Posted on 08/29/2006 9:09:31 PM PDT by STD
In a reversal which has monumental implications for thousands of chronic pain patients with implanted pain pumps, these two studies implicate all known opioid medications delivered via implanted intrathecal pumps for causing tumor generation within the sensitive area around the spinal cord. Thousands of patients are today living in wheelchairs due to these lesions, which the makers of the pumps denied. If I could draw an anology with the secret that "Big Tabacco" wouldn't admit; that cigarettes are not habit forming due to nicotine. Seldom is an industry more deserving of, or ripe for civil litagation. In 1983, DW Coombs published a warning about these infusions in JAMA. Hardly, a unknown or readerless publication; the industry took advantage of antiquated FDA standards to get the pump approved for a non-opioid drug. Once approved for that drug, the industry went to the chronic pain community and found physicians willing to use morphine off-label in the pumps for the treatment of non-malignant pain. Billions of dollars has been spent on this reckless technology, but much more sadly thousands of patients can no longer walk due to benign tumor growth compressing and destroying the spine.
Anesthesiology. 2006 Sep;105(3):581-589.
Time Course and Role of Morphine Dose and Concentration in Intrathecal Granuloma Formation in Dogs: A Combined Magnetic Resonance Imaging and Histopathology Investigation.
* Allen JW, * Horais KA, * Tozier NA, * Wegner K, * Corbeil JA, * Mattrey RF, * Rossi SS, * Yaksh TL.
* Project Scientist, Anesthesiology Research, Department of Anesthesiology, University of California, San Diego. Current position: Medtronic Neurological, Columbia Heights, Minnesota. dagger Staff Research Associate, double dagger Postdoctoral Fellow, # Project Scientist, ** Professor, Anesthesiology Research, Department of Anesthesiology, section sign Staff Research Associate, parallel Professor, Department of Radiology, University of California, San Diego.
BACKGROUND:: Intrathecal morphine infusion leads to intrathecal granulomas. In dogs, the authors examined time course of granuloma formation and the role of concentration in granuloma development. METHODS:: Dogs were prepared with lumbar intrathecal catheters and vest-mounted pumps. To define the time course of granuloma formation, serial magnetic resonance imaging was performed in animals receiving 10 or 31 days of morphine infusion (12.5 mg/ml at 40 mul/h). At these times, morphine was removed from the infusate, and further magnetic resonance images were acquired over 14-35 additional days. To assess dose versus concentration, dogs received 28-day infusions of vehicle, 12 mg morphine/day as 12.5 mg/ml at 40 mul/h, or 1.5 mg/ml at 334 mul/h (12 mg/day) for 28 days. Additional dogs received 3 mg/day as 12.5 mg/ml at 10 mul/h. RESULTS:: Serial magnetic resonance images in dogs receiving morphine (12.5 mg/ml at 40 mul/h) revealed pericatheter-enhancing tissues as early as 3 days with a prominent signal by 10 days. Removal of morphine reduced the mass volume within 7 days. At a fixed infusion rate, the incidence of granuloma formation with the continuous intrathecal infusion of morphine ranged from 0 in vehicle-treated dogs to 100% in dogs treated with 12.5 mg/ml at 40 mul/h (12 mg/day). Infusion of 12 mg/day at 1.5 mg/ml (334 mul/h) resulted in granuloma in one of four animals. The authors found that infusion of morphine in different concentrations at a fixed rate resulted in a dose-dependent increase in concentration, with the granuloma-producing, dose-yielding lumbar cerebrospinal fluid morphine concentrations around 40 mug/ml. CONCLUSIONS:: Serial magnetic resonance imaging showed a rapid formation and regression of the masses initiated by intrathecal morphine infusion. These masses are dependent on local concentration.
PMID: 16931993 [PubMed - as supplied by publisher]
Anesthesiology. 2006 Sep;105(3):590-598. Opiate Pharmacology of Intrathecal Granulomas.
Allen JW, Horais KA, Tozier NA, Yaksh TL.
* Project Scientist, Department of Anesthesiology, University of California, San Diego. Current position: Medtronic Neurological, Columbia Heights, Minnesota. dagger Staff Research Associate, double dagger Professor, Anesthesiology Research, Department of Anesthesiology, University of California, San Diego.
BACKGROUND:: Chronic intrathecal morphine infusion produces intradural granulomas. The authors examined a variety of opioids infused intrathecal for analgesic activity and toxicity. METHODS:: Two sets of experiments were undertaken in dogs with chronic intrathecal catheters: (1) Six-hour intrathecal infusions were used to determine the full analgesic dose and the maximum tolerated dose. (2) To establish toxicity, the maximum tolerated dose was given for up to 28 days by continuous intrathecal infusion. Drugs examined were morphine sulfate, hydromorphone, d/l-methadone, l-methadone, d-methadone, fentanyl, [d-Ala,N-Me-Phe,Gly-ol]-enkephalin (DAMGO), naloxone, or saline. RESULTS: ANALGESIA AND TOLERABILITY:: Six-hour intrathecal infusion of agonists resulted in a time-dependent increase in thermal escape latency. At higher concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity occurred. The concentrations, in mg/ml, for full analgesic dose/maximum tolerated dose were as follows: morphine, 0.9/12.0; hydromorphone, 1.0/3.0; d/l-methadone, 2.8/3; l-methadone, 1.0/> 1.0; fentanyl, 0.3/2.0; DAMGO, 0.1/> 2.0; d-methadone, > 1/> 1; naloxone, > 10/> 10. Spinal pathology: Chronic intrathecal infusion of the maximum tolerated dose revealed 100% intradural granuloma formation after morphine, hydromorphone, l-methadone, and naloxone. DAMGO induced a mass in only a single animal (one of three). d/l- and d-methadone produced intradural granulomas but were also associated with parenchymal necrosis. Saline and fentanyl animals displayed no granulomas. CONCLUSIONS:: Intrathecal opiate-induced granulomas are not strictly dependent on opioid receptor activation. Therefore, opiates at equianalgesic doses present different risks for granuloma formation. Importantly, d/l- and d-methadone also resulted in parenchymal necrosis, an affect associated with the N-methyl-d-aspartate antagonist action of the d-isomer.
PMID: 16931994 [PubMed - as supplied by publisher]
Baclofen was/is the "anchor drug" for the device.....
for the opiates, the half-life in circulation is short, but in this type of administration, it hangs....accumulates, permeates, obstructs, corrupts the sheath and its biology.
Spinal nerve blocks and ablations are effective and safe.
If removal of the drug causes reduction in the granuloma in dogs, wouldn't it do the same for the human patients?
the right answer is probably, maybe, or maybe not. The same goes for forming the tumors in humans, too. The dog experiment only shows what happens in dogs, albeit a possible or likely result in humans is suggested.....but not proven.
last sentence of first paragraph:
"...but much more sadly thousands of patients can no longer walk due to benign tumor growth compressing and destroying the spine."
(I think they really meant "spinal cord", not "spine")
Your link is to the abstract, is the opening paragraph your commentary on the abstract? Please clarify.
I.e. the FDA approved the devices for treatment of cancer related pain, but not specifically for other causes of intractable pain. Their off label use both saves millions of research dollars proving they work in each of the myriad non-cancer related causes of intractable pain and lets the myriad of miserable non-cancer patients with zero quality of life have an option to regain their lives instead of being locked into their misery by bureaucratic fiat. This smells of lawyers trying to get richer off pain doctors and drug companies, which will just lead to more patients unable to obtain effective care. Chronic, incurable, non-cancer pain patients are not rare. My father is one of them. Before he was accurately diagnosed he was having suicidal ideation from the pain. After failing the first two treatment options he finally responded to an nerve stimulator implanted along his spinal chord. The spinal morphine pump would have been his next option if that hadn't worked and I'm certain he'd take this risk over the pain.
These granulomas aren't really tumors, but rather collections of inflammatory cells from the immune system. Granulomas can be suppressed by drugs, at least in some organ systems. I'm a Dermatologist, not a Neurologist, so I can't claim specific expertise on spinal granulomas, but I have successfully treated various granulomas in the skin. The article even mentions the granulomas regressing. The proper response to this dog study would seem to me to be a study in which candidate drugs were mixed with the opiods in the infusion to see if they could safely suppress this side effect. As the problem is localized, delivering an anti-inflammatory agent via the same infusion may be able to suppress it with minimal systemic side effects. It sounds like they have a good research model to test out candidate drugs and concentrations thereof. Don't browbeat the problem, solve it! And don't prohibit the current treatment until the problem is solved; just obtain informed consent. Don't limit it to cancer patients as plenty of non-cancer patients also need and deserve this help. Paralysis is certainly a serious side effect, but pain can be bad enough to make it an acceptable risk if there really are no other possible solutions.
If you don't already have basically a paralyzing pain, you don't implant an opiod delivery system. Think sciatic nerve damage which makes it virtually impossible to walk to stand. You should have already passed the point of injectable steriodals or nerve blocks as well as a variety of neuralgia treatments. An implantable device is just before nerve stripping on the scale of extreme treatments, so its not like people are just doing this willy nilly to get some morphine kicks.
Correct, the first cases noted for granuloma development with isolated baclofen use were written in 1992. Here's an article recently written by an objective researcher not a company consultant,like in the previous 1992 cases.
1: Anesth Analg. 2006 Mar;102(3):848-52.
Intrathecal catheter granuloma associated with isolated baclofen infusion.
Murphy PM, Skouvaklis DE, Amadeo RJ, Haberman C, Brazier DH, Cousins MJ.
University of Sydney Pain Management and Research Institute, Department of Radiology, Royal North Shore Hospital, St. Leonards, NSW, Australia. drpmurphy@hotmail.com
Intrathecal (IT) baclofen is an effective management strategy for controlling spasticity in patients unresponsive to maximal oral therapy. We present the case of a 57-yr-old woman who was rendered quadriplegic after a complete spinal cord transection at the C6 level. Her course was complicated by severe spasms, which were uncontrolled despite titrating orally administered baclofen to 80 mg/d. IT baclofen testing was performed with good response, and administration was commenced via an implanted intrathecal pump 6 mo after the injury at an initial dose of 200 microg/d. Catheter revision was required 2 wk later as a result of catheter displacement. The initial IT baclofen dose was gradually increased to achieve good control at a level of 400 microg/d. After a period of stability lasting 38 mo, her lower limb spasms dramatically increased in severity and remained poorly controlled despite repeated dose increases. Contrast pumpogram and computed tomography myelogram were performed to exclude a mechanical cause for this apparent increase in baclofen requirement. These investigations revealed neither catheter displacement nor fracture as suspected but, rather, displayed the presence of a catheter tip-associated mass. Catheter tip granuloma has not previously been described in a patient receiving IT baclofen alone. This suggests that although uncommon, the possibility of catheter-associated granuloma must be considered in all patients receiving IT baclofen presenting with altered neurological function or significant increase in drug requirement.
Publication Types:
* Case Reports
PMID: 16492839 [PubMed - indexed for MEDLINE]
Spinal nerve blocks and ablations are effective and safe.
Because they are short term exposures to opioids or baclofen.
Yes, the first paragraph is mine. Look at thousands of reports of neurological injuries at MAUDE database under the term granuloma. Start here in 1998 and progress up til 2006. You will see thousands of physicians and patients without "Informed Consent"
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=189029
You know of what you speak? I agree, but new meds are as effective and safe without the risk of cord compression.
My mother has one implanted for Dystonia. She is on her second pump and has had everything from Baclophen, Morphine to Hydromorphone.
She doesn't care about the tumors, she only wants the relief from the chronic pain of Dystonia.
Her doctor spoke with her about the tumor issue and she said no to removal.
Can't say that I blame her, she has suffered horribly for the past 20 years.
I wrote...Spinal nerve blocks and ablations are effective and safe.
you replied...."Because they are short term exposures to opioids or baclofen."
looks to me like we have a different understanding of nerve blocks and ablations.....former is done w strong lidocaine type drug and steroid; latter uses current....and Baclofen is a "muscle relaxant", not an analgesic.......
I don't think we're on the same page about this.
I have a crumbling lumbar.....most discomfort to date has been "facet joint syndrome", due to missing vertebral discs causing increased facet joint pressures, although there a bit of nerve root compression.
After proving it w/steroid-analgesic injected into the actual facet joints with good result, they used the pulsed current on the medial branches for each facet joint that proved out. (medial branch is the first nerve-root branch, which services the facet joint uniquely).
This is sometimes referred to as "rhizotomy". The pain was referring itself to nearly all points south of lumbar. I spent 2+ years looking, and finally found myself facing the Emeritus Neurosurgeon of IU, who suggested pursuing this after listening to me for an hour......the very strong caveat was to prove it clinically before doing anything permanent, which to date hasn't......the pulse ablation is still good at 15 months. It doesn't "cook" the nerve, it only stuns it, thus far good for this long.
No we're still on the same page. My reference article above was about granulomas formed in dogs that got different opioids in 28 days. The third article above shows that their initial application drug; baclofen also causes granulomas when used in isolated treatment of spasticity as well.
What is so incedulous is that these "scientists" are claiming that this study of only 28 days in dogs has any resemblance of representing what happens in long term human exposure or "chronic" implantation situations that in some cases has lasted 8 years. Almost all of these patients have granulomas.
Did you actually go over to the FDA MAUDE site and look at the carnage? Here I'll make it easy for you! http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=189029
Granulomas on the database are called by 12 different names, because the provider didn't know what to call them; example catheter tip mass, inflammatory mass, fibroma, fibrositis, etc,,,
BTW, I have the best neurological surgery informed consent form you've ever seen, if you want a copy.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=189029
Neurosurgery. 1991 Nov;29(5):778-84.
Spinal cord compression complicating subarachnoid infusion of morphine: case report and laboratory experience.
North RB, Cutchis PN, Epstein JA, Long DM.
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
The intraspinal administration of morphine has been employed increasingly in the management of intractable pain of malignant as well as benign origin. We have encountered a previously unreported clinical complication: spinal cord compression by an inflammatory tissue mass surrounding a subarachnoid infusion catheter administering morphine, leading to paraplegia. The patient was referred to our institution after catheter and pump implantation for chronic, intractable pain associated with pre-existing lumbar arachnoid fibrosis, after multiple myelograms and surgeries. The patient may, therefore, have had an underlying propensity to foreign body reactions. We have encountered a similar phenomenon, however, in a canine laboratory model. The pathological features in both our patient and our laboratory preparation, with inflammatory tissue masses around the tip of the catheter but not around proximal subarachnoid segments, suggest an effect related to infusion, as opposed to infection or the presence of the catheter. We review the pathological features in both settings and the pertinent literature. PMID: 1961414 [PubMed - indexed for MEDLINE]
many drugs are involved here, but they seem to want to compress it to morphine.....I've done a couple hours reading on this now, and cant help but wonder if the culprit isn't the barium in or on the catheter itself. Just a wild guess, based on what is known re barium and the fact that catheters were recalled at least once due to reports of insufficient barium for radiovisibility.....I am presuming they upped the barium content as the remedy.....and it is very easy to document the coincidence of barium and granulomas at a variety of locations in the body, none of which bear the horrific consequence of dimpling the cord.....
Many moons ago, I worked on a med/surg ICU.....it was common to observe "pedicles" growing down 11 or 12 mm (chest or abd) drainage tubes.....no-one was concerned about them, because they came out with the tubes when removed and presumable the source point just healed over. I do believe these tubes had a wide stripe of radiopaque material on or in them. Is it fair to wonder if these "pedicles" were in fact the same bad actor as here?
Another way the true incidence of masses was hidden was by pointing fingers at everything but the real culprit, anything foreign to that sensitive tissue. BTW, they check these by MRI, so it's gadolinium (sp) that they use for contrast.
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