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       Page Last Updated 02/02/2008

What Your Doctor May Not Tell You About Fibromyalgia : The Revolutionary Treatment That Can Reverse The Disease [ILLUSTRATED] (Paperback) by Claudia Craig Marek

The Complete Idiot's Guide to Fibromyalgia by Lynne Matallana, Laurence A. Bradley, M.D., Stuart Silverman, and M.D., Muhammad Yunus

We are not health care professionals.  We are FM/CMP survivors who strive to put forth lnformation for educational purposes.
As always, do not make any changes to your health care routine without consulting with your doctor.

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

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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New drugs may help prevent migraines 12/07/2002 Associated Press

Doctors say one of most frustrating illnesses to treat is a migraine. But thanks to new medicines, patients are finding relief. These newer drugs can even help prevent migraines. At 56, Miriam Escobar is studying for a business degree. "I graduated in Cuba just before I came to this country," said Escobar. "But due to the government, I never could get my degree out." What also slowed her down: excruciating migraines.

"Sometimes they were so severe that I ended up in the hospital," said Escobar.

"They'll be left without a job, because of their headaches," said Priscilla Potter, MD, Ph.D., clinical neurologist. "It can be that debilitating for them."

Miriam finally got relief with the help of Dr. Potter.

"I have patients who will doctor shop for medicines," said Dr. Potter. "I have patients who will hoard medicine."   Previous drugs worked to treat the migraine at the time of the attack.

"Probably in the last five years or so, we started focusing more and more on prevention," said Dr. Potter.

The newer preventive medications, such as topomax, depakote, keppra, zonegran are a different class of drugs.

"As we developed more and more anti-epileptic medicines, we noticed the patients that had epilepsy and also had headaches, that their headaches got better," said Dr. Potter.

"Now I can say it's been two months without a migraine," said Escobar.

Now Escobar is focused on business instead of on migraines.

Patients who are on the preventive medications say they experience migraines once every few months, instead of every few days.

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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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FDA Approves New Medication for Pain Relief- Ultracet 10-04-2001

The U.S. Food and Drug Administration has approved Ultracet (TM), a new centrally acting prescription pain medication. Ultracet, comprised of 37.5 mg tramadol hydrochloride and 325 mg acetaminophen tablets, reportedly provides long-lasting pain relief and flexible dosing. Ortho-McNeil Pharmaceutical, Inc. will market the product in the United States.

Ultracet combines Ultram (tramadol hydrochloride), a leading prescription pain reliever, with acetaminophen, the most commonly recommended nonprescription pain treatment. Clinical trials demonstrated that the combination offers better pain relief over either medication alone. In the trials, Ultracet consistently began working faster than tramadol alone, and pain relief with Ultracet lasted significantly longer than with acetaminophen alone. Ultracet is indicated for the short-term (five days or less) management of acute pain.

"Pain is one of the most prevalent medical symptoms in the United States,"
said Warren A. Katz, MD, chief of Rheumatology at Presbyterian Medical Center/University of Pennsylvania Healthcare System in Philadelphia.
"Millions of people suffer from acute pain without relief, in part because their medications don't work or have side-effects that interfere with treatment. With Ultracet we have a product that offers effective relief and a positive side-effect profile."

Ultracet is a centrally acting analgesic that controls pain via different mechanisms of action than non-steroidal anti-inflammatory drugs (NSAIDs), the most commonly used pain medications. Ultracet is not an NSAID, and is not associated with potentially life-threatening gastrointestinal ulcers or bleeding that can occur with NSAIDs and the newer Cox-2 NSAIDs. In addition, Ultracet does not compromise the efficacy of certain antihypertensive agents, like NSAIDs and Cox-2 NSAIDs. Ultracet can also be prescribed in sulfa-sensitive patients. The most frequently reported side effects with Ultracet were constipation, somnolence (sleepiness) and increased sweating.

Ultracet should not be used concomitantly with alcohol. The use of Ultracet in patients with liver disease is not recommended. In addition, acetaminophen may cause liver damage.

Cases of abuse and dependence on tramadol have been reported. Tramadol should not be used in opioid-dependent patients. Since tramadol can reinitiate physical dependence, Ultracet is not recommended for patients with a tendency to drug or alcohol abuse, a history of drug or alcohol dependence or a history of chronic opioid use. Patients with a history of severe, life-threatening allergic (anaphylactoid) reactions to codeine and other opioids may be at increased risk and therefore should not receive Ultracet.

Please see the full prescribing information for more information on Warnings, Precautions and additional Adverse Reactions that may occur, regardless of drug relationship.

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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 ha