 January-February 2008; Issue 13
This edition of News/Research Updates was researched/compiled by Winnie Dawson, MA, RN, BSN [WD], and edited by Stewart B. Leavitt, MA, PhD [SBL]. Medical reviewers were: James D. Toombs, MD; Lee A. Kral, PharmD, BCPS; Paul W. Lofholm, PharmD, FACA; Seth I. Kaufman, MD. Posting Date: February 19, 2008.
Where noted, product brand names are for informational purposes only and are registered trademarks of their respective manufacturers. In some cases, additional brands may be available for specific products.
 Access to all external URL links was checked prior to posting; however, some may change or become obsolete over time and will no longer function. This is beyond our control.
Pain in the ER: Opioids Prescribed Less to Minority Patients
A study funded by the US Department of Health and Human Services, published in the January issue of JAMA, evaluated ethnic differences in opioid prescribing in emergency room (ER) visits. Investigators reviewed more than 370,000 patient records from the 500 US hospitals that participated in a national heath care survey during a 13 year period (1993 - 2005). Of the total visits, more than 150,000 were pain-related. Some key findings related to the use of opioid pain-relievers include:
- 31% of Caucasians with pain received opioids.
- 28% of Asians received an opioid pain-reliever.
- 24% of Hispanics in pain received opioids.
- 23% of Blacks received opioids for pain.
- Minority patients in severe pain, or with the pain of kidney stones or leg fractures, received fewer opioids.
- Blacks were prescribed opioids at lower rates than other ethnic groups for almost all types of pain-related visits, including: back pain, headache, and abdominal pain.
- Non-opioid pain medications, like acetaminophen or aspirin, were prescribed more for non-whites (36%) than for whites (26%).
Clinical Implications: In light of initiatives implemented in the past decade aimed at improving pain management, this study analyzed opioid prescribing trends by race. Overall, opioid prescribing for pain-relief increased from 23% in 1993 to 37% in 2005; however, in a related news story (Associated Press), Mark Pletcher, MD, observed, “The gaps [in opioid administration] between whites and nonwhites did not appear to close at all.” He added that patient behavior may influence prescribing and wondered if minority patients are less likely to complain about pain or to feel that they deserve good pain control.
Reference: Pletcher MJ, Kertesz SG, Kohn MA, Gonzales R. Trends in opioid prescribing by race/ethnicity for patients seeking care in US emergency departments. JAMA. 2008(Jan 2);299(1):70-78.
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New Survey Finds Lots of Pain, Much of it Untreated
The National Pain Foundation (NPF) sponsored a Pain Survey of almost 1500 American adults in December 2007. Results revealed that most of those persons experienced acute or chronic pain during the past 12 months:
- 72% of adults surveyed experienced some pain.
- 42% of adults were experiencing pain on the day of the survey.
- 27% had acute pain at some time during the previous 12 months.
- In those reporting pain, it disrupted everyday activities last year in a variety of ways:
-- 65% - recreational activities
-- 59% - doing household chores
-- 48% - reported lower productivity at work
-- 46% - leaving the house to run errands
-- 41% - taking care of themselves or family members
-- 22% - missed at least one day or work due to pain.
Despite the prevalence of pain, more than half of the respondents were reluctant to consult a healthcare professional or take prescription analgesics. Additional survey findings may offer some clues as to the high levels of unrelieved pain:
- 40% of those who did not seek healthcare reported that they would “tough it out.”
- 93% of respondents agreed with the statement “people take too many pills.”
- 86% of survey participants reported that they believe aches and pains are a normal part of aging.
- 26% of respondents were unaware that untreated acute pain could lead to chronic pain.
Practice Pointers: Results of this survey indicate that many people do not know how to treat their pain effectively or embrace attitudes that prevent them from seeking effective pain relief. The NPF believes that it would be helpful for patients to learn more about additional therapies for pain relief, like the transdermal patch or physical therapy, potentially offering some advantages in user acceptability. Healthcare providers can use the survey results to initiate conversations with patients who experience frequent unrelieved pain.
 Source: My Pain Survey. National Pain Foundation; 2007(Dec); Available at: http://www.nationalpainfoundation.org/MyResearch/PainSurvey2008.asp (access checked 2/8/08).
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Long-Term Opioids in Chronic Noncancer Pain Reviewed
In an effort to identify evidence for the efficacy and safety of long-term opioid therapy in chronic noncancer pain (CNCP), authors of this systematic review and meta-analysis evaluated 115 clinical trials of opioid therapy extracted from 11 databases (through April 2007). The researchers -- at ECRI Institute (a nonprofit organization dedicated to applied sciences research) -- then analyzed the 17 studies that included patients with moderate-to-severe chronic noncancer pain who were treated with opioid analgesics for a minimum of 6 months.
In patients treated with oral or intrathecal opioids for 6 months or >6 months, the mean reductions in pain scores were about 63% and 38%, respectively. It is notable, however, that almost one third of patients had withdrawn from the studies due to adverse events associated with oral opioid use, while the intrathecal-opioid administration dropout rate was just over 6%. Insufficient pain relief was the reason for study withdrawal in about 12% taking oral opioids and about 11% of those with intrathecal administration. Three studies of transdermal opioid administration were assessed but results were inconclusive. Also noteworthy, opioid abuse was reported in only 3 of 685 patients assessed for this problem, and signs of opioid addiction were evident in only 1 case out of 2042 participants assessed.
[Commentary: Systematic reviews and data meta-analyses such as this can be invaluable aids for clinical decision making. This present investigation, however, is more a case study in the poor quality of research in the pain field and a serious lack of knowledge regarding the value of long-term opioid therapy for CNCP. The authors conceded that ALL of the studies in the review were of low quality due to methodological and/or reporting deficiencies. There were NO randomized placebo-controlled trials (RCTs) available for analysis and only one long-term controlled trial, which compared 2 opioids rather than opioid versus non-opioid therapy.
Therefore, the most basic question -- “Are opioids more helpful than non-opioid approaches for the long-term relief of CNCP?” -- could not be addressed, despite the various and highly complex statistical manipulations used in this meta-analysis. Still, the analyses did show that opioids were indeed effective for the relief of CNCP in those patients who did not experience or who tolerated treatment-related side effects, but we are not informed by this research of the characteristics of those patients, their pain conditions, or their particular opioid therapies.
Only a small proportion of the studies selected as qualifying for review included assessments of opioid abuse or addiction. Those that did used very inclusive definitions and still found an addiction rate of only 0.042% and a 0.43% incidence of opioid abuse. This is in stark contrast to the much higher rates of abuse and addiction reported recently by Fleming et al. (2007) who used more rigid criteria for problem definition. Therefore, the issue of opioid abuse and addiction during long-term therapy for CNCP is still an open question worthy of ongoing investigation and debate.
Unfortunately, the unstated clinical conclusion expressed by this systematic review is that no definitive conclusions are available from the research regarding this subject. At the same time, there is no opposing evidence to suggest that opioids would not be helpful for at least some patients with CNCP, if the analgesics are appropriately and properly prescribed and patients are monitored for the emergence of adverse effects. – SBL]
References:
Noble M, Tregear SJ, Treadwell JR, et al. Long-term opioid therapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manage. 2008(Feb);35(2):214-228.
Fleming MF, Balousek SL, Klessig CL, et al. Substance use disorders in a primary care sample receiving daily opioid therapy. The Journal of Pain. 2007;8(7):573-582.
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Strength Training of Neck Muscles Relieves Chronic Pain
The incidence of neck pain in people who engage in repetitive tasks, like computer-based work, has been steadily increasing in the past 2 decades. Study results have conflicted regarding the benefits of exercise on the common symptoms of trapezius myalgia; namely, localized neck muscle pain, tenderness at palpation, stiffness, and constant muscle fatigue. For a controlled-trial in Denmark, investigators recruited 94 women with computer-intensive jobs from 7 workplaces to compare 10 weeks of general exercise versus neck-specific exercise for pain reduction. Participants were randomized to one of 3 groups: 1) supervised specific strength training (SST) exercises for neck and shoulder muscles, 2) high-intensity general fitness training (GFT) on a bicycle ergometer, or 3) health counseling without physical training group (control).
While the GFT group showed a minor decrease in neck muscle pain only immediately after exercising, the SST group showed a significant decrease in pain that lasted throughout the training period and after study completion. The average 10-week pain reduction from baseline (on a 100 mm visual analog scale) for the SST group was 20 mm for general pain and 35 mm for worst pain, compared with only 2 mm and 5 mm, respectively, for the GFT participants.
Clinical Concept: The authors concluded that local muscle training (designed to include the trapezius muscle) performed over time in the SST group was necessary to significantly decrease neck pain for prolonged change. Specifically, trapezius muscle pain gradually decreased as muscle strength increased in the SST group. Based on their study results, the authors recommend “supervised high-intensity dynamic strength training of the painful muscle 3 times each week for 20 minutes.” [Physical therapy professionals are available is most US communities and could easily create a brief, customized exercise routine for patients who receive a physician referral for neck pain. – WD].
References: Andersen LL, Kjaer M, Sogaard K, et al. Effect of two contrasting types of physical exercise on chronic neck muscle pain. Arthritis Care & Research. 2008(Jan);59(1):84-91.
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Therapeutic Methadone Doses & Cardiac-Related Death
Methadone, a drug commonly used as a maintenance treatment for opioid dependence, is also very effective in treating pain. Investigators at the Oregon Health and Science University, Portland, Oregon, prospectively examined records of all persons who experienced sudden cardiac death and underwent autopsy during a 4-year period in the city of Portland.
A total of 22 sudden cardiac-death cases had therapeutic levels of methadone compared with 106 sudden cardiac-death cases without evidence of methadone. Cardiac abnormalities potentially contributing to death were identified in 60% of patients without a history of methadone treatment and in 23% of patients receiving methadone. Twelve patients were taking methadone for pain control, 3 for opioid withdrawal, 3 for recreational use, and for unknown reasons in the remaining 4 persons.
Practice Perspective: The researchers assert that, due to the differences in detected cardiac pathology, the findings suggest that methadone itself played the dominant role in causing the sudden cardiac deaths in decedents who had therapeutic blood levels of methadone. This was possibly due to respiratory depression and/or methadone-related arrhythmias, as they note had been previously reported in the literature. They further propose that additional safeguards might be justified with methadone, such as pretreatment ECGs.
[Clinical Comment: Methadone already carries an FDA ‘black box’ warning about the arrhythmogenic potential of this drug (FDA 2007); however, prior evidence for this effect is equivocal and based strongly on anecdotal cases (see Leavitt 2007). ECGs for all patients prescribed methadone have not been recommended. In this present study, Chugh et al. do not indicate how a diagnosis of cardiac-related death was determined in the absence of cardiac pathology at autopsy. The apparent hypothesis -- if cardiac pathology was absent but methadone was present, then methadone must have been the cause -- was presumptuous. There are many factors that can play a role in such cases to influence fatalities, with methadone presence being only one of many variables. As with much of the prior research on the putative cardiac effects of methadone, this study did not seek to fully explore and explain the impact or predominance of all potentially interacting factors. – SBL]
References:
Chugh SS, Socoteanu C, Reinier K, et al. A community-based evaluation of sudden death associated with therapeutic levels of methadone. Am J Med. 2008(Jan);121(1):66-71.
FDA Public Health Advisory. Methadone use for pain control may result in death and life-threatening changes in breathing and heart beat. 2007(updated, July). Available at: http://www.fda.gov/cder/drug/advisory/methadone.htm.
Leavitt SB. FDA Advisory Raises Concerns About Methadone. Addiction Treatment Forum. 2007;16(1). Available at: http://www.atforum.com/SiteRoot/pages/current_pastissues/2007winter.html#clinicalconcepts.
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Psychotropic Drugs & False-Positive Methadone Screens
In response to a question about false-positive toxicology-screen results for methadone in patients taking quetiapine (Seroquel®), Medscape pharmacist Joel Lamoure, RPh, confirms that methadone-positive urine drug-screen results have been received by some patients who are taking another psychotropic drug but not methadone. In cases where there is a question of test accuracy, he suggests using gas chromatography/mass spectrometry (GC/MS) or another more specific and sensitive test.
Clinical Implications: In his article, Lamoure discusses how urine screens work and can produce false-positive results. Because concurrent mental illness, substance abuse, and/or pain are not uncommon, it can be important to verify the results of a questionable drug-screen result for methadone in any patient who also is taking psychiatric medications. Additionally, in cases where opioid analgesia is indicated for pain, or where a patient is unresponsive or unconscious, a false-positive result for methadone may lead to delays in appropriate treatment.
Lamoure J. Ask the Experts About Pharmacotherapy: Does Quetiapine Produce False-Positive Methadone Tests? Reported in Medscape Ob/Gyn & Women’s Health. January 15, 2008. Available at: http://www.medscape.com/viewarticle/568245?src=mp (access checked 2/8/08).
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Constipation a Common Cause of Pediatric Abdominal Pain
A retrospective study from researchers at the University of Iowa evaluated causes of acute abdominal pain in children aged 4 to 18. The charts of 962 children seen for one or more healthcare visits during a 6-month period were reviewed for complaints of acute abdominal pain.
Of the 83 children reporting abdominal pain during a clinic appointment or emergency visit, nearly half (48%) were diagnosed with acute (8 weeks or less) or chronic constipation (2 months or more). Acute abdominal pain due to colic, infection, or various other causes represented 7%, 15%, and 8%, respectively. A surgical condition, such as appendicitis or hernia, was the cause of abdominal pain in only 2% of the children, while the cause remained undetermined in 19% of the patients with pain. Girls were seen significantly more often than boys for abdominal pain.
Clinical Implications: Parents frequently do not have full knowledge of a child’s symptoms of constipation. In a related news story (ScienceDaily) Vera Loening-Baucke, MD, stated, “constipation can be overlooked as the cause of severe or intermittent abdominal pain” and, further suggests that healthcare providers “should perform an abdominal examination and a rectal examination.” While a rectal exam can be potentially upsetting to a child, the practitioner can reduce the child’s discomfort by explaining its purpose.
Reference: Loening-Baucke V, Swidsinski A. Constipation as cause of acute abdominal pain in children. J Pediatr. 2007(Dec);151(6):666-669.
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Massage Therapy Reduces Postoperative Pain
Post-surgical pain affects patient recovery, including undesired restriction of postoperative coughing and ambulation, as well as self-care functionality. Researchers at a Michigan Veterans Administration Health Center studied the pain-reducing effects of massage therapy in patients who had major surgery during a 2-year period. Patients (n=605) were randomized to one of the following 3 groups: 1) routine care (control), 2) individual attention (20 minutes of attention from a massage therapist without actual massage), or 3) massage (a 20-minute evening back massage).
The primary short-term outcomes of pain intensity, pain unpleasantness, and anxiety were measured by visual analog scales. Compared with the control group, patients in the massage group reported significant reductions in pain intensity (p = 0.001), pain unpleasantness (p < 0.001), and anxiety (p = 0.007) during the first 4 post-surgical days. Patients in the massage group reported a high level of satisfaction with the therapy (mean 8.3 on a 10-point scale). The 3 groups were similar in rates of decrease in long-term anxiety, length of stay, opioid use, and postsurgical complications.
Practice Pointers: One limitation of this study was the patient population, which was primarily male (median age, 64 years). Also, the study was limited to a short time frame and researchers could not examine the effects of longer or more frequent massages. However, the investigators concluded that the results of this study suggest that it is feasible for healthcare professionals, with proper training, to provide this nonpharmacological therapy at the bedside.
[Comment: Massage therapists, also called bodyworkers, employ a variety of techniques and methods to provide therapy. Effleurage massage (Swedish-style stroking motions using the pressure of the palm of the hand) was used in this study and the researchers stated that the technique is simple enough to teach any caregiver. However, training is necessary to avoid the use of stroking motions that can cause discomfort. Patients seeking massage services on their own should be cautioned to choose a therapist who is certified by the National Certification Board for Therapeutic Massage and Bodywork ( http://www.ncbtmb.com ) or maintains membership in the American Academy of Massage Therapists ( http://www.amtamassage.org ) which lists individual credentials and the techniques practiced for each therapist. – WD]
Reference: Mitchinson AR, Kim HM, Rosenberg JM, et al. Acute postoperative pain management using massage as an adjuvant therapy: a randomized trial. Arch Surg. 2007(Dec);142(12):1158-1167.
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Patients on Multiple NSAIDs May Have Poorer Quality of Life
Patients (n=138) from a large managed care organization who were taking at least one prescription nonsteroidal antiinflammatory drug (NSAID) were surveyed by telephone regarding their overall use of NSAIDs and their physical and mental health status. Dual NSAID use was defined as taking 2 NSAIDs (prescription and/or over-the-counter) at least twice per week during the previous month. Results showed that 26% of participants reported simultaneously taking at least 2 NSAIDs (prescription, OTC, or both) during the month prior to the survey, and these patients reported lower scores in health-related quality of life than participants who reported taking only a single NSAID medication.
Practice Pointers: The authors conclude that practitioners should inquire about NSAID use by all patients. Keeping a record of the medications each patient is taking could lead to better communication between the patient and the provider. Without adequate communication, it is difficult to know if a decision to take multiple NSAIDs is due to inadequate pain management or increasing levels of pain. Additionally, patients should be educated about the implications of taking 2 drugs that may be in the same therapeutic class and the potential for an increased risk of side effects.
Reference: Kovac SH, Saag KG, Curtis JR, et al. Association of health-related quality of life with dual use of prescription and over-the-counter nonsteroidal antiinflammatory drugs. Arthritis Rheum. 2008(Jan 31);59(2):227-233.
Also see important recent warnings on the risks of NSAID therapy in the Non-Opioid section of Pain-Topics.org at:
http://pain-topics.org/non_opioid_therapies/nsaids.php#NSAIDs (access checked 2/12/2008).
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Chronic Pain Can Disrupt Brain Function
Research has shown that patients with chronic pain often have additional symptoms -- depression, anxiety, disturbed sleep, and impaired decision-making -- that reduce their overall quality of life. Investigators at Northwestern University in Chicago scanned brain activity using function MRI (fMRI) while a group of patients with chronic back pain and a healthy control group each performed a simple visual attention task.
While both groups performed similarly on the task, brain activity of people in the control group demonstrated equilibrium state called the “default mode network” of the brain (that is, some areas were activated during the task while others were deactivated in balance). However, in the brains of patients with chronic pain there was less deactivation in several key regions of the brain, and the researchers explained that this imbalance and the constant firing of neurons in highly active areas of the brain can cause permanent damage over time, including altered connections among neurons or even the death of affected neurons.
Clinical Concept: In a related news story (ScienceDaily), Dante Chialvo, MD, hypothesized that changes in brain wiring due to a state of continual activity in certain components of the “default mode network” may make it harder for affected persons to make decisions, and can produce depression or mood changes. He adds that “pain could produce abnormalities because it disturbs the balance of the brain as a whole” in patients with chronic pain. This concept emphasizes the need to continue finding effective methods of treating pain as early as possible.
Reference: Baliki MN, Geha PY, Apkarian AV, Chialvo DR. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci. 2008(Feb 6);28(6):1398-1403.
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Depression-Associated Pain Improved With Duloxetine
Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), is commonly used to treat depression, generalized anxiety disorder, and pain caused by diabetic neuropathy. Researchers in Germany evaluated the effectiveness of duloxetine in the treatment of pain in 327 adults (18 years or older) with depression and moderate-to-severe pain.
Participants in the double-blind, 8-week study were randomly assigned to either duloxetine 60 mg once daily or placebo. The primary outcome measure was the change in average pain during the last 24 hours; secondary measures were scores on depression and symptoms checklists. Duloxetine effects were significantly positive as early as week one and, compared with placebo, duloxetine significantly reduced pain and improved depression at 8 weeks. The most common adverse events of nausea, excessive perspiration, and dry mouth were reported more frequently in duloxetine patients than in those receiving placebo.
Clinical Context: Pain accompanied by depression can be difficult to treat and frequently receives inadequate attention. In this analysis, duloxetine demonstrated an early therapeutic response and researchers concluded that the study results support the effectiveness and tolerability of duloxetine in the treatment of both pain and depression in patients with moderate-to-severe pain.
Reference: Brecht S, Courtecuisse C, Debieuvre C, et al. Efficacy and safety of duloxetine 60mg once daily in the treatment of pain in patients with major depressive disorder and at least moderate pain of unknown etiology: a randomized controlled trial. J Clin Psychiatry. 2007(Nov);68(11):1707-1716.
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Sickle Cell Pain Higher Than Previously Estimated
The pain of sickle cell disease -- an inherited red blood cell abnormality in which sickle-shaped hemoglobin cells tend to clot and block blood flow in limbs and organs -- can be severe and occur suddenly. Researchers in Virginia evaluated the relationship of pain, crises, and healthcare use in patients with sickle cell disease. A total of 232 patients with sickle cell disease (age 16 and older) who received care at community-based or academic healthcare practices were followed for 6 months. Each patient kept a daily diary to report the score of their worst sickle cell-related pain in the past 24 hours (0-9 scale), whether this became a crisis day, and the use of healthcare services on any crisis day.
Results showed that nearly one third of patients reported pain on almost 95% of their diary days while only 14% of patients noted pain on 5% (or less) of their reporting days. Additional data showed that, although patients reported sickle cell crises on 13% of diary days, they used healthcare services on less than 4% of diary days. The intensity of pain was significantly higher on healthcare utilization days (p < 0.001) and the average pain intensity increased as the percentage of pain days increased (p < 0.001).
Practice Perspective: In a related news story (ScienceDaily), Wally Smith, MD, stated that “the study’s major finding is that sickle cell pain can be a daily phenomenon and patients are struggling with pain at home rather than coming into the hospital or emergency department.” The researchers conclude that the pain of sickle cell disease is far more prevalent than has been reflected in previous studies, which assumed that the number of visits for medical care represented the true incidence of acute pain episodes.
Reference: Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008(Jan 15);148(2):94-101.
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Experiment Explores Opioid Tolerance
Existing literature on the treatment of chronic pain has raised concerns that some patients taking opioids analgesics develop a tolerance over time, requiring increased dosages to achieve the same pain relief. Researchers in Germany designed an experimental study to examine the effects of prolonged morphine treatment on rats with and without paw inflammation.
Results of several comparative experiments showed that persistent painful inflammation prevented the development of tolerance at peripheral opioid receptors in the rats with inflamed paws. The researchers concluded that the release of endogenous opioid peptides (eg, endorphins, endomorphins, etc.) from inflammatory cells aid the ability of external opioid drugs to stimulate opioid receptors, which allows better morphine binding and, thereby, reduces the development of morphine tolerance.
[Comment: Pain-Topics.org does not usually summarize experimental or animal studies but felt that the observations from this study might have interesting and useful clinical implications. While there is no certainty that the outcomes demonstrated in rats would be identical in human subjects, the results suggest that localized inflammation can have its benefits. It may help to explain why some patients with chronic pain conditions involving inflammation and taking long-term opioid agonists may not develop an increasing need for higher doses of the analgesics (tolerance). – SBL, WD]
Reference: Zollner C, Mousa SA, Fischer O, et al. Chronic morphine use does not induce peripheral resistance in a rat model of inflammatory pain. J Clin Invest. 2008. Early online publication prior to print — doi:10.1172/JC125911.
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Recent Drug or Device Approvals and Announcements
Following are briefs on new pain-management drug or device approvals or announcements, as well as items related to safety concerns for existing products. If the FDA or DEA news website posted a specific announcement, the link to it has been provided below. All brand names are registered trademarks of their respective manufacturers.
 Additionally, the FDA Center for Drug Evaluation and Research website offers the option to search on any approved drug name or active ingredient at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm, and safety information is posted by FDA’s MedWatch at http://www.fda.gov/medwatch/safety/2006/safety06.htm.
Natalizumab (Tysabri®) – Approved for Moderate-to-Severe Crohn’s Disease
The FDA has approved Tysabri (natalizumab), previously approved for the treatment of relapsing forms of multiple sclerosis, for the treatment of moderate-to-severe Crohn’s disease in patients who have failed to respond, or cannot tolerate, conventional therapies. Crohn’s disease is an inflammatory bowel disease that can cause chronic abdominal pain, cramping, diarrhea, fever, rectal bleeding, and other more debilitating symptoms. Patients with Crohn’s disease must be enrolled in a special distribution program called the Crohn’s Disease-Tysabri Outreach Unified Commitment to Health (CD TOUCH) Prescribing Program before using the drug. They must also participate in an educational program that informs them of the potential risks of treatment and receive an evaluation for treatment efficacy 3 months after initial administration and for the term of treatment. It is important to alert patients to the fact that Tysabri® increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that can lead to severe disability or death.
Access the FDA news release at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html (access checked 2/1/08).
 The Tysabri package insert can be downloaded at: http://www.fda.gov/cder/foi/label/2006/125104s015lbl.pdf (access checked 2/1/08).
Bisphosphonates Could be Responsible for Severe Musculoskeletal Pain
The FDA published a follow-up alert in a January 2008 reminder to healthcare professionals that discontinuation of therapy should be considered in patients taking bisphosphonates who present with unexplained musculoskeletal pain. Seven FDA-approved bisphosphonates are currently being marketed: alendronate (Fosamax®, Fosamax Plus D™), etidronate (Didronel®), ibandronate (Boniva®), pamidronate (Aredia®), risedronate (Actonel®, Actonel W/Calcium), tiludronate (Skelid®), and zoledronic acid (Reclast®, Zometa®). The occurrence of pain varies and can begin within days, months, or years of bisphosphonate administration; resolution of symptoms also varies and can be slow or incomplete in some patients.
Access the FDA Alert at: http://www.fda.gov/cder/drug/infopage/bisphosphonates/default.htm (access checked 2/1/08).
Diclofenac Epolamine (Flector® Topical Patch) Becomes Available
The Flector® Patch (diclofenac epolamine topical patch) 1.3%, a non-steroidal anti-inflammatory (NSAID) prescription pain relief patch, was made available by maker Alpharma in January 2008. The Flector Patch was FDA-approved a year ago and is designed to provide local analgesia directly at the site of pain, resulting in minimal systemic absorption of diclofenac. Each adhesive patch contains 180 mg of diclofenac epolamine and measures approximately 4 inches by 5.5 inches. Even though the systemic effect of diclofenac is minor, patients should be informed of the potential adverse effects of NSAIDs (cardiovascular effects, gastrointestinal symptoms) as well as dermal side effects (hypersensitivity, exfoliative dermatitis). This product should not be prescribed for patients with aspirin-sensitive asthma or during late pregnancy.
For more information, download the FDA product information at: http://www.fda.gov/cder/foi/label/2007/021234lbl.pdf (access checked 2/1/08).
Fentanyl 25 mcg/hr (Duragesic®) Patches Recalled
PriCara has voluntarily recalled all lots of 25 mcg/hr Duragesic (fentanyl transdermal system) patches sold by PriCara in the United States. The company has also voluntarily recalled from wholesalers and pharmacies all 25 mcg/hr fentanyl patches sold by Sandoz Inc. in the United States as a precaution. The recalled patches all have expiration dates on or before December 2009, and all are manufactured by Alza Corporation, an affiliate of PriCara. The recall is being conducted in cooperation with the U.S. Food and Drug Administration. All 25 mcg/hr fentanyl patches manufactured by Alza and sold in Canada also are being recalled.
The Duragesic website has a Question and Answer section for more information about the recall at: http://www.duragesic.com/duragesic/recall_qa.html (access checked 2/13/08).
Note: Other recalls of fentanyl transdermal patch products are being announced. See the FDA website for the latest information.
Fentanyl Transdermal Patch – FDA Issues Second Public Health Advisory
Reports of a small number of deaths and life-threatening adverse events in patients who may be misusing the fentanyl transdermal patch (Duragesic® and generic products) has prompted the FDA to remind healthcare professionals of the importance of educating patients in its proper use. In spite of the positive response to the July 2005 alert, an FDA spokesperson stated that “a small number of cases are still very concerning because they are preventable.” Patients with persistent pain should be instructed to use the patch precisely as prescribed. In addition, the fentanyl transdermal patch should only be prescribed for patients (age 2 or older) who are already receiving opioid therapy, have demonstrated opioid tolerance, and who require a total daily dose equivalent to 25 mcg/hour or more. Certain medications can interact with fentanyl resulting in dangerously high blood levels; additionally, patients should avoid using heating pads, electric blankets, heated waterbeds, and saunas while wearing the patch because heat may increase fentanyl levels in the blood.
Access the FDA notice at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01762.html (access checked 2/1/08).
Antiepileptic Drugs - FDA Analysis Discovers Increased Risk of Suicide
An FDA evaluation of 199 placebo-controlled clinical studies of 11 drugs used to treat epilepsy and other health conditions showed that patients receiving the examined drugs had almost twice the risk of suicidal behavior or suicidal ideation when compared with patients who received placebo. Three of the antiepileptic drugs in question are commonly used adjunctively in the management of neuropathic pain: Gabapentin (Neurontin®), Pregabalin (Lyrica®), and Carbamazepine (Tegretol®). However, it is important to note that the suicide risks were higher in patients taking the drugs for epilepsy than in those taking an antiepileptic drug for pain or another condition. Healthcare professionals should evaluate the relative risk of suicidality against the therapeutic need for the drug, as well as provide education to patients and family members on the potential increased risk of suicide and the need to be alert for unusual behavior.
For a complete list of the antiepileptic drugs evaluated and the FDA Alert, see: http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm (access checked 2/6/08).
FDA Acts Against Unapproved Injectable Drugs Containing Colchicine
In February 2008 the FDA announced a plan to enforce the marketing of unapproved injectable colchicine, a drug used to treat the pain and symptoms of gout. Fifty reported adverse events -- of which 23 were fatal -- have included low blood cell counts, cardiac events, and organ failure. The highly toxic drug can be difficult to administer precisely and there is a narrow margin between effectiveness and toxicity. Companies producing unapproved injectable colchicine must stop production within 30 days and stop shipping within 180 days. Colchicine dispensed in tablet form is not affected by this action.
Access the full FDA notice at: http://www.fda.gov:80/bbs/topics/NEWS/2008/NEW01791.html (access checked 2/8/08).
Varenicline (Chantix®) – FDA Warning of Potential for Behavior Change
Varenicline is a prescription aid for smoking cessation that has recently been shown to cause neuropsychiatric symptoms in some users during treatment or following the withdrawal of therapy. Due to the fact that smoking appears to play a role in chronic pain and impair healing, especially in patients with substance misuse problems, practitioners frequently counsel patients with pain to stop smoking. Before prescribing varenicline, healthcare professionals should ask candidates if they have any history of psychiatric illness. In addition, patients using varenicline therapy should be monitored for changes in mood or behavior, including symptoms of anxiety, tension, depression, unusual behaviors, or suicidal ideation.
Access the full FDA Public Health Advisory at: http://www.fda.gov/cder/drug/advisory/varenicline.htm (access checked 2/8/08).
Botulinum Toxin Type A and Type B – FDA Early Warning of Serious Adverse Effects
The FDA has released an early warning following reports of systemic and fatal adverse effects with the use of Botox (Botulinum toxin type A) and Myobloc (Botulinum type B) in both FDA-approved and unapproved uses. Serious systemic adverse reactions in children and adults -- respiratory compromise, dysphagia, numbness in lower extremities, and death -- occurred following treatment using a varied range of doses for different health conditions. Recent studies have reported on the use of botulinum toxins (type A and/or type B) in the treatment of a variety of pain-related conditions—including headache, cervical myofascial pain syndrome, chronic low back pain, and pelvic-floor spasm. The most commonly reported use of botulinum toxin in the FDA-reported cases was the treatment of limb-muscle spasticity associated with cerebral palsy, which is not an FDA-approved use in the United States. The FDA notice (linked below) provides a list of cautions for healthcare professionals related to the use of botulinum toxin. The FDA emphasizes that it is in the process of reviewing cases reported to the Adverse Event Reporting System and has not formed any final conclusions. Healthcare providers and the public are encouraged to report any adverse events to the FDA’s MedWatch reporting system at http://www.fda.gov/medwatch/report/hcp.htm or by phone to 1-800-FDA-1088.
Access the complete FDA notice at: http://www.fda.gov/cder/drug/early_comm/botulinium_toxins.htm (access checked 2/11/08).
Also see summaries of botulinum toxin studies reported in previous Pain-Topics.org News/Research Updates;
May-June 2006 at: http://pain-topics.org/news_research_updates/index3.php#botulinum and
Nov-Dec 2006 at: http://pain-topics.org/news_research_updates/issue6.php#botox (access checked 2/12/08).
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