 July-August 2008; Issue 16
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; Paul Lofholm, PharmD, FACA; Lee A. Kral, PharmD, BCPS; Seth I. Kaufman, MD. Posting Date: August 19, 2008.
 Development of these Pain Treatment Topics News/Research Updates was supported by an unrestricted educational grant from COVIDIEN/Mallinckrodt, St. Louis, MO. Any mention of product brand names is for informational purposes only and such brands 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.
A Bonus of Opioid Therapy: Psychotherapeutic Effects
Recent literature supports potential roles of methadone, buprenorphine, tramadol, morphine, and other opioids as effective, durable, and rapid therapeutic agents for anxiety and depression. In an extensive review, Peter L. Tenore, MD –– from the Albert Einstein College of Medicine, Division of Substance Abuse, Department of Psychiatry, Bronx, NY –– notes that opioids have been widely used for various disorders dating back to 3400 BC. In addition to their pain-relieving qualities, for centuries opioid mixtures also served to treat psychiatric disorders. However, with the development of newer antidepressant and anxiolytic medications in the early 1950s, so-called “Opium Cures” were abandoned.
In the classic “Opium Cure,” an opioid supplement was believed to overcome the brain’s deficiency of endorphin, which in turn releases more dopamine to presumably restore neurochemical balance and alleviate depression or anxiety. Tenore discovered clinical research evidence of this beneficial opioid effect; surprisingly, with depressive symptoms often relieved more rapidly by opioids than with antidepressant medications, such as fluoxetine or amitriptyline.
For example, a number of controlled clinical trials of buprenorphine in clinically depressed patients found potent beneficial effects in relieving depression. In similar research, an equivalent or greater antidepressant effect was found for methadone. Furthermore, methadone also was observed to lower excessive serum cortisol levels brought about by stress responses, and this helped relieve symptoms of anxiety.
Research also has demonstrated that opioid medications may alter a number of other brain chemicals and systems affecting mood regulation. Among these are serotonin, catecholamines (epinephrine/norepinephrine), and the glutamate-NMDA system – all of which play a role in mood disorders and are targets of psychiatric medications. Methadone has been shown to activate typical sites for tricyclic antidepressants and to increase catecholamines, according to Tenore’s review. Along with that, methadone was found to have actions similar to SSRIs (selective serotonin reuptake inhibitors) in raising brain serotonin levels, and thereby restoring deficiencies of this neurochemical.
Considerable research has demonstrated that methadone, as well as buprenorphine, also counteract serotonin-diminishing effects exerted by the glutamate-NMDA receptor system. NMDA (N-Methyl D-Aspartate) receptors, located throughout the brain, help regulate pain perception and mood, among other functions. When NMDA receptors are activated by the neurochemical glutamate, the production of new serotonin is decreased and existing serotonin is broken down faster, which strongly influences symptoms of depression and anxiety. Certain opioids, particularly methadone, function both to reduce glutamate effects and as NMDA antagonists (blocking glutamate from activating the receptors), according to the research evidence.
Clinical Implications: Tenore commented to Pain Treatment Topics that “it is clear that certain opioid medications may supply depressed and anxious brains with the serotonin, dopamine, and catecholamines that they are lacking. At the same time, these opioids help control the stress response and block mood-disrupting glutamate-NMDA and/or cortisol effects.” However, he advises that opioids do not have FDA approval for the treatment of psychiatric disorders. And, much of the evidence for opioid effects benefiting mood come from research involving opioid-dependent patients with cooccurring mood disorders attending methadone maintenance treatment programs for addiction.
[Comment: The concepts presented in this article are of interest; however, they should not be taken to imply that opioids could or should be used as replacements for well-established psychiatric medications (antidepressants, anxiolytics, etc.) At the least, there have been no clinical trials comparing any opioids to these other agents for the treatment of mood disorders. Furthermore, as regards methadone, readers should always consult the methadone PI (prescribing information) for proper analgesic dosing and precautions. – SBL]
Reference: Tenore PL. Psychotherapeutic Benefits of Opioid Agonist Therapy. J Addict Dis. 2008;27(3):49-65.
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IV Morphine Titration Relieves Acute Pain in the ED
Documented reports of the undertreatment of acute severe pain in the emergency setting prompted investigators in France to evaluate the safety and efficacy of intravenous opioid administration in this population. Consecutive adult patients (n=621) with severe acute pain admitted to a Paris hospital emergency department (ED) received IV morphine as a bolus of 2 mg (if patient body weight </= 60 kg), or 3 mg (if body weight > 60 kg) with 5 minute intervals between boluses until pain relief was achieved. Pain relief was considered significant when a patient’s visual analog score decreased to 30 or less (on a 0 – 100 scale).
Study results showed that the mean dose of morphine administered was 10.5 mg (+/- 6.4 mg), patients received a median number of 3 boluses, and the median duration of titration was 15 minutes. Morphine titration was interrupted before pain relief was achieved in 17% of patients, but 99% of the remaining 514 patients reached pain relief goals. Non-severe morphine-induced adverse events occurred in 11% of patients.
Clinical Implications: The authors concluded that intravenous morphine titration is effective in the treatment of severe acute pain in the ED when dosing is administered according to a strict titration protocol rather than a fixed low dose. Because failure to obtain pain relief was strongly associated with 2 significant variables — major deviation from the established titration protocol (44%) and morphine-induced side effects — the researchers recommend appropriate staff training and attentive clinical monitoring to improve success and safety.
Reference: Lvovschi V, Aubrun F, Bonnet P, et al. Intravenous morphine titration to treat severe pain in the ED. Am J Emerg Med. 2008(Jul);26(6):676-682.
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Guidelines for Parental Methadone in Palliative Care
Methadone is now being used as first- and second-line therapy in palliative care, yet difficulties with dosing methadone and lack of an established conversion protocol from other opioids have limited access to this medication for patients who could potentially benefit from it. This consensus guideline provides an overview on the use of parenteral methadone in pain and palliative care, with a focus on the transition from hospital to home/hospice care.
The purpose of this guideline is to assist clinicians who are providing chronic pain management in acute care hospital and non-hospital settings (ie, hospice, long-term care facilities, and community) for patients with life-limiting illnesses, where the goals of care are focused on comfort (ie, palliative care). The recommendations are intended to promote a standard of care involving the use of parenteral (ie, intravenous) methadone with the aim of reaching a broader population of patients for whom this therapy would provide important benefits. Recommendations of the consensus panel include:
- IV methadone should be considered in patients with cancer-related pain syndromes, HIV-related pain, pain in sickle cell disease, and for postoperative or acute pain in opioid-tolerant patients. Other patients in whom methadone analgesia may be beneficial include those with a history of opioid addiction, those with significant opioid tolerance, or in patients with neuropathic pain. IV methadone may also be used in end-of-life care with terminally ill patients.
- IV methadone should be administered via PCA with sufficient rescue dosing provided.
- When converting from oral opioids, methadone shows incomplete cross-tolerance, so the other opioid dose should be reduced by 75% to 90% of the calculated morphine equivalent; then IV methadone can be titrated with careful monitoring during 24-48 hours. This is the safest way to achieve conversion, although analgesia may not be achieved rapidly during this process.
- The risk with methadone of QTc prolongation (and therefore torsades des pointes and sudden cardiac death) should be discussed openly with the patient, family, and/or healthcare proxy so that an informed decision can be made. However, it should be noted that the risk is small and close monitoring with ECG can diminish such risk.
- In patients with life-threatening illnesses, the potential benefit of controlling otherwise refractory pain may far outweigh the risks of parenteral methadone, even when monitoring for arrhythmia is impractical.
- Use of IV methadone requires frequent monitoring for response to therapy and emergence of any side effects.
- Patient/family education and careful documentation are crucial.
[Comment: In this setting, methadone is being used strictly for analgesia rather than addiction therapy, for which special licensing is required. Also, in patients taking multiple medications, potential drug-drug interactions with methadone should be considered. Finally, it must be understood that any ratios used for conversion from another opioid to IV methadone do not work in reverse; ie, for converting from IV methadone to another opioid. – SBL]
Reference: Shaiova L, Bergera A, Blindermana CD, et al. Consensus guideline on parenteral methadone use in pain and palliative care. Pall Support Care. 2008;6:165-176.
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Rotation From Other Opioids to Methadone Reviewed
Investigators conducted a systematic review to analyze the evidence base for methods of converting from other oral opioids to oral methadone for analgesia. Clinical trials, retrospective analyses, case series, and case reports of human subjects published in the English language between January 1966 and June 2006 were included in their search. Relationships between previous morphine-equivalent doses and final methadone doses and dose ratios were assessed.
Twenty-two clinical studies and 19 case reports or series were reviewed (n = 730 patients). Rotations to methadone were most common in cancer patients and those prescribed morphine or hydromorphone. In clinical studies, the most common reason for switching to methadone was a combination of inadequate analgesia and adverse effects.
Clinical Concepts: Despite widely differing approaches to rotation, up to 89% of them were successful. Overall, there was a relatively strong, positive correlation between the previous morphine-equivalent dose and the final methadone dose and dose ratio; however, the ratios varied extensively. The authors concluded that there was no evidence to support the superiority of one method of rotation to methadone over another.
[Comment: These investigators conducted a very thorough review and a lengthy academic discussion of their findings; unfortunately, this is for the most part clinically unhelpful and possibly confusing. No specific prescribing guidance is provided and, as they note, numerous factors may influence the safety and tolerability of rotations to methadone, including: patient age or gender, expected pain control, existing disease, concomitant medications, and genetic influences. Their suggestion that further research is needed to explore the influence of these various factors on successful rotation to methadone is prudent but does not respond to today’s needs. Finally, as noted in the above item, any ratios for conversion from another opioid to methadone do not necessarily work in reverse; ie, for converting from methadone to another opioid. – SBL.]
Source: Weschules DJ, Bain KT. A systematic review of opioid conversion ratios used with methadone for the treatment of pain. Pain Med. 2008;9(5):595-612.
 For clinically-oriented methadone-prescribing guidance, see “Oral Methadone Dosing for Chronic Pain: A Practitioner's Guide,” by James D. Toombs, MD, from Pain Treatment Topics at: http://pain-topics.org/opioid_rx/methadone.php#methchropain
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Transdermal Buprenorphine Favorably Reviewed
Transdermal buprenorphine, marketed as Transect® in Europe, was first launched in Germany in 2001 and is now widely used in Europe and Australia. The patch structure — a polymer matrix that allows for slow, continuous release of buprenorphine — has demonstrated safety and effectiveness, but there also have been concerns about dosage ceilings and the drug’s mixed agonist/antagonist activity. This review by Hans G. Kress, MD — a pain specialist at the Medical University of Vienna — summarizes recent evidence related to the efficacy and safety of transdermal buprenorphine that dispels prior misconceptions. Key findings include…
- Significantly improved pain relief, better sleep, and less frequent rescue therapy (when compared with placebo) were reported in clinical trials of patients receiving transdermal buprenorphine. Studies also confirmed the efficacy of transdermal buprenorphine in the treatment of moderate-to-severe cancer and non-cancer pain, including neuropathic pain.
- Clinical evidence demonstrated that buprenorphine, a partial mu-opioid agonist, can be safely combined with full mu-agonists and that rotating from or to other opioids (using equianalgesic doses) is effective and safe.
- Buprenorphine exerts an anti-hyperalgesic effect — in contrast to hyperalgesia (increased sensitivity to pain) that may occur with other opioids.
- Central nervous system adverse events — including respiratory depression — with buprenorphine were reported to be lower than morphine, hydromorphone, methadone, or fentanyl.
- Fewer side effects, including a lower incidence of constipation were reported with buprenorphine when compared with morphine.
[Commentary: While an increasing number of studies are showing analgesic efficacy and a good safety profile for transdermal buprenorphine, this product has not been FDA-approved for use and is currently unavailable in the United States. Additionally, prior practice has advised against combining full opioid agonists with mixed agonists-antagonists, or partial agonists such as buprenorphine, so further study may be needed regarding this. We normally do not mention products not marketed in the US; however, buprenorphine is currently FDA-approved in other formulations. – WD, SBL]
Reference: Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain. 2008(Jun 20); [Early online publication prior to print].
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Whiplash Injury Trigger Points Identified
Whiplash injury, caused by sudden extension and flexion of the head, can damage a wide range of soft tissues in the neck. Twenty-four healthy subjects and 124 patients — including patients with whiplash-associated disorders, fibromyalgia syndrome, or nontraumatic chronic cervical syndrome — from a single rehabilitation center in Switzerland were manually examined for myofascial trigger points of the semispinalis capitis, trapezius pars descendens, levator scapulae, scalenus medius, sternocleidomastoideus, and masseter muscles. [Trigger points are hyperirritable spots in taut skeletal muscle that produce local and referred pain frequently accompanying musculoskeletal disorders.]
Examinations showed that 85% of the patients with whiplash injuries had positive trigger points in the semispinalis capitis muscle — a significantly higher prevalence than any of the healthy control subjects (p < 0.05). Trigger points in other neck and shoulder muscles, including the masseter muscle, did not differentiate patients with whiplash from patients with nontraumatic chronic cervical syndrome or fibromyalgia.
Practice Pointers: The authors reported that the patients with whiplash injuries showed a significantly distinct distribution of trigger points when compared with other patient groups or healthy subjects. These results suggest the importance of myofascial examination in patients with whiplash injury and highlight potential trigger points for therapeutic interventions.
Reference: Ettlin T, Schuster C, Stoffel R, et al. A distinct pattern of myofascial findings in patients after whiplash injury. Arch Phys Med Rehabil. 2008(Jul);89(7):1290-1293.
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Improved Coping Skills Help Headache Sufferers
Investigators at the American University in Beirut, Lebanon, studied the relationship between self-reported headache pain severity, depression, and patient coping styles. Interviews, headache characteristic inventories, and psychosocial scales were administered to 71 adults with a diagnosis of primary headache.
Data analyses showed that greater self-reported headache pain severity was associated with higher levels of depression; however, the relationship between headache severity and depression was diminished in patients having a high internal locus of control [that is, a patient’s perception that control of a situation is within his/her own power].
Clinical Implications: The authors stated that the data supported a relationship between pain severity and internal locus of control, including the possibility that this affected how patients perceived the effectiveness of pharmacologic interventions. The authors further suggested that stronger coping skills accompanying higher locus of control might reduce depression among headache sufferers. After appropriate evaluation, healthcare providers can look for opportunities to educate chronic headache sufferers who show evidence of low self-efficacy (the belief that one cannot produce an effect or attaining a goal) on better ways to make personal choices that may more positively influence their pain management.
Reference: Heath RL, Saliba M, Mahmassani O, et al. Locus of control moderates the relationship between headache pain and depression. J Headache Pain. 2008(Aug 5); [Early online publication prior to print].
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Taken Early, Sumatriptan/Naproxen Relieves Migraine Pain
Existing research shows that migraine treatment administered at the first sign of pain provides the most optimal headache relief. Researchers at the Jefferson Headache Center in Philadelphia studied the efficacy of a fixed-dose, single-tablet formulation combining sumatriptan 85 mg (a migraine-specific drug that constricts blood vessels) plus naproxen sodium 500 mg (a nonsteroidal anti-inflammatory drug that targets migraine inflammation) as an early intervention for acute migraine symptoms. A total of 1111 adult patients with a history of migraine were enrolled in 2 identical randomized, double-blind, placebo-controlled studies and treated with either a single dose of the sumatriptan/naproxen combination drug or placebo within 1 hour of migraine onset. The primary outcome measurement was the percentage of patients who became pain-free at 2 hours post-treatment.
Significant pain-free responses in the treatment group were evident at 30 minutes, maintained at 1 hour, and sustained from 2 to 24 hours. At 2 hours, more than half of the sumatriptan/naproxen-treated patients were pain free, compared with 16% of placebo-treated patients (p < 0.001). At 2 and 4 hours, patients receiving sumatriptan/naproxen combination treatment reported significantly lower rates of traditional symptoms (nausea, sensitivity to light or sound) and nontraditional migraine-associated symptoms (neck pain or sinus pressure/pain). Adverse drug effects of nausea and dizziness were reported in up to 4% of treatment-group patients.
Practice Pointers: The authors stated that the fixed-dose, combination tablet of sumatriptan/naproxen was effective and well-tolerated as an early intervention for the acute treatment of migraine. However, they did not compare this with effects of either drug alone. In a related news story (Science Daily), Stephen Silberstein, MD, stated that “this study provides more evidence that treating a migraine at the first sign of pain increases the likelihood of relief.”
[Comment: Treximet®, the trade name for the combination sumatriptan/naproxen formulation, was approved by the FDA in April 2008. Prescribing information can be downloaded at http://us.gsk.com/products/assets/us_treximet.pdf (access checked 8/09/08). Individually, sumatriptan has received tentative FDA approval as a generic drug but is not yet marketed as such and naproxen is a generic anti-inflammatory. Pain-Topics.org does not endorse any brand-name products. – WD, SBL]
Reference: Silberstein SD, Mannix LK, Goldstein J, et al. Multimechanistic (sumatriptan-naproxen) early intervention for the acute treatment of migraine. Neurology. 2008(Jul 8);71(2):114-121.
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Unexplained Chest/Epigastric Pain Could Signal Heart Disease
Pain in the chest or epigastric region that remains unexplained following normal endoscopy test results may be indicative of undiagnosed ischemic heart disease. Danish researchers examined the 10-year risk of ischemic heart disease and mortality in a cohort of 386 patients with chest or epigastric pain and normal endoscopy, but without diagnosed heart disease. Medical history data was compared with that of 3793 controls matched by age, gender, and residential region.
Results showed that the 10-year risk of hospitalization for ischemic heart disease in patients with unexplained chest/epigastric pain and a normal endoscopy was 60% greater than matched controls. The 10-year risk of mortality was just 10% higher; however, during the first year following a normal endoscopy in this study sample, the mortality risk was more than twice as high as that of the general population.
Clinical Implications: Since patients with reflux, heartburn, or other GERD/ulcer symptoms were excluded, the authors concluded that “unexplained chest/epigastric pain in patients with normal endoscopy is a strong marker for possible ischemic heart disease and increased mortality.”
Reference: Munk EM, Norgard B, Dethlefsen C, et al. Unexplained chest/epigastric pain in patients with normal endoscopy as a predictor for ischemic heart disease and mortality: a Danish 10-year cohort study. BMC Gastroenterology. 2008(Jul 15);8:28
 Download the full text PDF of this article at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2490769&blobtype=pdf (access checked 8/08/08).
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PTSD May Hinder Pain Relief
Researchers at the University of Michigan examined the potential of post-traumatic stress disorder (PTSD) to worsen the effects of pain, psychological distress, and disability associated with chronic pain. Patients (n=241) referred to the university hospital’s pain rehabilitation program with pain following a traumatic injury were asked to complete assessments measuring post-traumatic chronic pain, depressive symptoms, and disability.
Analysis of study data showed that PTSD and depression were significantly correlated and both disorders were associated with perceived disability attributed to chronic pain. Furthermore, PTSD directly influenced the severity of depressive symptoms which, in turn, affected the intensity of pain.
Clinical Implications: The authors concluded that unresolved PTSD symptoms may influence the pain, depression, and disability experienced by patients with chronic pain following injury. They further encourage pain rehabilitation practitioners to focus on interventions that ameliorate PTSD symptoms as a way to improve pain management outcomes in this population of patients.
[Commentary: The National Center for Posttraumatic Stress Disorder provides a screening fact sheet for healthcare practitioners that includes a discussion of PTSD signs and symptoms, including 4 key questions to aid the assessment. The fact sheet can be found at http://www.ncptsd.va.gov/ncmain/ncdocs/fact_shts/fs_screen_disaster.html (access checked 7/08/08). – WD]
Reference: Roth RS, Geisser ME, Bates R. The relation of post-traumatic stress symptoms to depression and pain in patients with accident-related chronic pain. J Pain. 2008(Jul);9(7):588-596.
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Yoga Helps Improve Low Back Pain, Flexibility
Chronic low back pain (CLBP) is common among adults and choosing an appropriate exercise regimen, once the acute phase of pain has passed, can be confusing. Recommendations against or in support of exercise can be contradictory, but too little activity can ultimately lead to loss of flexibility and strength, thereby prolonging pain and disability.
Physiatrists (rehabilitation physicians specializing in treating pain and restoring function lost through injury) at a residential integrative health center in India compared the effects of a 1-week intensive yoga program with a control intervention of physical exercise. Participants with CLBP were randomly assigned to either a yoga program (including physical postures designed for back pain, breathing exercises, meditation, and general yoga training) or a more traditional physical exercise plan (including activities with a trained physiatrist and classes on lifestyle modification).
In a comparison of pre- and post-intervention assessments, the yoga group demonstrated a significant reduction in pain compared with the exercise group (p = 0.01). Furthermore, while spinal flexibility measures improved significantly in both groups, the yoga group showed greater improvement in 4 measures of flexibility — spinal flexion, spinal extension, right lateral flexion, and left lateral flexion — when compared with controls.
Practice Pointers: The results of this study showed that the benefits of 7 days in an intensive yoga-based program were superior in reducing pain-related disability and increasing spinal flexibility when compared with a more traditional physical exercise program.
[Commentary: This study was conducted in India, where yoga may be more familiar to practitioners and patients, and the authors did not offer recommendations for yoga practices that are suitable for typical patients who cannot participate in a week-long, intensive, residential program. Furthermore, patients should be advised that not all types of yoga practice are the same and it may be wise to begin with a gentler form such as viniyoga. Since some yoga routines may be too challenging for a person with CLBP, it is always wise to discuss chronic back conditions with a certified yoga instructor in advance. – WD]
Reference: Tekur P, Singphow C, Nagendra HR, et al. Effect of short-term intensive yoga program on pain, functional disability and spinal flexibility in chronic low back pain: a randomized control study. J Altern Complement Med. 2008(Aug 3); [Early online publication prior to print].
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Drug Combo Increases Remission in Early RA
Researchers at the University of Leeds in the United Kingdom examined remission and radiographic non-progression rates in patients with active early rheumatoid arthritis treated with a combination of methotrexate and etanercept. They were compared with similar patients administered only methotrexate (monotherapy).
Methotrexate-naïve patients (n=542) with a 3 to 24 month history of early moderate-to-severe rheumatoid arthritis (RA) were randomized to receive either methotrexate (titrated) alone or methotrexate (titrated) plus etanercept 50 mg/week. Methotrexate administration for both study arms was initiated at 7.5 mg/week and increased to a maximum of 20 mg/week within 8 weeks. Co-primary endpoints at week 52 were remission — determined by a disease activity score of <2.6 in 28 joints (DAS28) — and radiographic non-progression.
At one year, 50% of evaluated patients who received the combination treatment of etanercept and methotrexate therapy achieved DAS28 remission, compared with 28% of patients taking methotrexate monotherapy. Radiographic examinations showed no evidence of joint damage in 80% of patients on combined therapy, compared with 59% of participants treated only with methotrexate. American College of Rheumatology ACR70 scores were also measured and reported as comparable to the DAS28 results. An additional quality-of-life assessment questionnaire reported functional improvement for 61% of patients treated with combination therapy and 44% for those on methotrexate monotherapy.
Clinical Concepts: The assessment tools DAS28 and ACR70 measure disease activity, including swelling and pain in joints, and showed that patients with RA who received combination therapy in this study were better able to continue daily-life activities. In a related news story (Therapeutics Daily), Paul Emery, MD, stated “we hope these data encourage physicians to use clinical remission as a new standard for evaluating symptom control in the treatment of early RA.”
Reference: Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomized, double-blind parallel treatment trial. Lancet. 2008(Aug 2);372(9636):375-382.
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Pot Provides Neuropathic Pain Relief, Study Says
According to new evidence, smoking marijuana may help relieve pain in patients with HIV-related neuropathy –– a form of nerve damage leading to burning and tingling sensations, which can be hard to treat with traditional medications. Researcher Ronald J. Ellis, MD, PhD – associate professor of neurosciences at the University of California, San Diego School of Medicine – and colleagues randomly compared medical marijuana with placebo in 28 patients with HIV-related neuropathic pain that was not adequately controlled by analgesics, including opioids.
The National Institute on Drug Abuse supplied cannabis cigarettes and the placebo resembling marijuana but not containing the drug's active chemical, THC. Participants smoked the material 4 times a day for 5 straight days, then abstained for 2 weeks, and then followed the same experiment again. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Each person also continued to take prescribed painkillers during the trial.
Smoking marijuana provided much greater pain relief than smoking the placebo. Clinically significant pain relief was provided in 46% of marijuana smokers compared with only 18% of those smoking the placebo product. Pain relief varied from "strong" to "mild to moderate."
Practice Perspective: The researchers said that medical marijuana significantly reduces HIV-related neuropathic pain when added to a patient's already-prescribed pain management regimen and may be an "effective option for pain relief" in those whose pain is not controlled with current medications. The findings, which appeared online in the journal Neuropsychopharmacology, add to a growing body of evidence suggesting that medical marijuana can be a helpful pain reliever for patients with neuropathy. However, the substance can have a negative impact on certain mental skills and can cause lung problems. Alternative delivery methods are approved in Great Britain and Canada and are being considered by the US, according to background information in the article.
Media report: Stacy KM. Marijuana Eases Nerve Pain Due to HIV. WebMD Health News. August 6, 2008.
Reference: Ellis RJ, Toperoff W, Vaida F, et al. Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial. Neuropsychopharmacology. Advance online publication, August 6, 2008; doi: 10.1038/npp.2008.120.
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Vitamin D for Chronic Pain: PPM Journal
In the July-August 2008 edition of Practical Pain Management, vitamin D is proposed as being helpful in resolving certain chronic pain conditions. Chronic pain – persisting more than 3 months – is a common problem leading patients to seek medical care. In many cases, the causes are nonspecific, without evidence of injury, disease, or neurological or anatomical defect. However, according to extensive clinical research examining adult patients of all ages, inadequate concentrations of vitamin D have been linked to nonspecific muscle, bone, or joint pain, muscle weakness or fatigue, fibromyalgia syndrome, rheumatic disorders, osteoarthritis, hyperesthesia, migraine headaches, and other chronic somatic complaints. It also has been implicated in the mood disturbances of chronic fatigue syndrome and seasonal affective disorder.
Practice Pointers: Current best evidence demonstrates that supplemental vitamin D can help many patients who have been unresponsive to other therapies for pain. Vitamin D therapy is easy for patients to self-administer, well-tolerated, and very economical. To start, a total daily supplementation of 2400 IU to 2800 IU of vitamin D3 is proposed as potentially benefitting patients. Along with that, some patience is advised regarding expectations for improvements; it may require up to 9 months before maximum effects are realized.
Further clinical research studies would be helpful, and vitamin D is not proposed as a “cure” for all chronic pain conditions or in all patients. Optimal clinical outcomes of vitamin D therapy might be best attained via multicomponent treatment plans addressing many facets of health and pain relief. Therefore, vitamin D is not suggested as a replacement for other approaches to pain management, if appropriate.
Reference: Leavitt SB. Vitamin D for chronic pain. Practical Pain Management. 2008;8(6):24-42.
Download the article PDF at: http://pain-topics.org/clinical_concepts/vitamind.php#VitDPPM
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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 websites 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.
Generic Oxycodone ER, Hydromorphone, Buprenorphine Approved
The FDA approved 3 generic opioid drugs in June and July 2008. These products may provide lower-cost prescription analgesic options for pain relief:
- Oxycodone Hydrochloride ER – Covidien/Mallinckrodt Pharmaceuticals – oral extended-release tablet in 10 mg, 20 mg, 40 mg, and 80 mg strengths.
- Hydromorphone Hydrochloride – Hospira, Inc. – 10 mg/ml injectable solution (similar formulation previously approved for other generic-drug manufacturers).
- Buprenorphine Hydrochloride – Roxane Laboratories –sublingual tablet in 2 mg and 8 mg strengths (tentative FDA approval 6/18/08, not on market yet).
Duloxetine (Cymbalta®) – FDA Approved to Treat Symptoms of Fibromyalgia
The FDA granted a June 2008 approval of Cymbalta, a serotonin-norepinephrine reuptake inhibitor, for the treatment of the signs and symptoms of fibromyalgia. As a chronic condition characterized by widespread pain and tenderness, fibromyalgia frequently exhibits a varied array of symptoms that may also interfere with normal sleep quality. The approval was based on the analgesic effect demonstrated in two 3-month-long studies involving 874 adult patients diagnosed with fibromyalgia syndrome. Cymbalta is also FDA-approved to treat major depressive disorder, generalized anxiety disorder, and diabetic peripheral neuropathy.
Duloxetine prescribing information can be downloaded at: http://pi.lilly.com/us/cymbalta-pi.pdf (access checked 8/7/08).
Lubiprostone (Amitiza®) – FDA Approval for Irritable Bowel Syndrome with Constipation
The first US drug to treat irritable bowel syndrome with constipation (IBS-C) in adult women was approved by the FDA in April 2008. Irritable bowel syndrome, a disorder that affects twice as many women as men, is characterized by abdominal pain, cramping, bloating, constipation, and diarrhea. Amitiza –– developed by Sucampo Pharmaceuticals, Inc. and co-marketed by Sucampo and Takeda Pharmaceutical Company –– is administered twice daily (8 micrograms per dose) for IBS-C. The efficacy and safety of the drug was established in 2 studies involving 1154 patients diagnosed with IBS-C and, because 90% of participants were women, the FDA stated that effectiveness was not conclusively demonstrated for men.
For the FDA patient information sheet on lubiprostone, see: http://www.fda.gov/cder/drug/InfoSheets/patient/lubiprostonePIS.htm (access checked 8/07/08).
Highlights of the lubiprostone prescribing information can be downloaded at: http://www.sucampo.com/downloads/amitiza-pi-2007-06.pdf (access checked 8/07/08).
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