29-34]

Anxiolytic Agents
The principal modulatory site of the -aminobutyric acid (GABA) receptor complex is found on its  subunit and is referred to as the benzodiazepine or
receptor. Three subtype  receptors have been identified, and it is thought that the v1 receptor is associated with sedation and that 2 is associated
with anticonvulsant, anxiolytic, and myorelaxant effects. The clinical effects of the 3 receptor have not yet been thoroughly investigated.
The 2 receptors are associated with memory dysfunction, such as forgetfulness and/or amnesia, because of anterograde amnesic effects.

Clonazepam offers a therapeutic option among other benzodiazepines. Lorazepam, temazepam, and oxazepam may be especially useful to patients with liver impairment, because these drugs do not have any active metabolites and are metabolized by phase II processes.**

Anticonvulsants
Anticonvulsants, or antiepileptic drugs (AEDs), have produced therapeutic benefits in a variety of painful neuropathic syndromes. Such agents include carbamazepine, phenytoin, valproic acid, tiagabine, gabapentin, oxcarbazepine, vigabatrin, zonisamide, lamotrigine, and topiramate and have been described elsewhere.[1-3] Topiramate has several mechanisms of action (1) diminishing action potential
by sodium channel blockade, (2) increasing GABA frequency activation at GABA receptor sites, (3) selectively antagonizing kainate activation at
kainate/-amino-3-hydroxy-5-methyl-4-isoxazolepropinate (AMPA) receptor sites, (4) providing glutamate antagonism, (5) calcium channel blockade, and (6) producing an acidosis that results in diminished N-methyl-D-aspartate (NMDA) mediated excitation and increased GABAA mediated inhibition. Additionally, some carbonic anhydrase inhibition occurs. Absorption is rapid with bioavailability of about 80%. The AMPA and kainate receptors have a role in mediating neuropathic pain. Pharmacokinetics are linear, with dose-proportional increases in plasma concentration, and the steady state is achieved in about 4 days. Plasma protein binding is only 13% to 17%. Metabolism is minimal, with 70% of a dose recovered unchanged in the urine; elimination half-life is 18 to 23 hours. The drug is cleared by hemodialysis. Clearance is diminished in those patients with moderate renal impairment and/or hepatic impairment.

Side effects of topiramate include paresthesia and anorexia, to name a few. A </=1% incidence of renal calculi requires adequate hydration. Central
nervous system-related side effects are dose-related and are generally not observed at doses of less than 250 mg/day. Cognitive motor slowing and
speech or work difficulty are seen only in a minimal percentage of patients when high doses are initiated, with rapid incremental dose changes, or with coprescription of other AEDs. In our clinical practice with a large number of patients, CNS event occurrence was not a clinically relevant finding.
Clinical applications may be available for bipolar disorder, neuromodulation, neurostabilization and disease modification, obesity
treatment, epilepsy, bulimia, neuropathic pain syndromes, essential tremor, and migraine headache.

Skeletal Muscle Relaxants
Baclofen acts as a GABAB agonist in hyperpolarized membranes. Carisoprodol is metabolized in the liver by CYP-450 2C19 to an active metabolite,
meprobamate. It should be avoided in patients with renal or hepatic disease. With prolonged use, this drug is associated with dependence. Use of
carisoprodol is discouraged. Cyclobenzaprine, a frequently used muscle relaxant, is structurally similar to TCAs. Side effects include drowsiness, dizziness, confusion, ataxia, xerostomia, and anticholinergic effects. Contraindications are similar to those of TCAs. Long-term use of cyclobenzaprine should be avoided, and the manufacturer recommends that administration not exceed a 3-week period.[1-3]

Topical Agents
Capsaicin is a topical analgesic that may inhibit the synthesis, transport, and release of substance P, a peripheral neurotransmitter of pain. Capsaicin is used to treat pain associated with neuralgia, neuropathy, and arthritis. Lidocaine (5%) topical patches are available for the relief of allodynia (painful hypersensitivity) and chronic painful postherpetic neuralgia; the patches are to be applied for 12 hours daily only.

Sleep-Promoting Agents
Treating disorders of initiating and maintaining sleep due to pain requires pharmacologic intervention when sleep hygiene methods have proved less than satisfactory. Selection of a pharmacologic agent necessitates pharmacodynamic and pharmacokinetic decisions that address a patient's
specific needs. Zaleplon, a nonbenzodiazepine hypnotic, effects the 1 receptor. Absorption is rapid, bioavailability is about 30%, and metabolism
is primarily by aldehyde oxidase and by minor CYP-450 3A4 substrate-forming inactive metabolites. The mean half-life is about 1 hour. Therefore, the rapid onset, absence of active metabolites, absence of CYP-450 drug interactions of clinical consequence, rapid clearance from the body, and
absence of major memory impairments make this agent highly suitable for use in patients with insomnia due to pain.[1-3]

Miscellaneous Agents
Several other medications can be used to relieve pain. Clonidine and tizanidine are both imidazole 2-agonists and are believed to inhibit pain
transmission by modulating norepinephrine and 5-HT release in the dorsal horn on the lamina of the spinal cord. Potentiation of µ-opioid receptors
and a decrease in the wide range of neuron excitability are additional mechanisms of 2 agonists, which also modulate specific calcium channels.
Botulinum toxin type A has been used investigationally for some painful syndromes.
** References 1-3,9,19,21,27,28,31,35,36.

Conclusion
By following this pharmacologic review, the clinician is able to evaluate pharmacotherapies for a specific patient's needs, basing the selection on
personal clinical experiences, patient-specific concerns, sides effects, adverse effects, drug interaction, pharmacodynamics, pharmacokinetics, and
pharmacotherapeutics.

Tables can be found at:
<http://neurology.medscape.com/SMA/SMJ/2001/v94.n08/smj9408.07.bark/mig-pnt-
smj9408.07.bark.html>

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National Institute on Drug Abuse, NIDA on Addiction vs. Dependence

There's a 0.03% chance you'll become addicted on narcotic medicine if  you're a pain patient. That's 3 hundredth's of 1 percent! What does this
tell us about Drug War Propaganda? 

"This is what distinguishes the pain patient who is tolerant to and physically dependent on morphine, from the addict who is also tolerant
to and physically dependent on heroin. Both are self-administering an addictive drug several times a day. But while the addict takes his drug
to get high, "mellow out," and largely avoid life, the pain patient takes his drug to get on with life. This apparently subtle distinction
between the contingencies surrounding drug use lead to a remarkably different outcome for these two different kinds of users. Heroin addicts
are lost to themselves, to their families, and to society. Not only can't they work, but they are almost certainly engaged in criminal
activity, and they are at high risk of a variety of infectious diseases, including hepatitis and AIDS. Indeed, intravenous drug users have become
the major vector for the spread of AIDS into the heterosexual community in this country. Current estimates are that more than 55% of addicts in
New York City are HIV positive. (16)"

"Pain patients, by contrast, couldn't be more different. Being on an opioid allows them to interact with their families, to get out of
hospitals, and to go back to work. Indeed, their efforts to maintain their health are in marked contradiction to the utter disregard addicts
show for their health. If we wish to equate addicts with pain patients, the more appropriate comparison is with the under treated pain patient."

"He is in the hospital or inactive at home, he is a major drain on his family's emotional and financial resources, and he does not contribute
productively to society."

"Another difference between addicts and pain patients comes when it is time to get off the drug on which they are physically dependent. For
addicts, this is a major hurdle. For the pain patient, it is typically an uncomplicated process. ... Drugs have a completely different meaning
to pain patients, however...."

"Because of the meaning of drugs in an addict's life, drug addiction is a chronic, relapsing condition. Because of the very different meaning of
drugs in a pain patient's life, drug addiction rarely, if ever, occurs after opioid use has stopped. (10-12) This is a crucial point. The data
most often cited to link addiction to medically administered opioids were derived from studies with addicts. (17-18) In the first place, this
group is highly unrepresentative of the general population. In the second, it is made up of highly unreliable people. Self-reporting about
drug use by addicts is not the method of choice in studying drug use. (9) The more appropriate data to address this issue have been derived
from retrospective reviews of large numbers of patients who received opioids to determine how many became addicts.ost important among these
are the legal barriers we have erected to limit the use of opioids a Of 24,000 patients studied, only 7 could be identified who got into trouble
with drugs as a result of medical administration." *

"The conclusions of this discussion are clear: (a) dependence and addiction are not equivalent to each other; (b) patients who become
dependent on opioids during the course of medical therapy rarely become addicted to those drugs; and (c) in managing pain with opioids, there is
little need to fear addiction. Tolerance to opioids is rarely a problem because it is possible to continuously increase the dose. Dependence is
only a concern when prescribing drugs with antagonist properties and in managing withdrawal."

"If addiction is not a reason to avoid using opioids, many of the other reasons that have led to widespread under prescribing can be addressed
more directly. Mnd the lack of knowledge among health care professionals about the proper use of these agents." End.

7 out of 24,000 would be: 7 into 24,000 = 0.0002916. In percentage that would read: 0.03% or 3 hundredth's of 1 percent!

And yet, the Drug War's Propaganda has even uncaring doctors telling their patients: "If I give you that you'll become addicted" when it's
NOT true at all. At Three Hundredth's of ONE percent, it's nearly impossible to "addict" a valid pain patient, and ALL pain patients
SHOULD BE a "drug seeker" just like any diabetic SHOULD BE an "Insulin seeker!"

"There is better than a "99.9% chance that you will NOT become addicted if your doctor gives you adequate and ongoing opioid medication for your
suffering, if you are a valid pain patient! Take this page to your doctor at once and demand the pain control you have every right to
have." Skip Baker, 2001.

Risk of Addiction Small say Experts:
http://www.docguide.com/dg.nsf/DGNews/0EBCE61FF58E3C148525688C005E4A89?OpenDocument&f=y


"You will not make any patient an addict if you give them drugs to treat their pain," says Henry Farkas, MD, MPH, Medical Director of the
Northern Chesapeake Hospice and a staff physician at Union Hospital, in Elkton, MD. He pointed to the results of a very large study done in the
1980s, which found that only four patients became addicted out of 12,000 treated with opiates for pain. "It's just not a problem for more than 99
percent of people," he said."

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Are antidepressant drugs efficacious in the treatment of fibromyalgia?
Journal: West J Med 2001 Nov;175(5):314
Authors: O'Malley P, Balden E, Tomkins G, Santoro J, Kroenke K, Jackson J. Corresponding author of original paper: P G O'Malley Department of
Medicine Walter Reed Army Medical Center 6900 Georgia Ave Washington, DC 20307-5001 PMID: 11694476

Conclusion: Antidepressant drugs improve overall symptoms and individual symptoms of fatigue, sleep, and pain in patients with fibromyalgia.

The entire article may be read at: http://www.ewjm.com/cgi/content/full/175/5/314

A commentary on this article by Johannes W G Jacobs and R Geenen, of the University Medical Centre, Utrecht, the Netherlands, wjm 2001 175: 314,
is available at: http://www.ewjm.com/cgi/content/full/175/5/314-a

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Brain Scans Show Antidepressants At Work

Feb. 6, 2003 -- Today's antidepressants have pulled millions of people from the depths of depression. But now researchers have a better understanding why they work.
For the first time, scientists have used sophisticated imaging technology --called functional magnetic resonance technology (fMRI) -- to view the brain as it is working, and in effect watch changes caused by antidepressants.

Their report appears in the January issue of the American Journal of Psychiatry.

Researchers studied a small group of people diagnosed with severe depression before and after treatment, and compared their brain reactions with those of people without any mood disorder, and who didn't take antidepressants.

They found that the drug caused significant changes in a section of the brain that governs focused attention and is used when people face conflict.  They also found that the depressed patients had lower overall brain activity in this region than did the untreated group.

In fact, these brain changes were observed just two weeks after they started the medication, writes researcher Richard J. Davidson, PhD, a psychologist with the University of Wisconsin-Madison.

"Conducting repeated brain scans in these patients allowed us to see for the first time how quickly antidepressants work on brain mechanisms," he says in a news release.

Researchers also found differences in reactions to the medication: Those depressed patients who showed more activity before treatment responded better to the medication than those who had less pre-treatment brain activity.

This information could help psychiatrists predict which patients will respond to certain antidepressants, he adds.
SOURCE: American Journal of Psychiatry, Jan. 2003  News release, The University of Wisconsin-Madison.

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Fentanyl patches

To add to the choice of opioid analgesics used in palliative care we now have in Australia fentanyl patches. Each patch is worn for 72 hours and has about the same effect as using twice daily oral sustained release(SR) morphine. However from a quality of life point of view there are some advantages in using fentanyl patches for some patients. It is not yet listed on the Pharmaceutical Benefits Scheme and is quite expensive. So what is its present role in palliative care and how is it used?

The main side effects complained of by patients on morphine are nausea, vomiting, constipation and drowsiness all of which can significantly impact on quality of life even though pain relief may be adequate. For total pain management both physical and psychological factors need to be taken into account. According to a study comparing transdermal fentanyl versus sustained release oral morphine the following has been found.20(1)

Pain control
No significant difference was found between fentanyl and SR morphine in regards to pain control. However those on fentanyl did require slightly more breakthrough doses of morphine.

Sedation and sleep
Fentanyl appeared to be less sedating than morphine both in the daytime and night.

Bowel function
Fentanyl treatment was associated with significantly less constipation than morphine.

Nausea
This was significantly lower in the fentanyl group.

Treatment preferences
Significantly more patients indicated that the fentanyl patches had caused less interruption to their daily activities and the activities of family and carers, and had been more convenient to take than morphine tablets.

Side effects
Skin - 3% erythema, 5% mild itching and 2% moderate itching.

Transferring from morphine to fentanyl
Withdrawl from morphine symptoms were common and symptoms such as abdominal pain, agitation or anxiety, sweating and 'flu' like symptoms were reported during the first few days of fentanyl treatment consistent with morphine withdrawl.

A second line drug
It should be emphasised that fentanyl is not suitable for unstable pain or rapid titration. In those situations morphine must first be used preferably on a four hourly basis until adequate pain control is acheived. If there are then indications to use fentanyl then the change is made according to the conversion formula listed below.

24-hour morphine (mgm/day) Fentanyl dose (mcg/hr)
<135 25
135-224 50
225-314 75
315-404 100
405-494 125
495-584 150
585-674 175
675-764 200
765-854 225
855-944 250
945-1034 275
1035-1124 300

There are four sizes of patch and more than one patch can be used if a higher dose is needed.The four sizes of patch have a delivery rate of 25,50,75 and 100mcg per hour.

Notes
(1) Fentanyl is excreted in the urine and the dose may need to be reduced if there is increasing dehydration or renal failure.
(2) As regards cost fentanyl is approximately three times as expensive as morphine.
(3) Care must be taken to adequately dispose of used patches and it is recommended that sharps containers be used for disposal.

Summary
Fentanyl is a very good opioid analgesic that is particularly useful for those people who are intolerant of morphine. However it should be considered a second line drug after morphine and is not nearly as flexible as 4 hourly morphine. It is used particularly for those with severe morphine related constipation or nausea, those who have excessive morphine induced sedation, those with poor compliance or inability to swallow and those who have inadequate pain relief with morphine. It is easy to use and well accepted by the patient. It will hopefully soon be listed on the PBS.

(1) Reference: Transdermal Fentanyl versus Sustained-Release Oral Morphine in Cancer Pain: Preference, Efficacy and Quality of Life. Journal of Pain and Symptom Management. Vol 13, No.5, May 1997.

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Oral Transmucosal Fentanyl Improves QOL in Patients With Severe, Nonmalignant Pain

NEW YORK (Reuters Health) Nov 29 - In a study of patients with severe, chronic, nonmalignant pain requiring opioid treatment, oral transmucosal fentanyl citrate (OTFC) proved to be effective and safe and permitted an overall reduction in the use of opioids for break-through pain. Many experienced improved quality of life (QOL), as exemplified by increasing mobility, energy and sleep.

Dr. Forest Tennant, of the Veract Intractable Pain Centers in West Covina, California, and associates enrolled 100 consecutive patients who had experienced severe pain for at least 3 years. More than half suffered from degenerative spinal disease. Other common conditions included fibromyalgia, migraine, neuropathies and congenital skeletal disease.

All were being treated with both a long-acting opioid and a short-acting opioid for break-through pain.

Patients were initially given OTFC lozenges for buccal or sublingual administration with the instruction to use them only for the most severe break-through pain. They then began reducing or eliminating the short-acting opioid, replacing it with OTFC.

At a 3-month follow-up, nearly half of the patients reported pain relief within 10 minutes of using OTFC, Dr. Tennant's team reports in the American Journal of Pain management for October. Almost three-quarters reported pain relief lasting at least 2 hours, and more than a quarter said relief lasted more than 4 hours.

Sixty-two percent reported fewer days confined to bed or house, and 57% said that OFTC had prevented them from visiting an emergency room. About 50% required less opioid medication and experienced less depression and anxiety, and 45% were sleeping better.

There were few side effects. The transmucosal route reduced constipation and nausea to no more than 12%, itching to 7% and headache to 6%.

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Drug for Opioid Constipation Effective in Phase III Trial

NEW YORK (Reuters Health) Nov 11 - Adolor Corp. released on Monday data from a phase III trial showing that its opioid bowel dysfunction (OBD) drug candidate alvimopan is safe and more effective than placebo.

Bowel dysfunction, namely constipation, is a common side effect of opioid drug use. Alvimopan, which will be co-promoted in the US with Britain's
GlaxoSmithKline Plc, is a gastrointestinal-tract-restricted opioid narcotic antagonist. The agent is designed to improve bowel motility without
interfering with pain relief provided by opioid drugs.

The drug is also being developed for postoperative ileus.

In the study, 168 patients who were chronic users of opioids were given either one of two doses of alvimopan or placebo once daily for 21 days. The
primary endpoint of the trial was the proportion of patients having a bowel movement within eight hours of receiving treatment.

According to Adolor, 55% patients treated with the highest dose of alvimopan reached the endpoint, versus 43% with the lowest dose and 29% for placebo. The drug was well tolerated, said the company, with side effects including diarrhea, abdominal cramps, nausea, and vomiting.

Adolor CFO Peter Schied told Reuters Health that the results were "highly statistically significant," adding that the company would hope to achieve
similar results in the additional phase III studies that must be completed before the drug can be filed with US regulators.

In regard to the ileus indication, Schied said that the first phase III study would likely wrap up by year-end, with data likely to be available in the
first quarter 2003. The other trials are expected to wrap up shortly thereafter, and Adolor is targeting a US Food and Drug Administration filing
in the second half of next year.

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The effects of two single doses of tramadol on sleep: a randomized,
cross-over trial in healthy volunteers. Eur J Anaesthesiol  2001 Jan;18(1):36-42
Walder B, Tramer MR, Blois R. Division of Surgical Intensive Care, Geneva University Hospitals, 1211
Geneva 14, Switzerland.

BACKGROUND AND AIM: The effects of analgesic drugs on sleep are poorly understood. We investigated short- and medium-term effects of tramadol
on sleep structure.


METHODS: Eight healthy volunteers received a placebo (predrug placebo-night), then, in a randomized, double-blind, cross-over fashion
a single oral dose of tramadol 50 mg or 100 mg (drug-night), and finally, again a placebo (postdrug placebo-night). Standardized polysomnography
(electroencephalogram, electro-oculogram, submental electromyogram) was continuously recorded during placebo- and drug-nights.


RESULTS: During drug-nights both doses of tramadol significantly increased the duration of stage 2 sleep, and significantly
decreased the duration of slow-wave sleep (stage 4). Tramadol 100 mg but not 50 mg significantly decreased the duration of paradoxical (rapid eye
movement) sleep. In the placebo-night after tramadol 100 mg (but not after 50 mg) duration of stage 2 sleep was significantly shorter, and duration of stage 4 sleep was significantly longer compared with the predrug placebo-night.


CONCLUSION: In healthy volunteers, a single dose of tramadol 50 mg disturbs sleep in
the night of drug application. With 100 mg, sleep is disturbed in both the night
of drug application and in the subsequent night. Publication Types: Clinical Trial
Randomized Controlled Trial PMID: 11270008

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Pregabalin Improves Pain and Fatigue Symptoms in Patients With Fibromyalgia
By Emma Hitt, Ph.D.

Pregabalin appears to be effective and safe in treating patients with fibromyalgia, according to new clinical trial findings. It may also appear to improve sleep quality, fatigue, and increase quality of life, research suggests. Leslie Crofford, M.D., from the University of Michigan, Ann Arbor, and colleagues presented their findings here Tuesday at the American College of Rheumatology (ACR) 66th Annual Scientific Meeting.

Patients with fibromyalgia experience chronic musculoskeletal pain, fatigue, and sleep disturbances. "There are no approved therapies, and treatments that are used often do not provide adequate relief, " Dr. Crofford and colleagues note.

According to Dr. Crofford, the mechanism of action of pregabalin is "not completely understood," but it binds to calcium channels, modulating calcium influx, which results in analgesic, anxiolytic, and anticonvulsant activity. In a study sponsored by Pfizer, Inc., researchers evaluated the efficacy and safety of pregabalin up to 450 mg/day (150 mg three times daily) for reducing pain and associated symptoms in patients with fibromyalgia.

A total of 529 patients were randomized to receive 150, 300, or 450 mg/day of pregabalin or placebo during the second of six required visits.

Compared with those receiving placebo, patients treated with pregabalin 450 mg/day showed significant improvement in their endpoint mean pain score (-0.93; P<.001), and they were more likely to experience a 50% reduction in pain from baseline (P=.003), the researchers report.

Patients receiving 300 and 450 mg/day pregabalin also experienced reduced fatigue and improved sleep quality compared with those receiving 150 mg/day pregabalin or placebo.

Forty-eight patients (9%) withdrew due to adverse events, and 44 patients (8%) withdrew due to lack of efficacy. The most common adverse events were dizziness and somnolence, the authors note.

"Treatments for fibromyalgia are limited," Dr. Crofford told Medscape, "and pregabalin represents another treatment option compared to tricyclic antidepressants and serotonin reuptake inhibitors, which have also been shown to be useful in smaller studies," she said.

According to Dr. Crofford, within the next year, an application will be filed for approval for neuropathic pain and anxiety indications in the U.S. and in Europe, and "then there will have to be other studies with respect to fibromyalgia," she said.

"This is a very important study with robust results over a long follow-up," session moderator Laurence Bradley, PhD, from the University of Alabama, Birmingham, told Medscape. "Most of the studies for fibromyalgia pain have produced very modest results," he added.

Also presented at the session were three studies on the efficacy and safety of cyclobenzaprine, tizanidine, and methylphenidate in patients with fibromyalgia. Another study suggested that multinutrient supplementation had no effect on fibromyalgia symptoms. ACR 66th Annual Meeting: Abstract 1653. Presented Oct. 29, 2002. Source: Medscape. Reviewed by Gary D. Vogin, MD

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Happiness Shouldn't Cause Cavities: Your meds can cause tooth decay
by Ed Tate III

The drugs that gave you back your grin may be wreaking havoc with your teeth. More than 170 million prescriptions for antidepressants are
written each year in the US. Now, researchers confirm a common side effect: dry mouth.
Dry mouth may affect up to 20% of those taking selective serotonin reuptake inhibitors such as Prozac, Paxil, and Zoloft and up to 55% of
those taking older tricyclic antidepressants. Dry mouth can set the stage for tooth decay, gum disease, oral infections, and other problems.


"It's not just the reduced quantity of saliva; the quality is also important," says researcher Joseph J. Keene Jr., DDS, of Southern
Illinois University's School of Dental Medicine. Changes in saliva can mean that debris adheres to the teeth more readily, contributing to
possible dental problems.


The greatest risk for dry mouth is reported with older antidepressants such as amitriptyline (Elavil), amoxapine (Asendin), and clomipramine
(Anafranil), as well as the newer drug mirtazapine (Remeron). Antidepressants taken alone and especially with other medications
producing dry mouth may raise your risk of tooth decay if preventive measures are not taken.


"Do not discontinue or change antidepressant therapy on your own," emphasizes Keene. "If dry mouth is severe, consult with your physician
for a possible drug-replacement therapy for depression." If it's mild, you can prevent dental problems with some simple measures.
Dry Mouth Rx Thoroughly brush your teeth after every meal using fluoride toothpaste. Floss daily.Use mouthwashes made for dry-mouth sufferers, and avoid those containing alcohol, which is drying. Drink more water. Prevention recommends eight 8-oz glasses a day. Most
Americans get far less.


Try using sugarless chewing gums and candies, particularly those made to
stimulate saliva production.
See your dentist twice a year.

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Venlafaxine Alleviates Pain and Disability Associated with Fibromyalgia

"Venlafaxine treatment of fibromyalgia" Annals of Pharmacotherapy
By Mary Beth Nierengarten

Pain and disability associated with fibromyalgia were alleviated in patients who were treated with the antidepressant venlafaxine, reports a study from Turkey.

Despite the unknown pathophysiology of fibromyalgia, the possible role played by central monoaminergic transmission suggests that antidepressants
that act on multiple neurotransmitters may improve symptom control.

Kemal Sayar, MD and colleagues from Farabi Hospital, Trabzon, evaluated the efficacy of venlafaxine in 20 patients with fibromyalgia given a fixed-dose of venlafaxine (75 mg/d). Primary outcomes evaluated at 6 and 12 weeks of the study were clinical severity of disease (measured by Fibromyalgia Impact Questionnaire (FIQ)) and degree of pain (measured by the Visual Analog Scale (VAS)). Other scales used to measure an association between psychological distress and physical symptoms included the Beck Depression and Anxiety
Inventories and the Hamilton Depression and Anxiety scales.

Of the 20 patients enrolled in the study, 5 discontinued treatment after 1 week of treatment because of treatment-related adverse effects. Of the
remaining 15 patients, the mean duration of disease was 3.7 years, the mean age was 37.7 years, 14 were married, 9 did not have any current psychiatric disorder (3 of whom had a history of major depressive disorder), 5 had generalized anxiety disorder, and 1 had bipolar disorder.

No significant decrease in pain was noted at 6 weeks after treatment initiation, but a significant improvement in pain intensity (P = .0001) and
disability caused by fibromyalgia (P = .0001) were found at 12 weeks. A significant decrease in anxiety and depression was also found at 12 weeks
compared to baseline. Having a current or past psychiatric disorder was not associated with any difference in perceived pain scores, with no significant associations found between FIQ scores and anxiety and depression measures.

Several limitations of this study include its study design (i.e., open trial), lack of measurement of tender points, withdrawal of 5 patients due
to treatment-associated adverse effects, and small sample size.

With these caveats, the authors conclude that venlafaxine is a promising treatment for alleviating symptoms of pain and disability associated with
fibromyalgia that should be further evaluated in placebo-controlled, double-blinded studies.
Ann Pharmacother 2003;37:11:1561-5. "Venlafaxine treatment of fibromyalgia"

Source: www.docguide.com. Copyright (c) 1995-2003 Doctor's Guide Publishing
Limited.

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APA: Paroxetine Helps Relieve Fibromyalgia Symptoms

Note!The study was funded by GlaxoSmithKline.

By Charlene Laino NEW YORK CITY --- May 5, 2004 --- Paroxetine can help to relieve symptoms in patients with fibromyalgia, according to a randomized placebo-controlled trial. Prakash Masand, MD, Consulting Professor of Psychiatry, Duke University School of Medicine, Durham, North Carolina, presented the findings here on May 4th at the American Psychiatric Association 157th Annual Meeting. The study enrolled 116 patients with fibromyalgia -- 97% of whom were women -- with a mean age of 46 years. Nearly 40% also had irritable bowel syndrome and 23% had a history of sexual or physical abuse. Patients were randomized to receive either controlled-release paroxetine at doses from 12.5 mg to 62.5 mg daily (mean dose 39.1 mg) or placebo. Response to treatment was defined as a reduction of at least 25% on the Fibromyalgia Impact Questionnaire. An increase of 1 to 2 points on Clinical Global Impression (CGI)-Improvement scale indicates symptoms are "much" or "very much" improved By the end of 16 weeks, 57% of patients in the paroxetine group had responded to treatment, compared with 33% of patients on placebo. Also, 58% of patients who received paroxetine improved by 1 to 2 points on the CGI scale, compared with 25% of placebo patients, according to Dr. Masand. Side effects were generally mild, although in the treatment group 26% of patients reported drowsiness and 36% reported dry mouth versus 6% and 9% of placebo patients, respectively. Noting that there is no known cure for "this debilitating illness," Dr. Masand called the results encouraging. The next step, he said, is larger, longer trial.

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Narcotic Actiq's use and abuse raise concern

The Associated Press 5/17/04 9:01 AM The Wall Street Journal

In the wake of the controversy over the prescription narcotic Oxycontin, health experts and insurers are raising concerns about the increasing use -- and abuse -- of Actiq, a newer and faster-acting prescription painkiller.

Actiq, derived from opium, comes in the form of a berry-flavored lollipop or lozenge that takes seven to 15 minutes to hit the bloodstream after a patient places it in the mouth. The drug, sold by Cephalon Inc. of West Chester, Pa., was approved by the Food and Drug Administration in 1998 for severe spikes in pain. It is so powerful and potentially addictive that its label says Actiq "is intended to be used only by oncologists and pain specialists" knowledgeable in using opioids to treat cancer patients who are already tolerant to opioid therapy for their underlying chronic pain.

But use of Actiq appears to have grown far beyond cancer treatment. Among the 321,463 U.S. prescriptions written for Actiq last year -- up from 77,478 in 2001 -- 26 percent were written by family-practice doctors or internists, five times the number in 2001, according to data from NDCHealth, a health-care information company.

Workers compensation programs usually handle relatively few cases of cancer. Yet in 2003, as more doctors prescribed the drug to patients, Actiq shot up to 15th on the list of total medication costs in worker's comp claims at The Hartford Financial Services Group. It had ranked 66th two years before.

In many cases, patients with back or neck pain or other ailments are taking the drug four or more times a day, racking up annual bills of $12,000 to $18,000 for Actiq alone, says George Furlong, vice president of provider and payment services for CHOICE Medical Management Services, a Tampa, Fla., workers-compensation managed care company. Those big bills have prompted many health plans to keep Actiq off their formularies for covered drugs or to require special authorization for its use. As of May 1, Medi-Cal, California's Medicaid program, will cover Actiq only after a doctor shows that it is for cancer-related pain. But provisions in many states prevent workers-comp administrators from restricting coverage of painkillers like Actiq, even for nonapproved use.

Off-label drug use, that is, administering a drug for an illness the drug wasn't specifically approved to treat, isn't illegal and is common in medical fields in which doctors tend to experiment with the latest advances in therapy. Some pain specialists report small doses of Actiq successfully treats sources of severe chronic pain such as migraines.

But some addiction specialists say the drug's growing use has coincided with an increase in its abuse and illegal trade. In recent months, police in Philadelphia made several arrests of people who allegedly sold Actiq on the street for $20 a dose under the name "perc-a-pop."

Jake Epperly, president and clinical director of Midwest Rapid Opiate Detoxification Specialists and New Hope Recovery Center in Chicago, says his staff treated their first cases of Actiq addiction about three years ago. In most of those early cases, patients originally had been prescribed the painkiller for a legitimate injury. In the past 18 months, Mr. Epperly has started seeing people who got Actiq illegally or by doctor shopping.

So far, no one is calling Actiq the next Oxycontin, which became a widely abused street drug. Actiq may not have as much street appeal because it isn't as cheap and its effects aren't as long-lasting.

But some addiction specialists and pharmacists say Actiq's powerful, sudden relief makes it particularly enticing for some drug abusers. Unlike Oxycontin, "Actiq is designed to deliver a quick effect in the first place," says Robert Bonner, vice president of medical claims and medical director at The Hartford. "It is ripe for misdirection."

In a survey of some 200 law enforcement agencies, diversions of Actiq to street sales were reported seven times in 2002, while diversions of Duragesic, a patch with the same pain-killing ingredient as Actiq, were reported 159 times, says James Inciardi, director of the Center of Drug and Alcohol Studies at the University of Delaware.

Doctors disagree on whether use of Actiq should be strictly limited to prevent abuse. "People start feeling the withdrawal and that makes them think they actually need more," says Clifford Bernstein, an anesthesiologist and medical director of the Waismann Institute in Beverly Hills, Calif. Dr. Bernstein says he uses a fraction of the opioids to treat patients' pain that many other pain specialists do.

Carl Hess, medical director of the Anaheim Memorial Pain Management Center, says the drug can bring long-sought relief to certain patients dealing with excruciating pain. However, he concedes that for some chronic-pain patients "it can almost work too well."

Actiq still accounts for a very small piece of the multibillion-dollar market for opioid pain medications. But sales have taken off since Cephalon inherited the drug in October 2000 after taking over Salt Lake City biotech firm Anesta Corp. Actiq sales have more than quadrupled since 2001 to $237 million last year, and Cephalon is predicting a 37 percent to 58 percent increase this year. Sheryl Williams, a Cephalon spokeswoman, attributes the growth to more recognition among physicians that pain remains an undertreated, widespread problem.

Nevertheless, some of the robust growth is being driven by increased visits by the company's 450 sales representatives to noncancer specialists. The reps now pitch the product to pain specialists and even some primary-care doctors who treat pain. Ms. Williams says the company calls on noncancer specialists because many of them also treat cancer patients suffering from pain.

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