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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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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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 illegal for me to give medical advice

without seeing you in office for history and examination.

I cannot respond to your medical questions unless you schedule an evaluation.

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

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11 Responses to “Bisphosphonates for Pain – Back Pain, CRPS Pain. Have You Received Pamidronate or Other IV Bisphosphonate for Pain?”

  1. Julie Says:

    I am a PTA, CSCS who contracted CRPS following a bunion procedure 15 months ago. The surgeon insisted that I not use anti-inflammatory medications as he felt that would delay bone healing. I was in horrendous pain for 10 months before another physician diagnosed me. I had all of the signs of the Budapest criteria and osteopenia only in my left foot. At 13 months, I received 4 infusions of neridronic acid at 62.5 mgs. per infusion. Side effects were: pyrexia, myalgia, blood calcium fell from 10.3 to 8.4 in 4 days, weakness, loss of breath, asthenia, but I own a gym and had to continue to work. It was very difficult. At 14 days post 1st infusion, I had dramatic results. (If you send me an email, I will forward you the amazing pictures). I am now at 10 weeks and thinking that maybe I am relapsing. My pain went from 10+ down to a 3 then at 8 weeks post infusion back up to a 5. I had an ingrown toe nail removed on my affected side at 8 weeks which really set me back.
    In Itlay, I have been in contact with physicians who tell me that they give 3-5 cycles and repeat at 24 months. Each infusion is 100 mgs. They have had “positive” results. I would like to get 200 more mgs. Do you or anyone else know about how long this whole process to remission takes? Maybe I’m doing great, maybe not. Do you know about treatment with a TNF-alpha blocker for the allodynia and hyperplasia? I am trying to get an appointment with Susan Ott as I am located in Seattle.

    Thank you

    • Nancy Sajben MD Says:

      Julie, thank you for your comments.

      How long did the ” weakness, loss of breath, asthenia” last?

      I reviewed some complications that may be seen with bisphosphonates in my three posts on them.

      The one year followup study by Grunenthal is double blind, and no one knows the dose or doses. How did you find out? Where did you receive it?

      You know the dose, so clearly you are not one of the three who received placebo.

      • Julie Says:

        I clearly had an acute phase reaction, but the fever and other symptoms lasted for weeks, not days. No one broke the double blind, but with every infusion my face, neck and chest would flush and my heart reacted. My calcium dropped from 10.3 to 8.4 in 4 days. The study Dr. said that it was apparent that I was getting the neridronic acid. Now at 12 weeks post my first infusion, the side effects seem to be gone. I’m pretty sure that the fatigue that I feel is inflammation from CRPS. Grunenthal has emailed me that the 250 mgs was the choice of the FDA. Italian physicians have told me that it takes 300-500 mgs. It also appears to be important that the patient has the osteopenia or bone component or the neridronic acid has no effect. I do have the osteopenia. The neridronic acid made an amazing difference with my CRPS, but it clearly is not enough to put me into remission. I fear that I may be relapsing. I would chalk it up to it just being another drug that works initially but then stops, but the Italian Dr’s have had “positive” results. My Dr. is currently trying to estimate how much of the pamidronate to give me to equal around 200 mgs more of neridronate. No physician in Italy will treat someone in the study. That is what I’ve been told.
        Thank you

        • Nancy Sajben MD Says:

          Oh dear, it is late, and in editing my reply, I accidentally deleted. I had already made the response into a separate post: https://painsandiego.com/2015/08/19/5295/.

          Please refer to that in which I mention the Skeletal Endocannabinoid System and the Entourage Effect that must be studied in context of intractable pain including CRPS pain.

          • Julie Says:

            Hello Dr. Sajben,
            For some reason, a mistake on my part, I thought that my messages were for your eyes only. I think that if others with CRPS read what my experience was, it may influence how they might take part in the neridronic acid study. Or, if they are in the study and they read what I wrote, they may think that they received the placebo and decide to quit. Just because I experienced these things doesn’t mean that others will. We all want this medication to come to the US. Please don’t jeopardize this chance by printing what I thought was a question for you. I feel that you should withdraw my comments and questions.
            Thank you

            • Nancy Sajben MD Says:

              Julie,

              I hope you will reconsider.

              Hundreds have read the RSDSA funded research I posted yesterday.

              Only 8 have read your post and my response yesterday – which I now revised. Never stay up all night writing.

              I agree with you: The world is waiting for the results of the neridronic acid study. That is why I wrote my response here:

              https://painsandiego.com/2015/08/19/5295/

              to put clinical trials in perspective. Everyone responds to medication differently. Your reaction may be very rare.

              We all hope for large numbers to volunteer or neridronic acid will never be available for anyone, not for CRPS or potentially for other forms of intractable pain for which we have nothing to offer after you have failed all known drugs.

              Sadly, as of now, we have no effective reliable means to reduce the flares that can occur with CRPS.

              We need this new drug and many more. Nothing works for everyone.

              If you still wish me to delete after you reread my response which has been revised, I will be happy to do so.

              Thank you.

            • Nancy Sajben MD Says:

              I again want to reiterate, I will be happy to remove your comment, but a tiny number even have an interest in reading that page.

              Overwhelmingly, the interest goes to the earlier post that day on CRPS research funded by RSDSA.

              Please reconsider, and let me know. I trust that we all expect side effects in some people, but not all. It can help others plan for transient symptoms. The important thing is that there is no toxicity.

              The clinical trials are eagerly awaited by people all over the world. I encourage all my patients to consider it. We have no better answers as yet.

  2. shane Jenner Says:

    Hi just on neridronic acid trail,My son Mark has CRPS and the Dr. at the pain clinic, Mark goes to wants to give him
    a infusion of Zoledronate ( Zometa ) once off treatment on the 11/17/15, is this any good for treating CRPS or should we go to Italy for treatment of neridronic acid. We live in Australia

  3. Damon Says:

    I am in the neridronic acid phase lll study and have just received infusion 2 of 4. I have crps lll from a surgery 2 1/2 years ago. I was told I would experience the flu like symptoms also, which I did not. I have gotten severe joint and bone pain as a side effect, starting in my wrist and spreading to my shoulders and chest. Severe enough that it takes my breath away. I am in a support group for phase lll volunteers and this seems to be a common side effect. Will it be temporary? I hope so.


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