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FMS Community Website FMS Community Newsletter #84 Pain Relief
FMS Community Newsletter #84
Editors Corner

Fibromyalgia does not have the same affect on all of us. It may be that you have mild Fibro as your only illness. In cases such as these a change in diet, light exercise and help with your sleeping pattern may make you feel better. Others of you may have sever Fibro that does not respond to any of the text book solutions.
Other may have Fibromyalgia and Chronic Myofascial Pain Disease, (CMP). This would change your treatment and lifestyle.
Many others may be dealing with Fibro in conjunction with CMP, Diabetes, Arthritis, Degenerative Disc Disease, CFIDS, Gulf War Syndrome, Post Traumatic Syndrome, heart disease, COPD and any number of other conditions that make it impossible for you to follow the initial recommendations to help FM pain.
For those people who are dealing with mulitple health issues the standard recommendations for dealing with FM symptoms just won't work. There may come a time when you have to approach your doctor for help with pain relief.
You need to understand that relief of long term, chronic pain is not a privelage, it is a basic human right.
Ask for help, be informed and never let a care provider make you feel like a drug addict for asking for some relief if you have tried all other avenues to help yourself.
This issue will discuss some of the options for pain relief, though I am sure we will just touch the tip of the iceberg here. This is a long newsletter full of information and it will be only one of many to touch on new therapies and drugs that seek to help with chronic pain.

Contents

~Magnet Therapy: Does It Really Relieve Pain?

~ KADIAN Improves Fibromyalgia Pain

~Opioids for chronic noncancer pain:

~A Dose of Logic: Opioids for FMS Pain Fibromyalgia:

~Improvement in fibromyalgia symptoms with acupuncture:

~Therapy Insight: fibromyalgia-a different type of pain needing a different type
of treatment.


~ Short and long-term results of connective tissue manipulation and combined ultrasound therapy in patients with fibromyalgia.

~Sodium Oxybate May Reduce Fibromyalgia Pain

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

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

~Pharmacologic Management of Acute and Chronic Pain:


The FMS Community does not promote any one medication, therapy or alternative treatment listed in this publication. We seek only to help educate you on the many options available. We urge you to consult with your health care team before trying any new medication, supplement or therapy.


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Opioids for chronic noncancer pain:

The full text for this article is available at:
http://www.cmaj.ca/cgi/content/full/174/11/1589
CMAJ. 2006 May 23;174(11):1589-94.

Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E.
Comprehensive Pain Program, Toronto Western Hospital, Ont.

BACKGROUND: Chronic noncancer pain (CNCP) is a major health problem, for which opioids provide one treatment option. However, evidence is needed about side
effects, efficacy, and risk of misuse or addiction. METHODS: This meta-analysis was carried out with these objectives: to compare the efficacy of opioids for
CNCP with other drugs and placebo; to identify types of CNCP that respond better to opioids; and to determine the most common side effects of opioids. We
searched MEDLINE, EMBASE, CENTRAL (up to May 2005) and reference lists for randomized controlled trials of any opioid administered by oral or transdermal
routes or rectal suppositories for CNCP (defined as pain for longer than 6 mo).
Extracted outcomes included pain, function or side effects. Methodological quality was assessed with the Jadad instrument; analyses were conducted with
Revman 4.2.7.
RESULTS: Included were 41 randomized trials involving 6019 patients: 80% of the patients had nociceptive pain (osteoarthritis, rheumatoid arthritis or back pain); 12%, neuropathic pain (postherpetic neuralgia, diabetic
neuropathy or phantom limb pain); 7%, fibromyalgia; and 1%, mixed pain. The methodological quality of 87% of the studies was high. The opioids studied were
classified as weak (tramadol, propoxyphene, codeine) or strong (morphine, oxycodone). Average duration of treatment was 5 (range 1-16) weeks. Dropout
rates averaged 33% in the opioid groups and 38% in the placebo groups.
Opioids were more effective than placebo for both pain and functional outcomes in patients with nociceptive or neuropathic pain or fibromyalgia. Strong, but not
weak, opioids were significantly superior to naproxen and nortriptyline, and only for pain relief. Among the side effects of opioids, only constipation and
nausea were clinically and statistically significant. INTERPRETATION: Weak and strong opioids outperformed placebo for pain and function in all types of
CNCP. Other drugs produced better functional outcomes than opioids, whereas for pain relief they were outperformed only by strong opioids. Despite the relative
shortness of the trials, more than one-third of the participants abandoned treatment.
Publication Types: Meta-Analysis PMID: 16717269 [PubMed - indexed for MEDLINE]

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A Dose of Logic: Opioids for FMS Pain Fibromyalgia: the answer is blowin' in the wind.
White KP. Source: J Rheumatol 31(4):636-9, 2004.

Full article can be downloaded for free at:
http://www.jrheum.com/subscribers/04/04/636.html

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Improvement in fibromyalgia symptoms with acupuncture: results of a randomized controlled rial. Mayo Clin Proc. 2006 Jun;81(6):749-57.
Martin DP, Sletten CD, Williams BA, Berger IH.

Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA. martin.david@mayo.edu

OBJECTIVE: To test the hypothesis that acupuncture improves symptoms of fibromyalgia.

PATIENTS AND METHODS: We conducted a prospective, partially blinded, controlled, randomized clinical trial of patients receiving true acupuncture compared with a control group of patients who received simulated
acupuncture. All patients met American College of Rheumatology criteria for fibromyalgia and had tried conservative symptomatic treatments other than
acupuncture. We measured symptoms with the Fibromyalgia Impact Questionnaire (FIQ) and the Multidimensional Pain Inventory at baseline, immediately after treatment, and at 1 month and 7 months after treatment. The trial was conducted
from May 28, 2002, to August 18, 2003.

RESULTS: Fifty patients participated in the study: 25 in the acupuncture group and 25 in the control group. Total
fibromyalgia symptoms, as measured by the FIQ, were significantly improved in the acupuncture group ompared with the control group during the study period (P
= .01). The largest difference in mean FIQ total scores was observed at 1 month (42.2 vs 34.8 in the control and acupuncture groups, respectively; P = .007).
Fatigue and anxiety were the most significantly improved symptoms during the follow-up period. However, activity and physical function levels did not change. Acupuncture was well tolerated, with minimal adverse effects.

CONCLUSION: This study paradigm allows for controlled and blinded clinical trials of acupuncture.
We found that acupuncture significantly improved symptoms of fibromyalgia.
Symptomatic improvement was not restricted to pain relief and was most significant for fatigue and anxiety.

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Therapy Insight: fibromyalgia-a different type of pain needing a different type
of treatment.


Nat Clin Pract Rheumatol. 2006 Jul;2(7):364-372.
Dadabhoy D, Clauw DJ. D Dadabhoy is a Clinical Lecturer in Rheumatology at the University of Michigan,
MI, USA, where DJ Clauw is a Professor of Medicine, the Director of the Chronic Pain and Fatigue Research Center and the Center for the Advancement of Clinical
Research, and the Assistant Dean for Clinical and Translational Research.

In the past decade, we have made tremendous progress in our understanding of fibromyalgia, which is now recognized as one of many 'central' pain syndromes
that are common in the general population. Specific genes that might confer an increased risk of developing fibromyalgia syndrome are beginning to be identified and the environment (in this case exposure to stressors) might also have a significant effect on triggering the expression of symptoms. After developing the syndrome, the hallmark aberration noted in individuals with fibromyalgia is augmented central pain processing. Insights from research suggest that fibromyalgia and related syndromes require a multimodal management
program that is different from the standard used to treat peripheral pain (i.e. acute or inflammatory pain). Instead of the nonsteroidal anti-inflammatory drugs
and opioids commonly used in the treatment of peripheral pain, the recommended drugs for central pain conditions are neuroactive compounds that downregulate
sensory processing.

The most efficacious compounds that are currently
available include the tricyclic drugs and mixed reuptake inhibitors that simultaneously increase serotonin and norepinephrine concentrations in the central nervous
system. Other compounds that increase levels of single monoamines (serotonin, norepinephrine or dopamine), and anticonvulsants also show efficacy in this
condition.

In addition to these pharmacologic therapies, which are useful in improving symptoms, nonpharmacologic therapies such as exercise and cognitive behavioral therapy are useful treatments for restoring function to an
individual with fibromyalgia.

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Short and long-term results of connective tissue manipulation and combined ultrasound therapy in patients with fibromyalgia.

Citak-Karakaya I, Akbayrak T, Demirturk F, Ekici G, Bakar Y.J Manipulative Physiol Ther. 2006 Sep;29(7):524-8. Mugla University, Mugla School of Health Sciences, Mugla, Turkey. ilkim74@yahoo.com

OBJECTIVE: The aim of the study was to evaluate the short-term and 1-year follow-up results of connective tissue manipulation and combined ultrasound (US)
therapy (US and high-voltage pulsed galvanic stimulation) in terms of pain, complaint of nonrestorative sleep, and impact on the functional activities in patients with fibromyalgia (FM).

METHODS: This is an observational prospective
cohort study of 20 female patients with FM. Intensity of pain, complaint of nonrestorative sleep, and impact of FM on functional activities were evaluated by visual analogue scales. All evaluations were performed before and after 20 sessions of treatment, which included connective tissue manipulation of the back
daily, for a total of 20 sessions, and combined US therapy of the upper back region every other session. One-year follow-up evaluations were performed on
14 subjects. Friedman test was used to analyze time-dependent changes.

RESULTS: Statistical analyses revealed that pain intensity, impact of FM on functional activities, and complaints of nonrestorative sleep improved after the
treatment program (P < .05).

CONCLUSION: Methods used in this study seemed to be
helpful in improving pain intensity, complaints of nonrestorative sleep, and impact on functional activities in patients with FM.

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Sodium Oxybate May Reduce Fibromyalgia Pain

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.

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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."

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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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Pharmacologic Management of Acute and Chronic Pain: Focus on Drug Interactions and Patient-Specific harmacotherapeutic 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, -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 () activity with a
secondary spinal mechanism of monoamine reuptake inhibition. With its weak affinity for -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 receptors (1 and 2) produces euphoria and is associated with morphine-like analgesia, respiratory depression, miosis, and inhibited GI motility. The 2 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 -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 g/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 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 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 ( 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 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 -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.

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KADIAN Improves Fibromyalgia Pain

At the 25th Annual Scientific Meeting of the American Pain Society, two supplemental analyses were presented indicating that the drug Kadian improved pain scores and pain symptoms in arthritis and fibromyalgia (FM) patients. It is important to note that Kadian is an opioid and a Schedule II controlled substance.
In a press release, study investigator Bruce Nicholson, MD, Director, Pain Specialists of Greater Lehigh Valley, Inc. said, “Opioid use in this patient population may be considered after first-line treatment has failed and these data further support this conclusion.

Kadian demonstrated efficacy and safety in these patient groups.”
In the study involving FM patients, the patients taking Kadian reported a 24 percent improvement in pain scores and a 15 percent improvement in sleep scores. It was noted that the FM patients initially reported lower scores in their overall quality-of-life (QoL) scales than those with other types of non-malignant pain, but by week four both patient groups showed similar improvements in QoL. The most common side effects were constipation and nausea.

As with other oral opioid analgesics, there can be serious adverse reactions associated with Kadian including: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock.

There are two extremely serious warnings associated with Kadian:

Kadian capsules must be swallowed whole and are not to be chewed, dissolved or crushed.
Patients must not consume alcoholic beverages while on Kadian therapy.
Ignoring either of these warnings can lead to the release of a potentially fatal dose of morphine.

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Magnet Therapy: Does It Really Relieve Pain?
New research on magnet therapy for pain relief shows it may actually help.
The quest for effective treatment for chronic pain is one that has kept many medical researchers busy and keeps many of those suffering from it with empty wallets. One of the most popular therapies for pain to come along in the last few years is the treatment of pain with magnets.
Magnets have been touted as therapy for everything from low back pain to the next best cure for cancer. As of this time the FDA has approved no magnet therapy for any condition. The FDA actively monitors those marketing magnets to ensure that no company marketing magnets is making claims for cures that have not been proven. This is a huge task as the number of companies marketing these devices grows every day. As I was researching this feature a search for magnets on the search engine Google came up with thousands of different pages on the Internet.

These results show the intense interest people have in this therapy. This interest can also leave the door wide open for fraud and abuse of people who are desperate to find pain relief.
While many people have made claims that magnet therapy has helped to relief pain, these reports are for the most part anecdotal or unscientific reports. There has however been a lot of interest in magnets for pain therapy from the scientific community.

A study reported in the Journal of Alternative and Complementary Medicine studied the effect of magnet therapy on fibromyalgia pain. Although the results of the study were inconclusive, magnet therapy reduced fibromyalgia pain intensity enough in one group of study participants to be "clinically meaningful" the researchers said.

This study, conducted by researchers at the University of Virginia studied results from 94 patients who suffered from fibromyalgia who were randomly divided into 4 groups. Half of these patients were in 2 control groups, one that received fake magnets and the other that just followed their usual treatment routine. The other 2 groups received active magnetic pads; one which provided whole body exposure to a uniform magnetic field and the other group used a pad which exposed the subjects to a magnetic field that varied both spatially and in polarity. The study tracked results over a six month periods.

The two groups that slept on pads with active magnets generally showed improvement in outcome scores of pain intensity level, number of tender points on the body and functional status at the end of the six month period of the test. The subjects in the control group did not exhibit the same type of improvement in their symptoms.

Researchers expressed surprise that they saw positive results from the study virtually nothing known as to how magnets work to relieve pain. They do feel that in light of the results from this study that more research on magnet therapy for pain is justified.

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