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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