IVIG Shown to Relieve Complex Regional PainSyndromeBut Study Has Limitations, Experts SayB y T o m V a l e o

MARCH 4, 2010 | NEUROLOGY TODAY | 27

Asmall but intriguing studyfound that intravenous im-munoglobulin (IVIG) can pro-

vide relief for people suffering fromcomplex regional pain syndrome, orCRPS, which causes chronic and oftenintractable pain, usually in an arm orleg, long after recovery from an illness orinjury.

While pain management experts notinvolved with the paper said the trialhad several limitations — including thesmall number of patients and the highcost of the therapy — they said it wasvaluable in offering evidence that modu-lating the immune system could help in

pain management.In the Feb. 2 paper in the Annals of

Internal Medicine, researchers at the PainResearch Institute at the University ofLiverpool in England reported that theyadministered a half-gram of IVIG perkilogram of body weight to 13 peoplewho had been suffering from CRPS be-tween six and 30 months. All had failedto achieve significant relief from conven-tional treatments including aceta-minophen, nonsteroidal anti-inflamma-tory drugs, opioids, antidepressants,gabapentin or pregabalin, and physicaltherapy.

The Liverpool researchers got theidea for the IVIG treatment several yearsago when they gave the drug to a patientwith primary hypo-gammaglobuline-mia, a blood disorder that leaves peopleunusually susceptible to infections suchas pneumonia and influenza. The pa-tient suffered from widespread pain ofunknown cause (not CRPS) that was re-lieved temporarily after IVIG was ad-ministered. Repeating the treatment al-leviated the pain. The researchers thenadministered IVIG to other pain pa-tients, who experienced some relief.

Only subjects who reported pain in-tensity of at least five on an 11-pointscale for seven consecutive days were in-cluded in the study. One subjectdropped out after becoming pregnant.Of the remaining 12, half the subjectsreceived IVIG and half received a salineplacebo. Then, after ending treatmentand waiting several weeks for responsesto diminish, the treatment was reversed,with the IVIG subjects receiving saline,and the saline subjects receiving IVIG.

Beginning six days after infusion,when discomfort from the injection andtransient side-effects had subsided, sub-jects were asked to rate their pain everyday for two weeks. Five of the 12 sub-jects reported median pain scores atleast 2 points lower with IVIG than withthe saline placebo, and three of the fivereported pain scores at least 50 percentlower. (One patient reported a 2-pointdrop in pain after receiving saline.) Theaverage drop in pain after receiving IVIGwas 1.55 points.

“To our knowledge, we have shownfor the first time that low-dose IVIG re-duces pain in patients with longstand-ing, refractory CRPS, with few adverse

reactions,” the study authors, led by An-dreas Goebel, MD, PhD, of the Universi-ty of Liverpool Pain Research Institute inthe UK, wrote. “Intravenous im-munoglobulin may emerge as an effec-tive and safe novel clinical treatment op-tion for otherwise refractory disease, butconfirmatory trials are required.”

STUDY LIMITATIONSBut an editorial in the same issue bypain researchers Frank Birklein, MD,PhD, of the Department of Neurology atthe University of Mainz in Germany,and Claudia Sommer, MD, PhD, of theUniversity of Wurzburg, asserted thateven if the results of this small study arereplicated by larger and more rigorousresearch, the high cost of IVIG — cur-rently $75-$124 per gram in the US —would make it impractical as a long-term treatment, especially when lesscostly alternatives such as ketamine,magnesium, and tadalafil (Cialis) haveshown similar efficacy. (At $100 pergram, one dose for a 200-pound man inthe study would cost about $4,500.)

“We remain skeptical that those whomake payment decisions will cover IVIGin CRPS … without much more con-vincing evidence that IVIG is more ef-fective than other therapies,” the authorsstated.

Another pain researcher, however,pointed out that other treatments forCRPS can be very expensive too. “Com-pared to prolonged IV ketamine, IVIG ischeap,” said Michael C. Rowbotham,MD, professor of clinical neurology andanesthesia at University of California-San Francisco Pain Clinical ResearchCenter. “Ketamine itself is cheap, butthe administration protocol is expen-sive. Putting people into a ketamine co-ma for days at a time requires intensivenursing support. Nerve blocks frequent-ly employed for treating CRPS also arevery expensive. CRPS is a pain problemwhere the cost of treatment can veryrapidly reach many thousands of dol-lars.”

Still, the study by the Liverpoolgroup has other imitations, according toRobert J. Schwartzman, MD, professorand chair of the Department of Neurol-ogy at Drexel University College of Med-icine in Philadelphia. “Only 13 patients

received the therapy, and they had min-imal response,” he said. “Only three pa-tients got 50 percent relief, and they on-ly studid the patients for three weeks.”

Dr. Schwartzman, like the authors ofthe accompanying editorial, was con-cerned about the blinding of the study.The study failed to show a placebo re-sponse, “which raises doubts about theadequacy of the blinding,” the editorialauthors wrote. “The observed responseto IVIG (20-30 percent pain reductionfrom baseline) is in the range that onewould expect for the placebo response.”

Dr. Schwartzman agreed that theweak response to IVIG that most pa-tients displayed is hard to distinguishfrom a placebo effect. “In the pain busi-ness you’ve got to beat 30 percent relief

DR. ANNE LOUISE OAKLANDER:“This builds on several other ar-eas of research showing the im-portance of immune interac-tions. These include epidemio-logical research showing thatpatients with CRPS more likelyto have asthma, and evidence ofcytokines and other pro-inflam-matory markers in tissue fluidsand cerebrospinal fluids fromthese patients. Data from threerat models of CRPS also high-lights the importance of the im-mune and inflammatory re-sponse to nerve injury.”

DR. ROBERT SCHWARTZMAN:In the pain business you’ve gotto beat 30 percent relief of pain– that’s the placebo effect. Also,IVIG is very hard to blind be-cause people who receive it geta very bad headache. I’ve al-ways used IVIG with steroidsbecause when I didn’t, at least50 percent of people got a verybad headache.”

ARTICLE IN BRIEF

4 A small study found IVIGeffective for alleviating

chronic regional pain syn-drome, providing evidence thatmodulating the immune systemcould help with managing pain.

Continued on page 28

Why The Truth About The Health of Our Leaders MattersFDR’s Deadly Secret. By Steven Lomazow, MD and Eric Fettmann. 296 Pages. Public Affairs: Perseus Books Group 2010.

B y J a m e s F . T o o l e , M D

28 | NEUROLOGY TODAY | MARCH 4, 2010

of pain – that’s the placebo effect,” hesaid. “Also, IVIG is very hard to blindbecause people who receive it get a verybad headache. I’ve always used IVIGwith steroids because when I didn’t, atleast 50 percent of people got a very badheadache.

While the authors of the study didnot administer steroids, they placed acotton bag over the IV apparatus to con-ceal the bubbles and foam that IVIGproduces in the drip chamber duringthe infusion. And because IVIG is stick-ier than saline, they primed the infusionline with normal saline to prevent thepatient or the physician from identifyingthe substance by its viscosity if itdripped from the end of the IV line.

ROLE OF IMMUNE SYSTEM:PAINThe study, while small, adds additionalevidence that the immune system playsa key role in generating the chronic and

disproportionate pain characteristic ofCRPS, said Anne Louise Oaklander,MD, PhD, associate professor of neurol-ogy at Harvard Medical School, who wasnot involved with the study.

The study authors noted, for exam-ple, that other researchers also havefound antineuronal autoantibodies inpatients with CRPS. “Intravenous im-munoglobulin not only potentially in-terferes with these autoantibodies butalso downregulates proinflammatory cy-tokines, which are important in themechanisms of CRPS pain and hyperal-gesia, in the peripheral and the centralnervous systems,” they wrote.

“This builds on several other areas ofresearch showing the importance of im-

mune interactions,” said Dr. Oaklander.“These include epidemiological researchshowing that patients with CRPS morelikely to have asthma, and evidence ofcytokines and other pro-inflammatorymarkers in tissue fluids and cere-brospinal fluids from these patients. Da-ta from three rat models of CRPS alsohighlights the importance of the im-mune and inflammatory response tonerve injury.”

These studies may help explain whyCRPS develops in just a few of the manypatients who sustain injuries, Dr. Oak-lander said. “I think this may be similarto peanut allergies,” she said. “Some pa-tients are primed to have a dispropor-tionate response to a stimulus that is in-

nocuous or trivial for the vast majorityof people.”

The immune system is very impor-tant in pain, Dr. Schwartzman agreed,adding that this is further evidence thatdampening the immune system helpsregional pain syndrome and probablyother pain syndromes. “We used tothink all pain had to do with pain trans-mission neurons, but a lot of it has to dowith turning on microglia and astrocytesthat make inflammatory cytokines thatstimulate pain processes. So if you canturn off the immune component of this,you really can help dramatically. It’s awhole new way of looking at pain.” •

REFERENCES:• Goebel A, Baranowski A, Ambler

G, et al. Intravenous immuno-globulin treatment of the complexregional pain syndrome :A ran-domized trial. Ann InternMed2010; 152:151-158.

• Birklein F, Somer C. Editorial —Intravenous immunoglobulin tofight complex regional pain syn-dromes: Hopes and doubts. AnnIntern Med2010; 152:188-189.

‘We remain skeptical that those whomake payment decisions will coverIVIG in CRPS…without much moreconvincing evidence that IVIG is moreeffective than other therapies.’

bookshelf

There is more and more evidencethat subterfuge and misinfor-mation have been part and par-

cel for maintaining the image of leadersof the world who have been impaired,if not totally unable to serve in officedue to physical and or mental illness.In many cases inep-titude caused by de-mentia or paranoiahave led to local orregional as well asnational and interna-tional armed con-flict. In the pastthese conflicts werelocal, regional, ornational but now the risk of interconti-nental nuclear missiles makes the dan-ger global.

No nation can protect itself unlessthe very best brains are in leadershippositions! Examples from history withwarriors equipped with swords, slings,and arrows abound and they were wel-

comed home as heroes. Now in war en-tire cities are targets for intercontinen-tal nuclear-tipped missiles.

A prime example of this is FranklinDelano Roosevelt whose disability frompoliomyelitis was kept quiet and whoseuntreated hypertension with heart fail-

ure was ignored by his doctors for fearof retribution if medical managementwent awry. Near death, he was a non-performer at the crucial Yalta meetingat the end of WW II. So too was it saidthat Sir Winston Churchill was de-mented and unable to perform, leavingJoseph Stalin, the sole person whose

paranoid mind controlled the divisionof major portions of the world into theSoviet or the Western Blocks, includingPoland, Vietnam, Korea and others,each of which led to international crisesand national disasters, some of whichpersist to this day.

Now wehave evidencethrough thesleuthing of theauthors ofFDR’s DeadlySecret that FDRhad a malig-nant melanomaabove his left

eyebrow in his left forehead, which theauthors opine may have led to intracra-nial metastases that further disabled hiscapacity for mental processing. Itseems that Roosevelt did have amelanoma, which was hidden from thepublic by altering the photographs of

DR. JAMES F. TOOLE WRITES:“Steven Lomazow and Eric Fettmannhave done a service for the nation bypublishing this book, which adds fuelto the thought that people with poorprognosis for survival throughouttheir term in office should not be candidates.”

CRPSContinued from page 27

‘No nation can protect itself unless the very best brains are in leadershippositions!’

Continued on page 29