Bisphosphonate – Pamidronate – Safety Summary – For Serious Pain from CRPS


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Bisphosphonates for Complex Regional Pain Syndrome?

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If you have Complex Regional Pain Syndrome and you have severe pain that has failed all remedies, you may wish to consider bisphosphonate infusions for pain relief. This area needs more research – there is almost none, only three or four small publications on pamidronate for chronic noncancer pain that I posted here.

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Those posts on bisphosphonates in the last two weeks have developed the background to the use of bisphonates for chronic noncancer pain. This is not everyday medicine for pain control, but it is common for certain cancers and for osteoporosis.

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There is a science behind this choice. There is a strong rationale, it makes sense, but this is serious therapy.

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We do not know if it will work or how many may benefit.

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To my knowledge, it has not been done outside of those three or four very small studies. No one is offering this therapy for CRPS. But we all see patients who have tried and failed every known therapy that exists, and pain has taken their lives.

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Here we review these specific points:

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-Safety

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-How soon you can consider pregnancy after treatment?

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-Side effects with the infusion

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-Calcium supplements you need to take

 

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Information has been taken from the award winning website of Susan Ott, Professor of Medicine at University of Washington and an expert on bisphosphonates and metabolic bone disease. Her teaching goes beyond what can be gleaned from publications, and thankfully spans the depth of the field. It is a concise encyclopedia of bisphosphonates for physicians and patients. Apologies to Professor Ott, I have quoted her work liberally.

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SAFETY

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Safety issues are discussed in this editorial Long Term Safety of Bisphosphonates by Professor Ott.

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“Unlike most medications, bisphosphonates remain in the body for decades. These drugs are not metabolized….The amount of drug within the bone will accumulate with use. There is no known method of removing the medication from the bones. The duration of physiological effect is still unknown.”

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Further, she notes the reduced risk of fracture is not closely linked to the increase in bone density. Fracture rate was higher with increased density. E.g., hip fracture decreased with 2.5 mg/d risedronate relative to placebo, but 5.0 mg/d was same as placebo.

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The issue:

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As bone mineralization increases, bone becomes more brittle.

Brittle bone may be more susceptible to fracture.

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PREGNANCY

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It is recommended that you not become pregnant while bisphosphonate is in your bones.

It is contraindicated in women who are pregnant or planning pregnancy.

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Her advice: wait at least one year after stopping the medication to try getting pregnant. The drugs are still excreted in the urine 8 years after stopping.

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Women who are pregnant should not take bisphosphonates. If women are already taking a bisphosphonate and want to become pregnant, it is not clear how long they should wait [my emphasis]. Until more information is available, I suggest waiting at least one year after stopping the medication to try getting pregnant. If a woman is taking a bisphosphonate and inadvertantly gets pregnant and wants to continue the pregnancy, she should be carefully followed, with measurements of calcium and optimal vitamin D levels. Calcitonin is a safe drug to use during pregnancy if bone loss is a concern.

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See below, for more details on toxicity studies in pregnancy.

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SIDE EFFECTS AFTER THE INFUSION

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The day after the infusion it is common to have a fever. Some patients feel like they are getting the flu and feel aching and tired. This usually lasts only one or two days. You may have pain in the bone, especially if you have Paget’s disease or fibrous dysplasia. Other complications are not common, and include a transient decrease in the white blood cell count or blood calcium. The infusion site may become sore or infected. Rare side effects are inflammation of the eyes, kidney damage, or problems with the bones underneath the teeth.

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To be safe, the following blood tests should be normal before giving pamidronate: calcium (greater than 9.0 mg/dl) creatinine, white blood cell count, vitamin D (at least 20 ng/ml). It should not be given during an active infection.

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More detailed studies of blood that I do will also include post infusion study of urine for urinary cross-linked N-terminal telopeptides of type I collagen (NTX).

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CALCIUM SUPPLEMENTS – WHICH ONES?

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Patients need to be sure to get adequate calcium and vitamin D after pamidronate infusions.

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Professor Ott recommends specific calcium supplements — not all are equal. “Many brands do not dissolve in the intestines, so the calcium is not absorbed into the bloodstream.”

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She lists these brands to take, with photos and cost in order of price:

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TUMS EX – least expensive, Caltrate, Oscal, Viactiv, Citracal – most expensive

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Calcium carbonate should be taken with food. Calcium citrate can be taken on empty stomach. Take twice daily. Do not get calcium with magnesium – magnesium may compete with calcium, i.e. block it.

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TOXICITY STUDIES

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Effects of bisphosphonates during pregnancy. Bisphosphonates should be avoided during pregnancy. Refer to her summary for details of animal toxicity studies and human studies.

 

Here is a copy of the 2004 FDA label information for pamidronate:
Pregnancy Category D (See WARNINGS)

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There are no adequate and well-controlled studies in pregnant women.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. As it has been shown that Aredia can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women during pregnancy.

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Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.

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Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aredia is administered to a nursing woman.

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The material on this site is for informational purposes only, and is not a substitute for

medical advice, diagnosis or treatment provided by a qualified health care provider.

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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Ketamine – small doses work in depression and bipolar disorder


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Everyone is very edgy right now with depression. Media is sensationalizing, which is the worst thing to do. I even hesitate to write this now.

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Ketamine really does work

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Small doses may be all that’s needed. Even large doses are safe.

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Two Cases

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I hate to play on emotion that is strong right now, but Robin Williams might be alive today if his doctors prescribed ketamine nasal spray.

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Every one, doctors and patients alike, worry about ketamine. It sells newspaper headlines and distorted media coverage that then overtakes the life saving stories of its profound safety when used under good medical supervision. Experience helps.

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Two cases from yesterday and today really must be shared. These two patients would not be alive today if they did not have ketamine nasal spray for their depression.

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I don’t mean to say every one will respond to these extremely tiny doses, but it’s always exciting to hear the effective dose is simply so small.

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These details would make good case reports if time permitted, but there is never enough time. I wanted simply to say a few things now because these two patients were seen.

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**1**

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In May 2014, saw a fifty-ish woman who is now responding to 20 mg (4 nasal sprays) given as one dose every 48 hours. She has been treated at well known university psychiatry departments, failed ECT 9 or 10 times – memory loss was so bad she got lost in her own neighborhood. Received IV ketamine once or twice weekly for one year before I saw her.

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Diagnoses:  dysthymia as long as she can remember, and 25 years of Major Depressive Disorder, PTSD, anxiety, etc. Olympic level athlete —

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**2**

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Second patient now in late teens, Juvenile Bipolar Disorder/Fear of Harm phenotype, profound thermoregulatory changes respond in seconds to ketamine, dose of 10 mg nasal spray every 3 days. That’s it! Temperature responds in seconds, and the depression responds in 10 minutes in her case. She was so violent before treatment that she had been hospitalized 7 times in 2-1/2 years. Doing very very well. And the low dose naltrexone, by the way, is involved in thermoregulation.

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I should mention, no side effects whatsoever. I have never seen toxicity. I watch kidney and bladder function meticulously, and patients with massive pain on very high doses have never had any organ toxicity.

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NEURO-INFLAMMATION AND GLIA – brain on fire.

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I mention Olympic athlete because so many people I see with Complex Regional Pain Syndrome – the pain that so often leads to suicide, seems to occur more often in top level athletes, either state or national level, professional or sponsored in their teens. Yes, they occur in others, but there is a striking predominance in athletes for unknown reasons.

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Glia are triggered by trauma, then they become activated and produce pro-inflammatory cytokines. Inflammation is out of balance. Ketamine profoundly reduces the pro-inflammatory cytokines, and so does low dose naltrexone. I write about these mechanisms with more frequency that anything else. This is what we must address – the brain is essentially “on fire.” And this inflammation, these pro-inflammatory cytokines, are involved in almost every known disease: Alzheimer’s disease, Parkinson’s disease, ALS, chronic pain, major depressive disorder, cancer, autoimmune disease, and atheroscloerosis.

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Inflammation kills. Unfortunately this new research on glia and inflammatory diseases, these diseases could be called gliopathies, all based on new research since the turn of the century. We now know glia are your innate immune system in brain and spinal cord. They need a balance the anti-inflammatory cytokines with the pro-inflammatory cytokines. Inflammation may be lifesaving when you have caught a virus, but not as a steady diet. Give the brain a break or it leads to hyperexcitable glutamate that triggers calcium flooding into the neuron, cell death, brain atrophy and memory loss. Seen in people with Major Depression and those with chronic low back pain.

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Do doctors know about the innate immune system? or the receptor that won the Nobel Prize 2 and 1/2 years ago? or glia?

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Answer: no.

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Papolos et al have published Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype

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Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated.

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Dr. Papolos’ video on treatment points out, ketamine nasal spray is off-label

for Bipolar Disorder. And I add, ketamine is off-label for pain and for major depression.

He posts this:

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PUBLIC WARNING

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Public Warning: Ketamine is a controlled substance.

Administered improperly, or without the guidance of a qualified doctor,

Ketamine may cause injury or death.

No attempt should be made to use Ketamine

in the absence of counsel from a qualified doctor.

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“Off label” means it is FDA approved for another purpose, but he prescribes it for Juvenile Bipolar Disorder. I would add that in qualified hands, ketamine is one of the safest medications we have in our formulary.

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More later, as time permits.

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PUBLIC WARNING

reprinted with permission of Demitri Papolos, MD
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Ketamine is a controlled substance.
Administered improperly, or without the guidance of a qualified doctor,
Ketamine may cause injury or death.
No attempt should be made to use Ketamine
in the absence of counsel from a qualified doctor..

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The material on this site is for informational purposes only.

It is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

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Please understand that it is not legal for me

to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Bisphosphonates in Treatment of Complex Regional Pain Syndrome, continued


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A new publication out of Germany, May 2014, in the journal Pain, suggests a strong rationale for the use of bisphosphonates in the treatment of Complex Regional Pain Syndrome (CRPS).  See my review of those infusions..\

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Impaired bone metabolism is a feature of CRPS.

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They found evidence that osteoprotegerin (OPG) was elevated in serum of persons with CRPS. That is not unique to CRPS, but it might be useful as a potential biomarker for CRPS. It is also increased with osteoporosis, coronary heart failure, irritable bowel syndrome, and is it associated with long term renal dysfunction.

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OPG is an inhibitor of osteoclast formation, important for bone remodeling and it may contribute to CRPS pathophysiology.

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They compared OPG with triple phase bone scan (TPBS).

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For the CRPS-affected hand, a significant correlation between OPG and TPBS region of interest analysis in phase III was detected. The persistent OPG increase in CRPS indicates enhanced osteoblastic activity shown by increased radiotracer uptake in TPBS phase III. A contribution of bone turnover to CRPS pathophysiology is likely. OPG might be useful as a biomarker for CRPS.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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This site is not email. If you wish an appointment, please telephone the office to schedule.

It is not legal for me to provide medical advice without an examination.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

 

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Do You Have Depression? Are you the one who runs into snow wearing shorts?


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Since you were a baby, thermoregulation may be the source of the problem

that triggers your depression or the depression of someone you know.

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You may be a candidate for a research study if you have other key characteristics.

Treatment may help.

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Contact the Juvenile Bipolar Research Foundation.

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OR

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Demitri Papolos, MD, is the psychiatrist who, in collaboration with many others, has discovered that body temperature appears to be at the origin of this condition:

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Juvenile Bipolar Disorder, Fear of Harm phenotype.

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Dr. Papolos has written many publications and has published a book, with Janice Papolos, describing this serious disorder. “The Papoloses were the first to sound a national alarm about the dangers of using antidepressant and stimulant drugs with this population of children.”

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Either the link to Dr. Papolos or the Research Foundation, above, can give you further information on treatment.

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Papolos et al have published Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype

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Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated.

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Dr. Papolos’ video on treatment points out ketamine nasal spray is off-label

for Bipolar Disorder and he posts this

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PUBLIC WARNING

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Public Warning: Ketamine is a controlled substance.

Administered improperly, or without the guidance of a qualified doctor,

Ketamine may cause injury or death.

No attempt should be made to use Ketamine

in the absence of counsel from a qualified doctor.

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“Off label” means it is FDA approved for another purpose, but he prescribes it for Juvenile Bipolar Disorder. I would add that in qualified hands, ketamine is one of the safest medications we have in our formulary.

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I am not affiliated with Dr. Papolos, but wish to call attention to the dedicated academic work they have been doing for this devastating mood disorder. .

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Of interest, thermoregulation appears to be modulated by low dose naltrexone (LDN).

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It has been anecdotally reported to relieve heat intolerance in persons with Multiple Sclerosis.

I have seen a response with Juvenile Bipolar Disorder/Fear of Harm, and

severe postmenopausal hot flashes were completely reversed by LDN.

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Naltrexone blocks the TLR4 receptor. There is a strong literature on TLR4 and temperature regulation. This raises the interesting question whether anyone has done objective studies to show that low dose naltrexone may be modulating temperature in patients. If you have experience with this, please add your comments below.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

~~~~~

Please understand that it is not legal for me

to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

 

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Spinal Cord Stimulators – Paralysis, Adverse Effects


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In April 2014, the Wall Street Journal published an analysis of adverse events associated with spinal cord stimulators:

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When Spine Implants Cause Paralysis, Who Is to Blame?

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These events were submitted to the FDA or were obtained from medical malpractice law suits. “In many cases, the injuries occurred after patients’ spinal cords were punctured or compressed by the stimulator electrodes….The FDA’s database contains 58 unique reports of paralysis with report or event dates from 2013, compared with 48 in the prior year.” The spinal cord stimulators were made by various companies.

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“Researchers at Duke University medical center recently found that nearly one in every 100 spinal stimulator patients experienced some degree of spinal cord or spinal nerve root damage, said Shivanand P. Lad, a Duke Neurosurgeon and the study’s lead researcher. The study, based on insurance claim records of 12,300 stimulator patients has been submitted for presentation at an upcoming medical meeting.”

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“A 2011 study based on adverse event reports submitted by device makers found the rate of paralysis or motor weakness in patients implanted with a commonly used type of stimulator was considerably lower, at around 3.8 per 1000, with about 60% of patients eventually experiencing complete or partial recovery.”

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Medtronic updated its product label in February to note “that scar tissue can form around device electrodes and cause nerve damage, including progressive quadriparesis, or gradual weakening of all four limbs.”

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“Medtronic estimates that as many as 50,000 people in the U.S. are implanted with spinal stimulators each year from all device makers.”

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“Stimulators cost between $20,000 and $60,000 each and have estimated global sales of $1.5 billion annually….”

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The FDA “cautions that the agency’s database cannot be used to ascertain comprehensive rates of adverse events because the events are under reported [my emphasis] and often contain incomplete or incorrect information.”

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The article describes a man with 40 years of back pain who had a spinal cord stimulator implanted at the University of Texas Southwestern Hospital, Dallas. He complained of numbness in his legs. A blood clot was removed on an urgent basis, but damage was irreversible. He was paralyzed from the waist down and left in a wheelchair.

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Spinal cord stimulators, abbreviated SCS, can cause many more problems that paralysis. They can cause pain, tethering of the cord, scarring of the battery pack that can slide across the back, infection that may cause death, and many other complications. Electrodes may not always be able to be removed and remain permanently scarred into the cord. Deeply troubling is that an MRI can never be done again even if the patient has cancer or stroke —none of my patients remember being told about this. Where are the five year studies that show benefit? Even with no complications, how long do they continue to relieve pain? Electrodes move and/or they malfunction. There is little to no federal investment in medications that relieve pain, but these devices are garnering sales of $1.5 billion annually without showing lasting benefit. This is a very big source or income for pain specialists, but what is the gain for patients? How can we weight the pros and cons of this money generating device?

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So many of my patients that have failed the small handful of medications now available for chronic pain were given only one choice by every major pain center: spinal cord stimulator. One choice. This is a very big business but where is the five year data?

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One of my patients with Complex Regional Pain Syndrome, in remission since 2010, submitted a comment on this my site:

 

06/07/2012 at 11:25 pm   I have been a surgical nurse for 40 years and have seen many patients receive SCS…and many, many fail, or return to surgery for fractured electrode wires, misplaced wires, or infected battery pockets, besides complicated problems, or “lack of positive results, or battery revisions, or electrode repositionings.” Some patients have even developed spinal fluid leaks when the spinal dura layer has been torn during implanting the electrode wires, and they develop severe headaches, and have to return to surgery for the leak to be repaired. Many pain management doctors are convincing patients that this is a great way to treat their pain, and they find out in 2-6 months that they wish they never had agreed to it. Sure, there are some patients that get some relief, but this procedure has been pushed on the population of chronic pain patients, when they are at their worse condition, and willing to try anything….at any expense, and the companies and implanting doctors are getting the money. More patients need to learn the truth about these devices! Anonymous…. and never allowed them to put one of those things in me…but many tried!

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Elsewhere on my site, Traci writes a very sad comment:

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03/29/2011 at 6:01 am I posted on your main blog, but haven’t heard back. I know you wanted information regarding issues or problems with Spinal Cord Stimulators, so here is some information that you can add to your file. I can also be contacted for additional information because this issue continue to date.

In one of your posts you asked for input from patients that currently have a SCS. I currently have a Medtronic SCS it was implanted early 2010 and I ended up having swelling in my Lt (affected) foot/ankle every time I would charge the “re-chargeable battery”. No one at Medtronic could figure out the issue. I turned into their “human lab rat”. After several months of this I was told to switch from a rechargeable battery to a non-rechargeable batter. Thus another operation… which I did. After this surgery (I have a paddle with 16 electrodes) all 8 electrodes on the Lt side that used to supply stimulation to my Lt foot/ankle now hit my pelvic area – thus I can no longer utilize these electrodes. And out of the 8 electrodes on the Rt 2 are providing stimulation to my Lt foot and the other 6 are hitting the wrong areas. In addition to this I have had continual instances where I am getting a very sharp pain/ sharp twinge (like a jolt) around where the electrodes area. When this happens if I turn off the SCS the pain immediately stops. I’ve been on a conference call with a Senior Engineer of Medtronic and a local Rep in person with me to do reprogramming… The Engineer only wanted to know if the electrodes were putting out stimulation. He didn’t want to know what the amperage was at before I could feel it or in what part of the body the stimulation was felt. These should have been critical pieces of information. All he wanted to state was that the electrodes were working. As for the Sharp Pain / Sharp Twinges that continue to occur in the electrode area their Senior Engineer has no idea what is causing this. He asked me to run an experiment the next time it happened – I did exactly what he wanted and reported back the findings. I have yet to hear back from Medtronic. They do not want to back up their product and they are not willing to admit that their is a problem. Although I have 2 doctors including a Neurosurgeon that feel there is some type of fault in their product or that it is faulty. Hopefully this gives you some additional information you were seeking. Please feel free to email me if you would like to discuss further. I am continuing my uphill battle with Medtronic.

I have spoke with Medtronic as recently as yesterday and they can not explain the continual sharp pain/sharp twinge that I continue to get where the paddle that holds the electrodes is placed. The “Patient Relations Rep” that has been assigned to me, (at one point she tried to tell me she was from their “Legal Department” and she was later introduced by a team member as a “Patient Relations Representative”), doesn’t feel this is a big issue. She told me yesterday that this is “just medicine” and sometime they can get it right and other times it just doesn’t work out… The Senior Engineer at their company can not figure out what the problem is, so he just wants to reset the “INS”. I asked exactly what the “INS” was and the Patient Relations Rep couldn’t answer that question. I have already had my system reset numerous times (too many to count) and reprogrammed numerous times.

The trial was aproximately $25,000; the hospital expenses alone and cost for the SCS implant were over $150,000 and the secondary surgery to replace the rechargeable battery with a non-rechargeable battery was aproximately $53,000. This is all for a system the now has 2 out of 16 electrodes that hit the correct area, creates an intermitent sharp pain/sharp twinge in the spinal area where the electrodes/paddle is placed, and they aren’t sure how to resolve this issue. But I was told yesterday that their system was working properly by their rep.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

~~~~~

Please understand that it is not legal for me

to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Donate to RSDS to Relieve Neuropathic Pain


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It is always a good time to make a tax-deductible 2014 financial contribution to RSDS.org.

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The link at top banner of my website also takes you to the RSDSA and some ways to donate directly to them.

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RSD is Reflex Sympathetic Dystrophy, a severe form of neuropathic pain. It was renamed in the mid 1990’s as Complex Regional Pain Syndrome, CRPS, but continues to go by the previous name RSD.

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The principles of treatment for RSD applies to all forms of neuropathic pain. It is not specific to RSD.

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Your support can help so many others regardless of their diagnosis. Please give today.

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I am not affiliated with the Reflex Sympathetic Dystrophy Association. I recommend them because they support some of the best research in pain, work that has contributed greatly to the understanding of newer approaches to treatment. And because their work and collaboration together with other organizations of people with pain, with chronic fatigue, with dystonia, and fibromyalgia helps all. Their scientific advisory committee is comprised of some of the most distinguished pain specialists in the world.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

~~~~~

Please understand that it is not legal for me

to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

.

For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Bisphosphonates for Pain – Back Pain, CRPS Pain. Have You Received Pamidronate or Other IV Bisphosphonate for Pain?


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Bisphosphonates have been used for treatment of pain.

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I have reviewed a few studies on pamidronate infusions for pain,  below.

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Based on these small studies, there is a growing rationale for use of I.V. pamidronate in the setting of selected chronic intractable pain syndromes.

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Have you received IV Pamidronate or Reclast or any bisphosphonate

for treatment of pain caused by any condition?

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Bisphosphonates are effective for reducing bone loss and, separate from that mechanism, they have been used to reduce pain in persons with various conditions including Complex Regional Pain Syndrome, ankylosing spondylitis, rheumatoid arthritis, chronic back pain, and other conditions.

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After you vote, if you wish to see results, click on the words “View results.” You do not need to sign in or give your email. Simply view results.

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If you have any experience with bisphosphonates even if for osteoporosis, please comment below. Do you know which academic centers are giving IV bisphosphonates for pain?

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The mechanism of pain relief is not clear and there are no standardized protocols for the use of bisphosphonates for pain, but relief of pain is believed to be separate from mechanisms related to bone.

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Many patients have no other options for treatment. There are no large randomized controlled studies – where is NIH funding for pain?

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Many medical treatments do not work for some patients with Complex Regional Pain Syndrome or for chronic low back pain. When all else has failed, pamidronate may be given IV, often in a series of infusions that take up to four hours. There may be some flu-like symptoms for 1 to 3 days after.

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For reasons unknown to us, Complex Regional Pain Syndrome is often associated with bone loss in the area of pain. It is more marked and prolonged than in immobilized trauma patients.

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What dose should be used, how often should it be given? Few studies have been published.

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MEDICATIONS for OSTEOPOROSIS

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Bisphosphonate therapy is commonly used for diseases of bone such as osteoporosis or Paget’s Disease, multiple myeloma, bone metastasis, osteogenesis imperfecta, fibrous dysplasia. For example alendronate (Fosamax) or residronate (Actonel) tablets,  pamidronate infusions,  or others.  Zoledronic acid (Reclast) is given IV, usually only once each year. One form of ibandronate (Boniva) is also given IV, usually every 3 months.

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Other medications that are not bisphosphonates are used for osteoporosis such as calcitonin-salmon (Miacalcin) SC or IM injections, Forteo (rhPTH ) SC injections, or estrogen.

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MECHANISM of BISPHOSPHONATES

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Bisphosphonates slow the rate of bone loss, they do not actually build bone. Bone requires a balance of osteoblasts that form new bone, and osteoclasts that resorb bone. Osteoporosis occurs with age and especially with loss of estrogen that dramatically increases loss of bone. Other factors that lead to bone loss are lack of exercise, hormonal, nutritional and genetic predispositions.

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RISKS of OSTEOPOROSIS

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Some of the worst pain I have seen in my career is pain due to fractures of fragile osteoporotic bones. It may be impossible to treat. With osteoporosis, you may simply roll over in bed and 7 rib fractures occur. One woman developed hundreds of fractures throughout her pelvis and was bedridden for years after a very minor incident. Bone stimulators did not help and she could not walk or stand without help. Years later there was a 1-1/2 inch gap between the fractures in her pelvis and of course being inactive and bedridden can only make osteoporosis worse.

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RISK of MEDICATION for OSTEOPOROSIS

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Osteoporosis is more dangerous by far than any medication used to treat it. As with any drug, the benefit must outweigh side effects. Bisphosphonates increase bone thickness and reduce risk of fractures. Osteoporosis medications causes less than 1% risk of bone fractures. Fractures from the medications may be seen in the midshaft of the femur which is the mid thigh; and they may cause osteonecrosis of the TMJ, the jaw bone. Serious problems with bone healing after dental surgery may occur in those who take bisphosphonates. But the risk of osteoporosis is far greater than this small risk.

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Non-bisphosphonates also have dangers: Calcitonin may increase risk of cancer. PTH is the only one that can actually build bone – an anabolic agent that induces bone formation, not just prevent resorption of bone, but abrupt termination leads to rapid loss of bone density. Estrogen increases risk of clotting, thromboembolism that is a risk for stroke.

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Neridronate is a new bisphosphonate available so far only in Europe the last few years. They are making claims that a series of neridronate infusions can reduce pain 100% in persons with Complex Regional Pain Syndrome. That seems highly unlikely:  100% effective? Really? Oh, and so far no reports of necrosis of bone. But it has not been available as long as pamidronate, so it may be years before we get a better assessment of this drug that is confirmed by other laboratories.

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PUBLICATIONS

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Dr. Pappagallo published three of the studies below. He is one of the foremost scientist-pain specialists in the world.

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A pilot trial of intravenous pamidronate for chronic low back pain

PAIN, Volume 155, Issue 1 , Pages 108-117, January 2014,  Pappagallo et al, found no serious adverse events.

They tested four groups of 11 subjects (7 active, 4 placebo) at differing doses. They conclude:

i.v. pamidronate, administered as two 90 mg infusions four weeks apart, decreased pain intensity for 6 months in subjects with CLBP.

[Pain was decreased by > 4 points. They showed no relationship between bone density and analgesic response, but did find a relationship between PTH, vitamin D status and pain response.]

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Bisphosphonates are known to have significant analgesic activity in addition to their well-characterized role in inhibiting bone resorption. For example, pamidronate (Aredia®, Novartis), an aminobisphosphonate, demonstrates clinically significant pain relief when administered intravenously for the treatment of Paget’s disease, metastatic breast cancer and osteolytic lesions of multiple myeloma [5], [24], [51]. In addition, i.v. pamidronate has been shown to have analgesic activity in a wide variety of painful conditions, including complex regional pain syndrome [12], [44], [53], fibrous dysplasia [10], recurrent multifocal osteomyelitis [22], [35], ankylosing spondylitis [33], rheumatoid arthritis [31], and others (for review, see [49]). The mechanism(s) of this analgesic effect is not fully known, but antinociceptive effects of pamidronate and other bisphosphonates have been reported in animal models of pain [7], [8], [25], [52]. Inhibition of osteoclast proton secretion and other cellular and molecular mechanisms may contribute to the analgesic effect [37], [54].

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The molecular mechanisms of pamidronate’s analgesic effects are not fully understood. Bisphosphonates are known to inhibit the activity and/or cause apoptosis of osteoclasts [20], [46], which remodel bone by creating an acidic microenvironment via the release of protons through vacuolar H+-ATPase [6], [45]. Osteoclast-induced high concentrations of protons may activate acid-sensing ion channels and transient receptor potential vanilloid type 1 channels expressed by small nerve fibers involved in pain signal transmission [37], [42], [54]. Osteoclasts appear to have a role in inflammatory pain adjacent to bone and in the hyperalgesia observed in type IX collagen-deficient mice [2], [37]. Of interest, inhibition of osteoclasts by bisphosphonates in a rat model of degenerative joint disease has recently been found to prevent subchondral bone resorption and cartilage loss, and decrease pain [50]. Clinical findings may also suggest a role for subchondral bone changes in the early development of painful osteoarthritis [13], [36]. Furthermore, the anatomical core structure of the spine is made of bone tissue, and immunohistochemical studies have revealed the presence of a widespread network of peptidergic small sensory fibers throughout the bone marrow, mineralized bone, and periosteum [28], [32]. Thus it is conceivable that: a) nonspecific low back pain (associated with degenerative disk disease or spondylotic disease as in our study population) may be related to sensitization of bone nociceptors, plausibly in the context of subchondral bone resorption (eg, at the vertebral endplates and/or facet joints) and b) inhibition of subchondral osteoclasts (and possibly of other phagocytic or inflammatory bone resident cells) by i.v. pamidronate might be clinically relevant to the treatment of CLBP.

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The responder rate for pamidronate 180 mg increased from 50% at 24 hours after the second infusion to 100% at month 2; the 100% responder rate was maintained at all subsequent time points. [There were 7 patients in each group of this small study.]

(Fig. 3) illustrates that all subjects receiving 180 mg pamidronate had at least 50% pain relief at both 3 and 6 months postinfusion, and approximately 80% of subjects receiving 180 mg pamidronate had 100% pain relief at 6 months.

Fig. 3. Continuous responder analysis. Blue solid line, placebo; red dashed line, 30 mg pamidronate; green dashed/dotted line, 60 mg pamidronate; brown dashed line, 90 mg pamidronate; purple dashed/dotted line, 180 mg pamidronate.

 

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Pamidronate treatment in rheumatology practice: a comprehensive review

Clinical Rheumatology, Volume 28, Issue 12, pp 1359-1364, December 2009, Slobodin et al. from Israel.

The efficacy of pamidronate in patients with spondyloarthropathies; synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome; hypertrophic osteoarthropathy; osteoporotic vertebral fractures; chronic back pain due to disk disease or spinal stenosis; Charcot arthropathy; transient osteoporosis; and complex regional pain syndrome-I, has been demonstrated in more than 40 reports, the majority of which, however, were not controlled studies. In some of reviewed conditions, aside from providing analgesic relief, pamidronate may also have disease-modifying properties. While used in different doses in a variety of rheumatic disorders, pamidronate was generally reported to be well tolerated with an overall good safety profile. Pamidronate may represent an effective and safe choice for a spectrum of rheumatic patients, suffering from intractable musculoskeletal pain, unresponsive to traditionally recommended therapies. Large randomized, controlled studies examining the efficacy of pamidronate in the rheumatic conditions are urgently needed.

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Complex regional pain syndrome (CRPS/RSD) and neuropathic pain: role of intravenous bisphosphonates as analgesics. ScientificWorldJournal. 2008;8:229–236Yanow J, Pappagallo M, Pillai L.  They review multiple studies for pain of CRPS.

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Efficacy of pamidronate in complex regional pain syndrome type I. Pain Med. 2004;5:276–280, Robinson JN, Sandom J, Chapman PT from New Zealand.

Pamidronate 60 mg iv was given only one time to 14 patients, 13 placebo controls.

Overall improvements in pain score, patient’s global assessment of disease severity score, and physical function (SF-36) score were noted in the pamidronate group at 3 months, and improvements in role physical (SF-36) score were noted at 1 and 3 months. There was variability in pamidronate response among individuals. CONCLUSIONS: Pamidronate may be a useful treatment option in the management of patients with CRPS Type I. Although treatment response was variable, the majority of patients improved.

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Treatment of chronic mechanical spinal pain with intravenous pamidronate: a review of medical records. J Pain Symptom Manage. 2003;26:678–683, Pappagallo M, Breuer B, Schneider A, Sperber K.

[They] reviewed the charts of 25 patients who had experienced disabling spinal pain for several years, and whom we treated with [iv] pamidronate. None had a history of osteoporotic vertebral fractures or metastatic disease. Pain rating scores decreased in 91% of patients: on a 0–10 numeric rating scale, the mean pain change was 3.6 points and mean percentage change was 41% (P <0.0001).

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Treatment of severe, recalcitrant reflex sympathetic dystrophy: assessment of efficacy and safety of the second generation bisphosphonate pamidronate. Clin Rheumatol. 1997;16:51–56, Cortet B, et al. from France infused 14 patients 1 to 3 days, followed 3 months and in one case for 9 months. “results suggest an efficacy” and they recommended double blind placebo controlled studies.

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