Primecuts-This Week in the Journals

October 18, 2010

By: Demetrios Tzimas, MD

Faculty Peer Reviewed

While the rest of the world was watching the rescuing of “Los 33,” I was searching for love; actually, love found me!  This week, the front pages of both CNN and the New York Times online referenced a study conducted by Younger et al, from the Stanford University School of Medicine, that discussed the benefits of being with someone we love as a method of reducing pain (“Love may be as good as morphine”).  The study, which looked at 15 Stanford University undergraduates in the first nine months of a romantic relationship, exposed participants to differing levels of thermal pain to the hand while viewing pictures of their romantic partner, an acquaintance of the same gender (of equal attractiveness), and while performing a distraction task [1].  Participants underwent fMRI during these exercises.  The authors found an association between reward systems in the brain (amygdale, hypothalamus, pregenual anterior cingulated cortex, medial orbitofrontal cortex) and a subjective reduction of pain when viewing pictures of one’s romantic partner, distinct from viewing an acquaintance and participating in a distraction task.  Although the results do point us in a direction of successfully reducing pain via non-pharmacologic methods, the size of the study and subjectivity of pain rating makes further study important in this field.  Love and pain, something I am unfortunately very familiar with.

On the topic of pain, a common problem we see in our outpatient clinics is the pain of migraines.  While there are different types of analgesia to deal with migraines, and behavioral methods of preventing them, Holroyd et al studied the effects of β-blockers in the prevention of migraines [2].  The authors conducted a randomized placebo controlled trial over 16 months, and looked at 232 adults with diagnoses of chronic migraines who were optimally managed on triptans (ie. Sumatriptan) for the acute treatment of their migraines.  The participants were randomized into four groups, β-blockers (nadolol or propranolol with up-titration as tolerated), a matched placebo group, β-blocker with behavioral migraine management (relaxation techniques, biofeedback, stress management) to prevent, abort, and cope with migraines, and behavioral migraine management with a matched placebo.  Participants recorded headaches and any associated symptoms in a handheld device over the 16 month study period, and were allowed to switch β-blockers and dosage based on adverse effects, most commonly being fatigue.  The four treatments all yielded clinical improvements in migraines, yet only the β-blocker with behavioral management group showed a statistically significant decline in migraines per 30 days, totally migraine days per 30 days, and an increase in migraine specific quality of life scores.  The other treatment groups were on the whole not significantly different in their ability to help these patients with migraines.  Interestingly, the behavioral management group with placebo did show a significant increase in migraine specific quality of life scores.  This is an important study, as headaches and migraines are an extremely common complaint in outpatient medicine, and are difficult to manage.   Of note, half of the patients taking nadolol as a β-blocker ended up switching to propranolol, although the study was not designed to test the differences amongst the β-blockers.  It is also noteworthy that the behavioral group with placebo also showed a significant increase in quality of life, although it is not clear whether this was an effect of the placebo or from behavior modification.   It is clear from this study that it truly takes a village (and medicine) to help patients with chronic migraines. 

The New England Journal of Medicine also focused on pain this week, reporting a study by Lane and colleagues, which looked at suppressing nerve growth factors as a role in augmenting pain in patients with osteoarthritis [3].  Authors described how neurotrophins regulate the structure and function of sensory neurons, and how a humanized IgG2 monoclonal antibody directed against the interaction between these nerve growth factors and their receptors could modulate pain in patients with osteoarthritis.  The authors randomized 450 patients with advanced osteoarthritis (as defined by radiographic imaging) who were surgical candidates secondary to non-responsiveness to medications, to six treatment groups to receive either placebo, or intravenous Tanezumab (10 µg/kg in one group, 25 µg/kg in another, 50 µg/kg, 100 µg/kg, and 200 µg/kg in the last group) on day 1 and on day 56.  The primary efficacy measures of Tanezumab were knee pain while walking, pain, stiffness, and physical function as defined by WOMAC criteria, the rate of response via OMERACT-OARSI criteria, and safety. Tanezumab at all the doses had a statistically significant improvement in pain, stiffness, and function, and there was a reported decrease in knee pain while walking, as well as rate of response, throughout the 16 weeks of the study.  An issue with this study is that it was not powered to assess a dose response, and thus optimal efficacy and safe management of the drug cannot be garnered from this study, although authors did note a trend in adverse effects (including headache, parasthesias) that seemed to be dose dependent.   Also, while there were baseline radiographs to define osteoarthritis, the study did not include radiographs in analyzing decline, improvement, or stability in knee joint osteoarthritis.   These are important issues, as authors mentioned in their discussion that trials of this drug are now on hold by the FDA, as in certain phase 3 studies participants tended to require more joint replacements and had worsening osteoarthritis via radiographs. 

 The New England Journal of Medicine also focused on the organ of affection this week, the heart.  With a great deal of controversy involving the use of proton-pump-inhibitors and clopidogrel, Bhatt et al  published an article looking at clopidogrel with or without omeprazole in patients with coronary artery disease [4].  This study was originally the COGENT Trial (Clopidogrel and the Optimization of Gastrointestinal Events), although the sponsor, Cogentus Pharmaceuticals, lost its financial backing causing the trial to end prematurely.  Authors randomly assigned 3,761 participants to a clopidogrel (75mg)/omeprazole (20mg) combination pill group or a clopidogrel (75mg)/placebo pill treatment group.  The pre-specified gastrointestinal efficacy endpoint was to the first occurrence of upper gastrointestinal clinical events (overt GI bleeding, upper GI bleed of unknown origin, occult GI bleed with decrease in hemoglobin of 2, gastroduodenal ulcer, pain, obstruction, or perforation).  The pre-specified primary cardiovascular safety endpoint was a composite of death from cardiovascular causes, nonfatal MI, coronary revascularization, or ischemic stroke.  The event rate for the composite of gastrointestinal primary end points was significantly reduced from 2.9 to 1.1 percent after 180 days.  The only individual endpoints that didn’t meet significance were occult bleeding and symptomatic ulcer, although there were fewer episodes of these in the treatment group.  There were no significant differences in the rate of primary cardiovascular endpoints between the two treatment groups after 180 days (4.9 % in the omeprazole group, and 5.7% in the placebo group).  This is an important article, as there has been a great deal of controversy the past few years regarding the effects of proton-pump-inhibitors on the cytochrome P-450 system, and thus their interaction with clopidogrel.  Methods to minimize these theoretical risks have included using H-2 blockers or dosing PPI’s at different times than clopidogrel.  Although the article does support the use of PPI’s with clopidogrel, as authors mentioned, this was specifically a trial for a combination pill, and thus the pharmacokinetics of a combination pill may be different than dosing clopidogrel and PPI’s as two separate entities, as is currently practiced.  Also, the study looked at an endpoint of 180 days; many of our patients are on life-long clopidogrel (and therefore concurrent PPI prophylaxis), and this study may not have looked long enough for the deleterious theoretical effects and clopidogrel and proton pump inhibitors. 

Still on the topic of the heart, the Archives of Internal Medicine recently published a meta-analysis looking at the effects of B vitamin supplementation to lower homocysteine levels, and its effect on cardiovascular disease, cancer and mortality [5].  Clarke et al wanted to investigate the homocysteine hypothesis, which states that moderate elevations in homocysteine may be related to cardiovascular disease in the general population.  This theory stems from the high rates of cardiovascular disease seen in untreated children with homocystinuria.    Since it is known that folate lowers homocysteine levels, the authors looked at studies that tested this hypothesis.  They found 8 randomized trials that met their eligibility criteria, and thus included 37,485 individuals.  The meta-analysis showed that overall, a 25% reduction in homocysteine levels was maintained on average for 5 years in these trials, but had no effect on strokes (ischemic or hemorrhagic), vascular outcomes (number of coronary and non coronary revascularizations), or coronary events (non-fatal MI, CHD, death).  Seven of the trials showed no significant difference between cancer, despite doses of folic acid given to patients, and folic acid was not associated with any significant differences in total mortality in any of the trials.  We must use caution in interpreting these results, as it is a meta-analysis, but as authors stated in the article, even though no beneficial effect in these outcomes was noted, no poor outcomes were noted either, so the public health measure of folate supplementation to help reduce neural tube defects should continue.  Looks like Vitamin D is still king when it comes to vitamins, but we’ll leave that discussion to upcoming Primecuts!

Demetrios Tzimas is a second year internal medicine resident at NYU Langone Medical Center

Peer Reviewed by: Barbara Porter, MD, Associate Program Director, NYU Internal Medicine Residency Program, Section Editor, Clinical Correlations

Image Courtesy of Wikimedia Commmons

 References:

[1] Younger J, Aron A, Parke S, et al.  Viewing pictures of a romantic partner reduces experimental pain: Involvement of neural reward systems.  Plosone.  5 (10): e13309. Published online October 13, 2010.  Web.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0013309

[2]  Holroyd K, Cottrell C, O’Donnell F, et al.  Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimized acute treatment in frequent migraine: randomised controlled trial.  British Medical Journal.  2010 Sept; 341:c4871.  Web.  http://www.bmj.com/content/341/bmj.c4871.full

[3] Lane N, Schnitzer T, Birbara C, et al.  Tanezumab for the treatment of pain from osteoarthritis of the knee.  New England Journal of Medicine.   2010 Sept; 363 (16): 1521-1531.  Print.

http://www.nejm.org/doi/full/10.1056/NEJMoa0901510

[4] Bhatt D, Cryer B, Contant C, et al.  Clopidogrel with or without Omeprazole in coronary artery disease.  New England Journal of Medicine.  Published online October 6, 2010.  Web.

http://www.nejm.org/doi/full/10.1056/NEJMoa1007964#t=article

 [5] Clarke R, Halsey J, Lewington S, et al.  Effects of lowering homocysteine levels with B vitamins on cardiovascular diease, cancer, and cause-specific mortality.  Archives of Internal Medicine.  2010 Oct; 170 (18): 1622-1631.  Print.

http://archinte.ama-assn.org/cgi/content/full/170/18/1622

One Response to Primecuts-This Week in the Journals

  1. [...] New England Journal of Medicine that found significantly decreased upper gastrointestinal events and no difference in cardiovascular endpoints in patients taking a clopidogrel/omeprazole combinatio….[3]  The authors of the latest consensus document admit combined use of PPIs and anti-platelet [...]

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