Adherence to prescribed medication regimens is essential for effectively treating chronic pain conditions. However, a new study reports that therapeutic nonadherence, or “medical misuse,” of analgesics is common, with underuse more prevalent than overuse or abuse.
Researchers at a single multidisciplinary pain treatment center in Belgium assessed adherence to prescribed analgesic regimens in 281 patient during a 19-week period [Broekmans et al. 2010]. On self-reported measures nearly half (48%) of the patients were nonadherent, with 34% of them admitting underuse and 14% overuse of their prescribed medications. Overall, older patients were significantly more adherent, although age-group differences were not vast; the mean age in adherent patients was 54 years compared with 47 to 49 years in nonadherent patients. Underuse was significantly associated with taking non-prescribed analgesic agents as a form of supplemental self-medication. Overuse was significantly influenced by tobacco smoking, being prescribed opioid analgesics, and regimens requiring a higher number of medication doses per day. The researchers conclude that therapeutic nonadherence, especially underuse of medication, occurs frequently among patients with chronic nonmalignant pain; however, prospective research is needed to learn about the impact of such misuse on clinical outcomes.
FURTHER ANALYSIS: This was an observational study of European patients predominantly suffering from back pain (n=91), neuropathic pain (n=60), and fibromyalgia (n=42); persons with cancer-related pain were excluded. Patients overusing or underusing their medication only once were considered to be nonadherent, although the researchers claimed an alternate analysis using less stringent adherence criteria produced equivalent results (69% of under-users were doing so daily, as were 54% of over-users). Either over- or underuse might be considered as “medical misuse” of analgesics, since patients did not appear to be abusing or diverting the medications for nonmedical purposes. While 25% of participants admitted taking a non-prescribed analgesic agent, none of them claimed to have used illegal drugs (albeit, 13 patients acknowledged smoking cannabis occasionally, which may have been for analgesic effect). However, patients might be reluctant to admit illicit drug use, resulting in underreporting, and self-reports were not cross-checked via urine drug testing.
Friday, February 5, 2010
Thursday, February 4, 2010
Bogus Drugs & Opioids Touted by Online Pharmacies
The National Association of Boards of Pharmacy (NABP) announced that nearly all (96%) of the 5,200 Internet drug outlets that it evaluates were selling prescription drugs outside of pharmacy laws and practice standards that protect the public health. Pain practitioners need to be aware not only of what medications patients are taking but where those products are being purchased.
According to NABP President Gary A. Schnabel, RN, RPh, "There is a common misconception that prescription medications purchased from any website calling itself a pharmacy are safe." However, patients fail to realize that when buying medications from unknown sources online, established safeguards vanish, and the odds of getting counterfeit or substandard medication rise substantially.
Of the more than 5,200 Internet drug outlets NABP has assessed since May 2008, greater than 5,000 (96%) were found to be out of compliance with basic criteria for legitimate pharmacy practice and were posted as “Not Recommended” on the NABP website. Here are some of the infractions:
According to NABP President Gary A. Schnabel, RN, RPh, "There is a common misconception that prescription medications purchased from any website calling itself a pharmacy are safe." However, patients fail to realize that when buying medications from unknown sources online, established safeguards vanish, and the odds of getting counterfeit or substandard medication rise substantially.
Of the more than 5,200 Internet drug outlets NABP has assessed since May 2008, greater than 5,000 (96%) were found to be out of compliance with basic criteria for legitimate pharmacy practice and were posted as “Not Recommended” on the NABP website. Here are some of the infractions:
Wednesday, February 3, 2010
Opioids Relieve Pain with Little Addiction Risk
According to a comprehensive updated Cochrane review, opioid analgesics effectively relieve chronic noncancer pain in most patients, with only a small (though not zero) risk of developing abuse or addiction. However, it must be appreciated that a portion of patients may have inadequate pain relief or develop intolerable opioid side effects; further research is needed to identify patients who will benefit the most.
Many still consider opioid therapy for chronic noncancer pain (CNCP) as controversial due to concerns about long-term effectiveness and safety, particularly risks of tolerance, dependence, or abuse. To expand and update an earlier Cochrane Review on this subject, investigators searched 10 bibliographic databases up to May 2009 [Noble et al. 2010]. They discovered for review 26 studies with 27 treatment groups that enrolled a total of 4,893 participants taking opioids for as long as 48 months. Twenty five of the studies were case series or uncontrolled long-term trial continuations, the other was a randomized controlled trial comparing two opioids. Twelve studies investigated administration of opioids orally (n=3,040), 5 transdermally (n=1,628), and 10 intrathecally (n=231).
Within each modality, a portion of participants discontinued opioid therapy due to side effects (oral, 22.9%; transdermal, 12.1%; intrathecal, 8.9%). To a lesser extent, insufficient pain relief was a cause of discontinuation (oral, 10.3%; intrathecal, 7.6%; transdermal, 5.8%). Serious adverse events were rare and signs of opioid addiction were reported in only 0.27% of participants in the studies that reported that outcome. All 3 modes of administration were associated with clinically significant reductions in pain in the majority of patients, but the amount of pain relief varied across studies. Findings regarding quality of life and functional status were inconclusive due to an insufficient quantity of evidence for oral administration studies and inconclusive statistical findings for transdermal and intrathecal administration studies.
CLINICAL COMMENTARY: Cochrane reviews — following well-developed protocols for data search, extraction, analysis, and validation of findings — are perhaps the most rigorous and robust approaches for assessing current knowledge of particular therapies. In this analysis of studies evaluating long-term opioids for chronic noncancer pain, both the quantity and quality of evidence were disappointing; so, clearly, better and longer-term trials are needed to help identify patients who are most likely to benefit.
Most of the patients in the reviewed studies had chronic back pain following failed surgeries, severe osteoarthritis, or pain related to nerve damage, so the findings cannot be extended to other conditions such as headache, fibromyalgia, etc. Opioid analgesia was not ideal for all patients; some discontinued therapy (especially oral opioids) due to side effects or insufficient pain relief; however, it is unknown whether they transferred to alternate opioids or administration regimens with greater success after dropping out of the respective studies.
Among studies assessing opioid abuse or addiction, only 7 of 2,613 patients (0.27%) developed such opioid-use problems, and the researchers estimated that the rate would be merely 0.14% if no addictive behaviors occurred among studies that did not report addiction rates at all (which seems speculative). Our own review of studies reporting rates of opioid analgesic abuse/addiction in patients with pain found a range of 0.19% to 3.7% (see PDFs at [Leavitt 2007, p. 1] and [Leavitt 2008, p 6]). While there have been inconsistencies across studies in definitions of abuse and addiction, or in distinguishing between patients with/without prior substance-use problems, the rates, even at the higher end, suggest that prescription-opioid abuse/addiction in patients with pain is not anywhere as severe or widespread as some authors and agencies have depicted. On the other hand, there have been some disturbingly high rates of illicit or unauthorized substance use (particularly marijuana) alleged in certain patient populations, but Noble et al. did not examine this concern. These issues need further and unbiased examination; meanwhile, during everyday practice, iatrogenic (therapy induced) opioid abuse or addiction might be considered as merely a rather rare side effect in very select patients.
REFERENCE: Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database of Systematic Reviews. 2010;1(#CD006605) [abstract/summary].
Many still consider opioid therapy for chronic noncancer pain (CNCP) as controversial due to concerns about long-term effectiveness and safety, particularly risks of tolerance, dependence, or abuse. To expand and update an earlier Cochrane Review on this subject, investigators searched 10 bibliographic databases up to May 2009 [Noble et al. 2010]. They discovered for review 26 studies with 27 treatment groups that enrolled a total of 4,893 participants taking opioids for as long as 48 months. Twenty five of the studies were case series or uncontrolled long-term trial continuations, the other was a randomized controlled trial comparing two opioids. Twelve studies investigated administration of opioids orally (n=3,040), 5 transdermally (n=1,628), and 10 intrathecally (n=231).
Within each modality, a portion of participants discontinued opioid therapy due to side effects (oral, 22.9%; transdermal, 12.1%; intrathecal, 8.9%). To a lesser extent, insufficient pain relief was a cause of discontinuation (oral, 10.3%; intrathecal, 7.6%; transdermal, 5.8%). Serious adverse events were rare and signs of opioid addiction were reported in only 0.27% of participants in the studies that reported that outcome. All 3 modes of administration were associated with clinically significant reductions in pain in the majority of patients, but the amount of pain relief varied across studies. Findings regarding quality of life and functional status were inconclusive due to an insufficient quantity of evidence for oral administration studies and inconclusive statistical findings for transdermal and intrathecal administration studies.
CLINICAL COMMENTARY: Cochrane reviews — following well-developed protocols for data search, extraction, analysis, and validation of findings — are perhaps the most rigorous and robust approaches for assessing current knowledge of particular therapies. In this analysis of studies evaluating long-term opioids for chronic noncancer pain, both the quantity and quality of evidence were disappointing; so, clearly, better and longer-term trials are needed to help identify patients who are most likely to benefit.
Most of the patients in the reviewed studies had chronic back pain following failed surgeries, severe osteoarthritis, or pain related to nerve damage, so the findings cannot be extended to other conditions such as headache, fibromyalgia, etc. Opioid analgesia was not ideal for all patients; some discontinued therapy (especially oral opioids) due to side effects or insufficient pain relief; however, it is unknown whether they transferred to alternate opioids or administration regimens with greater success after dropping out of the respective studies.
Among studies assessing opioid abuse or addiction, only 7 of 2,613 patients (0.27%) developed such opioid-use problems, and the researchers estimated that the rate would be merely 0.14% if no addictive behaviors occurred among studies that did not report addiction rates at all (which seems speculative). Our own review of studies reporting rates of opioid analgesic abuse/addiction in patients with pain found a range of 0.19% to 3.7% (see PDFs at [Leavitt 2007, p. 1] and [Leavitt 2008, p 6]). While there have been inconsistencies across studies in definitions of abuse and addiction, or in distinguishing between patients with/without prior substance-use problems, the rates, even at the higher end, suggest that prescription-opioid abuse/addiction in patients with pain is not anywhere as severe or widespread as some authors and agencies have depicted. On the other hand, there have been some disturbingly high rates of illicit or unauthorized substance use (particularly marijuana) alleged in certain patient populations, but Noble et al. did not examine this concern. These issues need further and unbiased examination; meanwhile, during everyday practice, iatrogenic (therapy induced) opioid abuse or addiction might be considered as merely a rather rare side effect in very select patients.
REFERENCE: Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database of Systematic Reviews. 2010;1(#CD006605) [abstract/summary].
Monday, February 1, 2010
What You Need to Know About Acetaminophen Safety
Acetaminophen has provided safe and effective pain relief in adults and children for more than a century; however, writing in the Cleveland Clinic Journal of Medicine, the authors of a new review describe important risks and potential harms of the drug that must be taken more seriously by healthcare providers and patients. The article examines the epidemiology of acetaminophen overdose and the clinical management of related hepatotoxicity.
According to Amy Schilling, PharmD, and coauthors from the Cleveland Clinic, acetaminophen misuse is the leading cause of acute liver failure in the United States, and nearly half of toxicity cases are due to unintentional overdose [Schilling et al. 2010]. Concerned about this, the U. S. Food and Drug Administration (FDA) has mandated new labeling on acetaminophen packaging and is also considering (but still has not enacted) several measures: 1) reducing the maximum daily dose from 4,000 mg (possibly to 3,250 mg), 2) banning acetaminophen-opioid combination products, and 3) changing the current maximum single dose of 1,000 mg to prescription status, making 650 mg the highest nonprescription dose.
While acetaminophen (eg, Tylenol®, also generically called paracetamol or APAP) is an effective and relatively safe analgesic for many pain conditions, it also is far easier than patients (or practitioners) may realize to exceed the maximum 4 grams per day generally considered the upper limit of safety. Besides combinations with opioids, a wide range of products contain acetaminophen in their formulations; persons who do not study product labeling will not be aware of this, and others may not go to the trouble of calculating their total daily intake of acetaminophen from all sources. Acetaminophen hepatotoxicity can occur at much lower daily doses in patients who a) have liver disease, b) consume more than 3 alcohol drinks per day, c) are malnourished, or d) take medications or OTC products that induce cytochrome P450 enzymes. Severe, accidental acetaminophen toxicity generally is not a sudden event; rather it usually occurs during 3 or more days of harmful dosing, providing ample time for remedial actions if healthcare providers and patients are alert to warning signs and symptoms.
CLINICAL COMMENTS: We agree with the conclusion by Schilling et al. that the new labeling of acetaminophen products will be helpful but disagree with their suggestion that the other proposed FDA actions are “sensible.” Using data available from the FDA for 2005, we previously noted that more than 28 billion doses of products containing acetaminophen were distributed in the United States that year and, taking into account a conservative, worst-case scenario, we calculated that the severe adverse event incidence rate was only 0.14% affecting 0.001% of the U.S. population. Put another way, 99.86% of the time acetaminophen products were used safely [see: Acetaminophen Debacle; Much Ado About Very Little]. Furthermore, in their review, Shilling and colleagues emphasize that there is a safe and effective antidote for acetaminophen toxicity — acetylcysteine (Mucomyst®, Acetadote®, others) — that should be given immediately either orally or intravenously when overdose is suspected. Both approaches have incurred minimal adverse effects; although, IV administration may on some occasions (15% of cases) trigger anaphylactoid reactions, which can be medically managed [see also, Heard 2008]. Whether or not healthcare providers are widely familiar with this antidote, including when and how it should be administered to reverse acetaminophen-induced hepatotoxicity, needs examination. Interestingly, generic acetylcysteine capsules, as an antioxidant allegedly supporting liver health, are readily available without prescription via Internet sources.
The above commentary is not intended to dismiss risks or harms of acetaminophen misuse; however, overdoses could probably be reduced at least in half merely by early recognition of potential problems and/or more timely treatment of toxicity if it occurs. We agree with Schilling and her coauthors that, “To prevent unintentional acetaminophen overdoses, education of patients and healthcare professionals is urgently needed so that the dangers of consuming excess acetaminophen daily are understood.” However, their article also suggests that roughly half of all severe hepatotoxicity cases are due to intentional acetaminophen overdoses in suicide attempts, which raises the spectre of complex problems that education alone, or even limiting access to the drug, will not fully resolve.
REFERENCES:
> Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359:285-292 [abstract].
> Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleveland Clin J Med. 2010;77(1):19-27 [full article PDF here].
According to Amy Schilling, PharmD, and coauthors from the Cleveland Clinic, acetaminophen misuse is the leading cause of acute liver failure in the United States, and nearly half of toxicity cases are due to unintentional overdose [Schilling et al. 2010]. Concerned about this, the U. S. Food and Drug Administration (FDA) has mandated new labeling on acetaminophen packaging and is also considering (but still has not enacted) several measures: 1) reducing the maximum daily dose from 4,000 mg (possibly to 3,250 mg), 2) banning acetaminophen-opioid combination products, and 3) changing the current maximum single dose of 1,000 mg to prescription status, making 650 mg the highest nonprescription dose.
While acetaminophen (eg, Tylenol®, also generically called paracetamol or APAP) is an effective and relatively safe analgesic for many pain conditions, it also is far easier than patients (or practitioners) may realize to exceed the maximum 4 grams per day generally considered the upper limit of safety. Besides combinations with opioids, a wide range of products contain acetaminophen in their formulations; persons who do not study product labeling will not be aware of this, and others may not go to the trouble of calculating their total daily intake of acetaminophen from all sources. Acetaminophen hepatotoxicity can occur at much lower daily doses in patients who a) have liver disease, b) consume more than 3 alcohol drinks per day, c) are malnourished, or d) take medications or OTC products that induce cytochrome P450 enzymes. Severe, accidental acetaminophen toxicity generally is not a sudden event; rather it usually occurs during 3 or more days of harmful dosing, providing ample time for remedial actions if healthcare providers and patients are alert to warning signs and symptoms.
CLINICAL COMMENTS: We agree with the conclusion by Schilling et al. that the new labeling of acetaminophen products will be helpful but disagree with their suggestion that the other proposed FDA actions are “sensible.” Using data available from the FDA for 2005, we previously noted that more than 28 billion doses of products containing acetaminophen were distributed in the United States that year and, taking into account a conservative, worst-case scenario, we calculated that the severe adverse event incidence rate was only 0.14% affecting 0.001% of the U.S. population. Put another way, 99.86% of the time acetaminophen products were used safely [see: Acetaminophen Debacle; Much Ado About Very Little]. Furthermore, in their review, Shilling and colleagues emphasize that there is a safe and effective antidote for acetaminophen toxicity — acetylcysteine (Mucomyst®, Acetadote®, others) — that should be given immediately either orally or intravenously when overdose is suspected. Both approaches have incurred minimal adverse effects; although, IV administration may on some occasions (15% of cases) trigger anaphylactoid reactions, which can be medically managed [see also, Heard 2008]. Whether or not healthcare providers are widely familiar with this antidote, including when and how it should be administered to reverse acetaminophen-induced hepatotoxicity, needs examination. Interestingly, generic acetylcysteine capsules, as an antioxidant allegedly supporting liver health, are readily available without prescription via Internet sources.
The above commentary is not intended to dismiss risks or harms of acetaminophen misuse; however, overdoses could probably be reduced at least in half merely by early recognition of potential problems and/or more timely treatment of toxicity if it occurs. We agree with Schilling and her coauthors that, “To prevent unintentional acetaminophen overdoses, education of patients and healthcare professionals is urgently needed so that the dangers of consuming excess acetaminophen daily are understood.” However, their article also suggests that roughly half of all severe hepatotoxicity cases are due to intentional acetaminophen overdoses in suicide attempts, which raises the spectre of complex problems that education alone, or even limiting access to the drug, will not fully resolve.
REFERENCES:
> Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359:285-292 [abstract].
> Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleveland Clin J Med. 2010;77(1):19-27 [full article PDF here].
Surprise: Surgeons Downplay Surgery for Back Pain
A recently reported study in the journal Spine found that surgeons are less likely than family physicians or patients to view surgery as a preferred treatment for low back pain. Surgeons placed greatest importance on location of pain (leg vs back only), while physicians considered multiple factors, and patients placed high importance on quality of life symptoms. Better communication is essential for shared decision-making and appropriate action.
Researchers in Ontario, Canada presented hypothetical back pain scenarios to 131 surgeons (orthopedic and neurosurgeons), 202 family physicians, and to 164 patients with back and/or leg pain [Bederman et al. 2010]. The vignettes reflected 6 key clinical factors related to back pain: walking tolerance, pain duration, severity, neurologic symptoms, typical onset, and dominant location of pain. Each group rated their preference for surgery in each scenario and the factors affecting preferences were analyzed.
Unexpectedly, surgeons indicated the lowest overall preference for surgery, while family physicians had the highest preference. Surgeons placed greatest importance on the location of pain, with leg pain being more salient than back pain only; orthopedic surgeons had a significantly lower preference for surgery than neurosurgeons (p < 0.05). Family practitioners considered neurologic symptoms, walking tolerance, and pain severity to be of greatest and equal importance. Somewhat similarly, patients considered pain severity and its duration, and walking tolerance as the most important factors in choosing surgery. Older patients and those having a previous surgical consultation had significantly greater preferences for surgery to remedy their pain.
Clinical Concepts: The investigators note that when other treatments have failed, surgery can help patients with moderate to severe lower back pain, and family physicians play an important role in sending patients for surgical evaluation. However, according to this study — which was of limited scope — family doctors may be unaware of diagnostic factors that most commonly affect the chances of good outcomes from back surgery, such as the specific location of pain. Meanwhile, patients appear to favor factors that are highly related to quality of life and have little direct bearing on surgical outcomes. The final decision-making process should include the patient, family physician, and surgeon; all having a mutual understanding of factors that are most critical in determining successful back surgery. "This can directly result in a significant improvement in patient satisfaction with the healthcare process and even overall health status following treatment," the researchers write. An excellent overview for patients on back surgery, why it may be needed, and some common types is available from the Mayo Clinic [here].
Reference: Bederman SS, Mahomed NN, Kreder HJ, et al. In the eye of the beholder: preferences of patients, family physicians, and surgeons for lumbar spinal surgery. Spine. 2010;35(1):108-115 [abstract here].
Researchers in Ontario, Canada presented hypothetical back pain scenarios to 131 surgeons (orthopedic and neurosurgeons), 202 family physicians, and to 164 patients with back and/or leg pain [Bederman et al. 2010]. The vignettes reflected 6 key clinical factors related to back pain: walking tolerance, pain duration, severity, neurologic symptoms, typical onset, and dominant location of pain. Each group rated their preference for surgery in each scenario and the factors affecting preferences were analyzed.
Unexpectedly, surgeons indicated the lowest overall preference for surgery, while family physicians had the highest preference. Surgeons placed greatest importance on the location of pain, with leg pain being more salient than back pain only; orthopedic surgeons had a significantly lower preference for surgery than neurosurgeons (p < 0.05). Family practitioners considered neurologic symptoms, walking tolerance, and pain severity to be of greatest and equal importance. Somewhat similarly, patients considered pain severity and its duration, and walking tolerance as the most important factors in choosing surgery. Older patients and those having a previous surgical consultation had significantly greater preferences for surgery to remedy their pain.
Clinical Concepts: The investigators note that when other treatments have failed, surgery can help patients with moderate to severe lower back pain, and family physicians play an important role in sending patients for surgical evaluation. However, according to this study — which was of limited scope — family doctors may be unaware of diagnostic factors that most commonly affect the chances of good outcomes from back surgery, such as the specific location of pain. Meanwhile, patients appear to favor factors that are highly related to quality of life and have little direct bearing on surgical outcomes. The final decision-making process should include the patient, family physician, and surgeon; all having a mutual understanding of factors that are most critical in determining successful back surgery. "This can directly result in a significant improvement in patient satisfaction with the healthcare process and even overall health status following treatment," the researchers write. An excellent overview for patients on back surgery, why it may be needed, and some common types is available from the Mayo Clinic [here].
Reference: Bederman SS, Mahomed NN, Kreder HJ, et al. In the eye of the beholder: preferences of patients, family physicians, and surgeons for lumbar spinal surgery. Spine. 2010;35(1):108-115 [abstract here].
Wednesday, January 27, 2010
Methadone Analgesia Cardiac Concerns Unfounded
Some past reports have suggested that methadone may negatively affect cardiac function, potentially leading to the serious arrhythmia known as torsades de pointes. A recently-reported study in patients with cancer finds that methadone analgesia has little detrimental effect on the QTc interval and can be safely used even in very ill patients.
Researchers at the M.D. Anderson Cancer Center, Houston, Texas, enrolled 100 patients with cancer in a prospective observational study [Reddy et al. 2010]. Subjects were followed clinically and via serial ECGs for QTc changes at baseline prior to initiating methadone analgesia and at 2, 4, and 8 weeks thereafter. QTc prolongation was defined on ECG tracings as >430 milliseconds (ms) in males and >450 ms in females, and clinically significant effects were defined as a QTc interval >25% from baseline or ≥500 ms. All patients had a cancer diagnosis, with most having a limited prognosis of less than 3 months. ECG assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-weeks follow-up, respectively. Reasons for discontinuation were primarily due to hospice transfers or return to the local community and 11 patients discontinued methadone due to typical opioid-related side effects; no dropouts were cardiac related.
At baseline prior to methadone induction, 28 patients (28%) had QTc prolongation and by weeks 2, 4, and 8 after beginning methadone 5 (8%), 3 (8%), and 3 (11%) patients, respectively, still exhibited QTc prolongation. None of the patients had a >25% increase in QTc and only 1 patient had a QTc >500 ms; this person had a QTc of 498 ms at baseline and after increasing to 509 ms without adverse effect at week 2 the QTc resolved by week 4. There was no clinical evidence in any patients of torsades de pointes, ventricular fibrillation, or sudden cardiac death. The researchers conclude that their study supports the safety of methadone analgesia and that it can be“… prescribed without reservation in the palliative care population.”
Commentary: Most publications discussing methadone these days — as well as the ‘black box’ caution on labeling in the U.S. [PI here] — prominently note concerns about its alleged cardiotoxicity, specifically prolongation of the QTc interval that might incur serious arrhythmia including torsade de pointes. However, we have previously discussed controversies surrounding these allegations and limitations of the evidence behind them [see prior blogpost 8/8/09]. This present study by Reddy et al. is of some importance in this ongoing debate about methadone’s cardiac safety for several reasons…
Reference: Reddy S, Hui D, El Osta B, et al.. The effect of oral methadone on the QTc interval in advanced cancer patients: A prospective pilot study. J Palliative Med. 2010,13(1):33-38 [abstract here].
Our thanks also to Andrew Byrne, MD, Redfern, Australia for bringing this article to our attention.
ADDENDUM: Also from M.D Anderson Cancer Center recently, an article on methadone analgesia initiation and rotation in outpatient settings for patients with cancer. The authors note that methadone was safe, with high success rates (ie, relatively few discontinuations) and low side effect profiles. See: Parsons HA, de la Cruz M, El Osta B. Methadone initiation and rotation in the outpatient setting for patients with cancer pain. Cancer. 2010;116(2):520-526. Full article PDF [here]. Insightful discussion by palliative care specialists at the Pallimed weblog [here].
Researchers at the M.D. Anderson Cancer Center, Houston, Texas, enrolled 100 patients with cancer in a prospective observational study [Reddy et al. 2010]. Subjects were followed clinically and via serial ECGs for QTc changes at baseline prior to initiating methadone analgesia and at 2, 4, and 8 weeks thereafter. QTc prolongation was defined on ECG tracings as >430 milliseconds (ms) in males and >450 ms in females, and clinically significant effects were defined as a QTc interval >25% from baseline or ≥500 ms. All patients had a cancer diagnosis, with most having a limited prognosis of less than 3 months. ECG assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-weeks follow-up, respectively. Reasons for discontinuation were primarily due to hospice transfers or return to the local community and 11 patients discontinued methadone due to typical opioid-related side effects; no dropouts were cardiac related.
At baseline prior to methadone induction, 28 patients (28%) had QTc prolongation and by weeks 2, 4, and 8 after beginning methadone 5 (8%), 3 (8%), and 3 (11%) patients, respectively, still exhibited QTc prolongation. None of the patients had a >25% increase in QTc and only 1 patient had a QTc >500 ms; this person had a QTc of 498 ms at baseline and after increasing to 509 ms without adverse effect at week 2 the QTc resolved by week 4. There was no clinical evidence in any patients of torsades de pointes, ventricular fibrillation, or sudden cardiac death. The researchers conclude that their study supports the safety of methadone analgesia and that it can be“… prescribed without reservation in the palliative care population.”
Commentary: Most publications discussing methadone these days — as well as the ‘black box’ caution on labeling in the U.S. [PI here] — prominently note concerns about its alleged cardiotoxicity, specifically prolongation of the QTc interval that might incur serious arrhythmia including torsade de pointes. However, we have previously discussed controversies surrounding these allegations and limitations of the evidence behind them [see prior blogpost 8/8/09]. This present study by Reddy et al. is of some importance in this ongoing debate about methadone’s cardiac safety for several reasons…
- These were quite ill patients who might be considered at high risk for cardiac stress and, indeed, more than a quarter of them had prolonged QTc intervals prior to methadone treatment.
- Of the 28 patients with baseline QTc prolongation, almost all (79%) had one or more risk factors that might have been viewed as a further contraindication for methadone therapy, including: medications known to prolong QTc or invoke torsade de pointes, structural cardiac disease, electrolyte abnormalities, and/or female sex.
- Despite these many risks, there was only 1 instance of clinically significant QTc prolongation (>500 ms), which was asymptomatic and occurred in a patient with excessive prolongation at baseline; this prolongation became apparent at week 2 and resolved by the week 4 ECG tracing. Remarkably, there was a slight trend toward decreasing median QTc measures in all patients at 4 and 8 weeks, which is worthy of further investigation.
- QTc prolongation during methadone therapy was more frequent among patients with QTc interval prolongation at baseline; however, there was no significant association between QTc interval and methadone dose (p=0.45).
Reference: Reddy S, Hui D, El Osta B, et al.. The effect of oral methadone on the QTc interval in advanced cancer patients: A prospective pilot study. J Palliative Med. 2010,13(1):33-38 [abstract here].
Our thanks also to Andrew Byrne, MD, Redfern, Australia for bringing this article to our attention.
ADDENDUM: Also from M.D Anderson Cancer Center recently, an article on methadone analgesia initiation and rotation in outpatient settings for patients with cancer. The authors note that methadone was safe, with high success rates (ie, relatively few discontinuations) and low side effect profiles. See: Parsons HA, de la Cruz M, El Osta B. Methadone initiation and rotation in the outpatient setting for patients with cancer pain. Cancer. 2010;116(2):520-526. Full article PDF [here]. Insightful discussion by palliative care specialists at the Pallimed weblog [here].
Saturday, January 23, 2010
Wrist Pain? Maybe Too Much Sex is to Blame.
Chronic wrist pain due to repetitive strain has plagued computer keyboard users and those working awkwardly with heavy equipment; now, a new report suggests a spicier explanation in some patients — too much sex. So, maybe healthcare providers need to question patients about their sex lives to help reveal the root causes of their wrist complaints.
The condition might be somewhat facetiously charted as “RSI – Repetitive Sex Injury”; however, writing seriously in the journal Medical Hypotheses, researcher John Zenian, says: "Sexual intercourse can explain the increase in the overall incidence of carpal tunnel syndrome seen in recent years, since it is the most widely practiced activity that uses both hands at the same time" [Zenian 2010]. Carpal tunnel syndrome (CTS) is a prevalent form of repetitive strain injury in the United States, affecting anywhere from 1 of 20 persons in the general population to half of all persons in select high-risk groups [data here]. Sexual activity is generally not considered in the workup for a differential diagnosis of CTS; nor as a major contributor to “overuse injury” or cumulative trauma disorder.
Zenian proposes that carpal tunnel syndrome (CTS) can develop during sexual intercourse in the missionary position when the hands of the top person are repeatedly extended while under pressure from the weight of the upper body. Of the well-known risk factors associated with non-occupational carpal tunnel syndrome, age, marital status, and use of hormonal agents may also relate to the frequency of sexual intercourse. Along with those factors, obesity, macromastia (excessive breast size), and large chest circumference incur increased pressure on the wrists due to a heavier upper body. According to Zenian, the bilaterality of CTS in afflicted persons can be explained by the fact that both hands are needed to support the upper body during sexual intercourse. The overall decrease in the frequency of sexual intercourse and a declining incidence of CTS between the 6th and 7th decades of life suggests a possible cause and effect relationship between sexual intercourse and CTS, he notes. However, the popularity of erectile dysfunction medications (eg, sildenafil, tadalafil, others) appears to be eliminating age differences in recent years.
If sexual activity seems a plausible explanation for chronic wrist pain in patients young or old, short of abstinence, what can be recommended?
The condition might be somewhat facetiously charted as “RSI – Repetitive Sex Injury”; however, writing seriously in the journal Medical Hypotheses, researcher John Zenian, says: "Sexual intercourse can explain the increase in the overall incidence of carpal tunnel syndrome seen in recent years, since it is the most widely practiced activity that uses both hands at the same time" [Zenian 2010]. Carpal tunnel syndrome (CTS) is a prevalent form of repetitive strain injury in the United States, affecting anywhere from 1 of 20 persons in the general population to half of all persons in select high-risk groups [data here]. Sexual activity is generally not considered in the workup for a differential diagnosis of CTS; nor as a major contributor to “overuse injury” or cumulative trauma disorder.
Zenian proposes that carpal tunnel syndrome (CTS) can develop during sexual intercourse in the missionary position when the hands of the top person are repeatedly extended while under pressure from the weight of the upper body. Of the well-known risk factors associated with non-occupational carpal tunnel syndrome, age, marital status, and use of hormonal agents may also relate to the frequency of sexual intercourse. Along with those factors, obesity, macromastia (excessive breast size), and large chest circumference incur increased pressure on the wrists due to a heavier upper body. According to Zenian, the bilaterality of CTS in afflicted persons can be explained by the fact that both hands are needed to support the upper body during sexual intercourse. The overall decrease in the frequency of sexual intercourse and a declining incidence of CTS between the 6th and 7th decades of life suggests a possible cause and effect relationship between sexual intercourse and CTS, he notes. However, the popularity of erectile dysfunction medications (eg, sildenafil, tadalafil, others) appears to be eliminating age differences in recent years.
If sexual activity seems a plausible explanation for chronic wrist pain in patients young or old, short of abstinence, what can be recommended?
- Patients can be instructed to limber up their wrists before sex by doing some gentle exercises.
- They should try different positions that are less straining on the wrists.
- Avoid prolonged sexual activity in the same positions, especially those that put pressure on wrists.
- Fitness outside the bedroom counts, too, including exercise and weight control.
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