Pamidronate and Clodronate – hope for CRPS and Back Pain

Pamidronate can significantly help over 3/4 of RSD and reduce chronic back pain through a series of simple infusions. It is expensive and because of a poorly designed negative study, has not reached full acceptance for the good it can do. Fortunately an IV Clonronate double blind randomized study settled that doubt.

Pamidronate is a bone building bisphosphonates drug given intravenously. It has pain reducing properties. studies of its use are hampered by the extreme variability of drug to bone attachment which might explain why some subgroups may benefit more.
1) Originally used in bone metastatic disease:

Different doses of pamidronate in patients with painful osteolytic bone metastases
Journal Supportive Care in Cancer
Publisher Springer Berlin / Heidelberg
Issue Volume 6, Number 2 / February, 1998
S. Cascinu1, F. Graziano1, Paolo Alessandroni2, Marco Ligi1, Elena Del Ferro1, David Rossi2, Rita Ficarelli2, Giuseppina Catalano2

90 mg IV every 3 weeks – relief noticed at 6 weeks (ie. needed TWO doses before effect which was observed in 69% cases

I t works for pain in a bone condition called Osteogenesis Imperfecta

J Coll Physicians Surg Pak. 2014 Sep;24(9):653-7.
Effect of intravenous pamidronate treatment in children with osteogenesis imperfecta.
Atta I, Iqbal F, Lone SW, Ibrahim M, Khan YN, Raza http://www.ncbi.nlm.nih.gov/pubmed/25233970

 

It also helped the pain of a case of chronic multifocal osteomyelitis:
Miettunen, P. M., et al.
“Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO).”
Pediatr Rheumatol Online J 7 (2009): 2.
http://www.biomedcentral.com/content/pdf/1546-0096-7-2.pdf

 

It seems to work best in breast cancer where it can also prevent bone mets – multiple infusions
Acta Oncologica
Volume 35, Issue SUPPL. 5, 1996, Pages 50-54
Analgesic effect of bisphosphonates on bone pain in breast cancer patients: A review article
Strang, P.
Bisphosphonates exert their analgesic effect by several mechanisms. The long-term effects are probably due to osteoclast inhibition. The acute pain-relieving effect, which occurs within days or a week, is likely to be associated with the reduction of various potentially pain-producing substances. As regards pamidronate, several open, controlled studies have shown a significant effect on bone pain in 30-70% of breast cancer patients. The effects have been dose-dependent: a mean dose of 15 mg i.v./week is obviously suboptimal, whereas higher doses yield markedly better effects. The dose response is most evident at doses between 15 and 30 mg/week. Furthermore, the total dose per infusion is of interest: 30 mg every 2 weeks is an ineffective treatment, whereas 60 mg every 4 weeks is more effective. Thus, both the dose per week and the total dose per infusion are of importance in order to achieve optimal treatment. Patients with rapid progression of their disease require higher doses than patients with slow progression. Parenteral therapy is more effective than oral treatment. Both oral and parenteral clodronate exert a significant, positive effect on total skeletal morbidity and thus probably also on bone pain. Unfortunately, pain measurements have not been performed and evidence for pain reduction is indirect. Specific pain studies and studies of quality of life, with few exceptions, are, however, still lacking.”
Also Helps Multiple myeloma pains and also can prevent vertebral fractures there. However, a recent study of Advanced Prostate Cancer found it only worked in a subgroup at 9 weeks; perhaps, as the suggested, because they were to far gone and may have had nerve root compressions from the bone disease.”
2) Found helpful in chronic low back pain:

It helps Mechanical back pain:
J Pain Symptom Manage. 2003 Jul;26(1):678-83.

Treatment of chronic mechanical spinal pain with intravenous pamidronate: a review of medical records.

Pappagallo M, Breuer B, Schneider A, Sperber K.

Comprehensive Pain Treatment Center, Hospital for Joint Diseases, Orthopaedic
Institute, and Department of Neurology, New York University School of Medicine,
New York, New York 10003, USA.

We explored the effect of intravenous infusions of a bisphosphonate, pamidronate, in the management of chronic mechanical spinal pain, a worldwide public health problem in terms of lost workdays, medical treatment costs, and suffering. Bisphosphonates have an anti-nociceptive effect in animals. In
humans, intravenous pamidronate relieves numerous painful conditions, including metastatic bone pain, ankylosing spondylitis, rheumatoid arthritis, and complex regional pain syndrome. We reviewed the charts of 25 patients who had experienced disabling spinal pain for several years, and whom we treated with
intravenous 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). There was no increase in opioid or nonopioid analgesic medications associated with pain relief. The apparent analgesic effect of pamidronate for chronic mechanical spinal pain needs to be confirmed with placebo-controlled trials.

They used the following protocol: “A solution containing 90 mg of pamidronate dissolved in 10 cc of sterile water and 250 cc of 5% dextrose solution was infused intravenously over 4 hours…All patients were scheduled to receive at least THREE INFUSIONS within a period of three months.”

They make note of the following side effects:

“Before starting treatment, we informed our patients that they might experience “flu-like” symptoms (i.e., myalgias and/or fever,) for two to three days after each infusion. After treating the initial 6 patients, we began to recommend as part of our treatment protocol the use of acetaminophen 500 mg or ibuprofen 400 mg three times a day from the day of the infusion through two days post-infusion. This treatment
protocol precaution was found to be useful in improving patients’ compliance with their subsequent pamidronate infusions.”

3) It also appeared helpful in ankylosing spondylitis in which 3 shots were used :

Also some benefit in Ankylosing spondyliltis, where the question of anti-inflammatory effects was made.
Journal of Rheumatology
Volume 25, Issue 4, April 1998, Pages 714-717
An open study of pamidronate in the treatment of refractory ankylosing spondylitis
Maksymowych, W.P.a b c e , Jhangri, G.S.a d , Leclercq, S.a c , Skeith, K.a c , Yan, A.a c , Russell, A.S.a c
a Department of Medicine, University of Alberta, Edmonton, Alta., Canada

Objective. Bisphosphonates inhibit the development of delayed type hypersensitivity chronic inflammation and suppress inflammation and cartilage/bone erosion in diverse murine arthritis models. We evaluated antiinflammatory properties of the bisphosphonate pamidronate in patients with ankylosing spondylitis (AS) refractory to nonsteroidal antiinflammatory drugs. Methods. Patients included 14 men and 2 women. The first group of 8 patients (Group 1) received pamidronate as a 30 mg intravenous infusion once a month for 3 months, followed by a 60 mg dose once a month for an additional 3 months. Eight additional patients (Group 2) received only the 60 mg dose once a month for 3 months. Clinical assessments included the BASDAI (Bath AS Disease Activity Index), BASFI (Functional Index), and BASMI (Metrology Index), and laboratory assessments hemoglobin and erythrocyte sedimentation rate (ESR) at baseline and one month after final 60 mg dose of pamidronate. Mean BASDAI score at study entry was 6.7 for both groups.

Results. A significant improvement was observed in disease activity score in Group 1 after 6 monthly infusions of pamidronate (mean BASDAI 4.21; p = 0.03), in the BASMI score (p = 0.01), and the ESR (p = 0.009). A significant improvement in the BASMI was noted in Group 2 patients (p = 0.007) after 3 monthly infusions of pamidronate, but not in the BASDAI score (mean 5.01; p = 0.07) or the ESR (p = 0.12). Conclusion. Preliminary data suggest pamidronate may possess antiinflammatory activity in patients with AS, particularly with prolonged administration; this agent deserves further evaluation in a controlled trial.

A more recent study in RA found pamidronate’s anti-inflammatory properties could be due to inhibition of interleukin 1-beta by inducing apoptosis of monocytic cells.

Clinical and Experimental Rheumatology Volume 19, Issue 1, 2001, Pages 13-20
Influence of cyclic intravenous pamidronate on proinflammatory monocytic cytokine profiles and bone density in rheumatoid arthritis treated with low dose prednisolone and methotrexate; Van Offel, J.F.

4) It also “mitigates” the pain of Paget’s disease, with 3-6 infusions, and its effects are not endorphin related.

Neuroendocrinology Letters Volume 27, Issue 4, August 2006, Pages 513-514
The analgesic effect of pamidronate is not caused by the elevation of beta endorphin level in Paget’s disease – A controlled pilot study Bender T. et al

5) Also recently found to take the pain out of vertebral compression fractures – NOTE it took THREE infusions.

There was initially a pilot study in 2000: article here

Then came the confirmatory study:

Osteoporos Int. 2006 Aug 8; [Epub ahead of print] Intravenous pamidronate for pain relief in recent osteoporotic vertebral compression fracture: a randomized double-blind controlled study.
Armingeat T, Brondino R, Pham T, Legre V, Lafforgue P. Service de Rhumatologie (Sud), Hopital de la Conception, 147, Boulevard Baille, 13385, Marseille Cedex 05, France, Thomas.Armingeat@ap-hm.fr. I

INTRODUCTION: We performed a randomized, double-blind, controlled clinical trial comparing intravenous pamidronate and placebo for pain relief in recent osteoporotic vertebral compression fractures (VCF).
METHODS: Patients suffered from recent (30 mg pamidronate for three consecutive days (total pamidronate: 90 mg). The main criterion for efficacy was improvement in standing pain on a 100-mm visual analogical scale (VAS) at day 7. Secondary criteria were standing pain at days 3 and 30; supine pain at days 3, 7, and 30; patients’ overall assessment of improvement; mobility index; and number of “20% responders” and “50% responders” (respectively, 20% and 50% improvement in standing pain at days 7 and 30). Statistical analysis with non-parametric tests was carried out on an intention to treat basis.
RESULTS: Thirty-two patients were enrolled in the study; 16 were given placebo and 16 pamidronate. Thirty-one patients were evaluated at day 7 and 26 patients at day 30. VAS pain decreased significantly in both groups at day 7 (placebo -23 mm, pamidronate -42 mm, p<0.01). The difference in pain scores between groups was -23.25 mm (confidence interval (CI) [-42.3; -4.2], p=0.018) at day 7 and -26 mm at day 30 (p=0.03), in favor of pamidronate. At day 7, there were 4 versus 12 “50% responders,” respectively, in the placebo and in the pamidronate groups (likelihood ratio: 8.372; p=0.004) and 9 versus 14 “20% responders” (likelihood ratio: 4.038; p=0.044). At day 30, there were 5 versus 10 “50% responders,” respectively, in the placebo and in the pamidronate groups, and 7 versus 11 “20% responders.” Patients’ overall assessment of improvement at day 7 was 37+/-26 mm in the placebo group and 59+/-30 mm in the pamidronate group (p=0.019), and 42+/-26 mm and 72+/-21 mm at day 30 (p=0.07). The two groups did not differ significantly at days 7 and 30 for supine pain, Schober index, or finger-ground distance. No significant adverse reaction related to treatment occurred.
CONCLUSION: Pamidronate provides rapid and sustained pain relief in patients with acute painful osteoporotic VCF and is well tolerated. Further investigations are needed to better define the place of pamidronate in the management of painful recent osteoporotic collapse.

6) Most exciting is its use in Reflex Sympathetic Dystrophy (Complex Regional Pain Syndrome CRPS)

A priliminary study was done in 1997. Note it is THREE infusions

Clin Rheumatol. 1997 Jan;16(1):51-6.

Treatment of severe, recalcitrant reflex sympathetic dystrophy: assessment of efficacy and safety of the second generation bisphosphonate pamidronate.

Cortet B, Flipo RM, Coquerelle P, Duquesnoy B, Delcambre B. Department of Rheumatology, University of Lille, CH & U Lille, France.

The objective of the study was to assess the efficacy and the safety of pamidronate (APD) in recalcitrant reflex sympathetic dystrophy (RSD). Ten women and 13 men with a mean (+/-standard deviation, SD) age of 44 +/- 11 years were included. The involved sites were: the ankle (n = 10), the foot (n = 7), the hand (n = 3), the hip (n = 2), the knee (n = 2) and the shoulder (n = 1). Some patients had more than one site involved. Mean (+/-SD) duration of the disease was 15 +/- 13 months. RSD was in pseudo-inflammatory phase in 16 patients and in ischaemic phase in 7 patients. RSD was post-traumatic in 17 cases; 11 patients have been previously treated unsuccessfully by sympathetic blockades. APD was administered intravenously (perfusion) to a dose of 1 mg/kg/day during 3, 2 or one day. Fourteen patients received APD during 3 consecutive days whereas 7 patients have been treated during 2 consecutive days and 2 patients only during 1 day mainly due to adverse events. Efficacy was assessed by a decrease of pain = visual analogic scale (VAS, 0-100 mm) and verbal scale (PVS, range 0-3). Moreover, the patient and the observer have estimated the efficacy of the treatment on a verbal scale (EVS, range 0-3). Measurements of these parameters were performed immediately before the treatment and 7, 30, 60 and 90 days later. The maximum duration after treatment was 9 months. A significant decrease of VAS and PVS were observed between D0 and D30 (p = 0.0002 and p = 0.0002 respectively), D0 and D60 (p = 0.0004, p = 0.0004 respectively), and D0 and D90 (p = 0.00003, p = 0.0001 respectively). A significant increase of EVS was only observed between D0 and D90 (p = 0.03). Adverse events were noted in 14 patients: transient fever (n = 6), venous inflammation (n = 2), transient symptomless hypocalcaemia (n = 3), nausea (n = 1), lymphopenia (n = 1), transient hypertension (n = 1). These results suggest an efficacy of APD in recalcitrant RSD. Double-blind placebo controlled studies are required to back up these preliminary results.

This was confirmed in 2001:
It can relieve the pain of Complex Regional Pain Syndromes (Reflex Sympathetic Dystrophy) – Note it took THREE shots:

Rheumatology (Oxford). 2001 Dec;40(12):1394-7.

Treatment of reflex sympathetic dystrophy with pamidronate: 29 cases.

Kubalek I, Fain O, Paries J, Kettaneh A, Thomas M.

full text here

OBJECTIVE: To evaluate the efficacy of treatment with pamidronate in reflex sympathetic dystrophy (RSD) refractory to previous treatment.
METHODS: We studied the response (disappearance of pain and functional improvement) to
pamidronate (60 mg/day for 3 days) in 29 patients with RSD refractory to previous treatment for at least 14 days.
RESULTS: On day 45, complete pain disappearance was observed in 86.2% of patients and functional improvement in 70%. The mean delay until the pain disappeared was 20+/-14 days and the delay until functional improvement was observed was 29+/-18 days. The mean delay of functional improvement was shorter in patients with post-traumatic RSD. Multivariate analysis did not reveal any factor predictive of response to treatment. Six (20.7%) patients suffered from side-effects (fever, diarrhoea).
CONCLUSION: Pamidronate appeared to be effective in the treatment of refractory RSD; however, these results need to be confirmed by a controlled placebo study.

Now enters the MORON study. Against all the wisdom that it takes multiple infusions to achieve substantial results, the following was done on RSD using a single infusion. The results were mediocre, but this was the one quoted because it was done double blind randomized.

Pain Med. 2004 Sep;5(3):276-80.

Efficacy of pamidronate in complex regional pain syndrome type I.

Robinson JN, Sandom J, Chapman PT. Pain Management Centre, Burwood Hospital, Christchurch, New Zealand. jon.r@xtra.co.nz

OBJECTIVES: Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy (RSD), is a painful, disabling disorder for which treatment is difficult. The aim of this study was to determine the efficacy of pamidronate in a double-blind randomized placebo-controlled trial.
METHODS: Patients referred to our regional multidisciplinary pain management center who fulfilled the International Association for the Study of Pain criteria for CRPS Type I were enrolled in the study over a 2-year period. Patients were administered, intravenously, either pamidronate, 60 mg as a single dose, or normal saline. Patients’ pain scores, global assessment of disease severity scores, and functional assessment (SF-36) scores were documented at baseline and at 1 and 3 months.

RESULTS: Twenty-seven patients (18 female, 9 male; average age 45 years) were recruited, of whom 14 received pamidronate and 13 received placebo. 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. Early administration in tandem with other treatment measures is recommended.

Fortunately a better randomized double blind study was done using another Bisphosphonate, chodronate (Bonefos), showed spectacular results. Note they did TEN treatments.

Intravenous Clodronate in the Treatment of Reflex Sympathetic Dystrophy Syndrome. A Randomized, Double Blind, Placebo Controlled Study

MASSIMO VARENNA, FRANCESCA ZUCCHI, DANIELA GHIRINGHELLI, LUCIA BINELLI, MAURIZIO BEVILACQUA, PAOLO BETTICA, and LUIGI SINIGAGLIA

ABSTRACT.

Objective. To evaluate the efficacy of intravenous (iv) clodronate in patients with reflex sympathetic dystrophy syndrome (RSDS) and to assess the urinary excretion of type I collagen crosslinked N-telopeptide (NTx) before and after the treatment.

Methods. Thirty-two patients with RSDS were randomized to receive either iv clodronate 300 mg daily for 10 consecutive days or placebo. Forty days later, the placebo treated patients received the clodronate treatment. Outcome measures included as a primary endpoint the visual analog scale of pain (VAS, range 0–100); secondary endpoints were a clinical global assessment (CGA, range 0–3) and an efficacy verbal score (EVS, range 0–3). Clinical and biochemical assessments were performed before the treatment, 40 (T40), 90 (T90), and 180 (T180) days later.

Results. At T40 the 15 patients randomized to clodronate treatment showed significant decreases of VAS and CGA (p = 0.002, p = 0.001, respectively). Compared with the placebo group (17 patients), significant differences were found in all clinical variables (VAS: p = 0.001; CGA: p = 0.001; EVS: p < 0.0001). A further clinical improvement was observed throughout the study. Pooling the results of all 32 patients after clodronate treatment, at T180 the overall percentage decrease of VAS was 93.2 ± 15.6%, with 30 patients [my note – out of 32] significantly improved or asymptomatic. Significant inverse correlations between baseline NTx values and decreases of VAS were found at T90 (p = 0.03) and T180 (p = 0.01). No adverse events related to treatment occurred.

Conclusion. A 10 day iv clodronate course is better than placebo and effective in the treatment of RSDS. NTx seems to be a predictive factor for clodronate efficacy. (J Rheumatol 2000;27:1477–83)

This drug is advailable in Canada. Clodronate is not cheap on web site was selling 5 IV vial 300 mg/5ml doses for $420.00:
Bonefos (clodronic acid)

My comment – There seems no doubt that IV bisphosphonates can cure or significantly help CRPS. I have had experience with pamidronate. ONE infusion does Nothing. The relief is delayed for 2-6 weeks. You will note the infusion was given over 4 hours – faster infusion makes them feel sick and runs risk of problems like hypercalcemia YOU MUST WARN THE PATIENT THEY MAY FEEL WORSE WITH MYALGIAS AFTER THE FIRST INFUSION – THIS DOES NOT MEAN YOU DO NOT GO ON WITH THEM. As mentioned above use of oral Ibuprofen with infusions was recommended.

One of my patients with post laminectomy syndrome felt much better after two infusions separated by weeks. Another with a vertebral fracture felt much better after a course of three daily. Each response was some delayed.

It looks like Pamidronate 60 mg in 250 mls dextrose given IV over 4 hours daily X 3 would be a good standard. Each 60 mg may cost $400.00. (do not have pharmacy get 30 mg bottles – they are more expensive). Few are able to afford this. Ambulatory care at our Pasqua hospital will administer it with instructions on their IV administration form.

Addendum:

Pamidronate found useful in CRPS in children :

Bone. 2009 Dec 4. [Epub ahead of print]

The successful use of pamidronate in an 11 year old girl with complex regional
pain syndrome; response to treatment demonstrated by serial peripheral
quantitative computerised tomography (pQCT) scans.

Simm PJ, Briody J, McQuade M, Munns CF.

Bone and Mineral Medicine, Dept of Endocrinology and Diabetes, Children’s
Hospital at Westmead, New South Wales, Australia.

Complex regional pain syndrome (CRPS) is a disorder which can cause significant
functional morbidity. While it usually presents in adulthood, it has also been
reported in children. Multiple treatment modalities have been reported with mixed
success. Bisphosphonate therapy has been shown to be effective in adult patients
but there are limited data in children. We report the successful use of
intravenous pamidronate therapy in diminishing pain, improving function and
restoring bone mass in an 11 year old girl with CRPS of her left lower limb
following a tibial fracture. Previous treatment with intense physiotherapy and
regional sympathetic blockade had not improved her symptoms. Pain improved within
weeks of the first pamidronate infusion, with subsequent improvement in function.
The benefit in pain reduction and function was sustained during the 2 year
treatment regime. Improvement in bone mass and density was demonstrated by dual
energy X-ray absorptiometry (DXA) and peripheral quantitative computerised
tomography (pQCT). pQCT scans showed marked improvement in bone size and
geometry, and muscle bulk on the affected side. No adverse affects were reported.
We conclude that intravenous pamidronate was associated with reduced pain, a
return of function and recovery of bone and muscle parameters in a child with
CRPS. Before definitive conclusions can be drawn, a randomised controlled trial
similar to those undertaken in adults previously is required to fully validate
this approach.
There needs to be political pressure to cover this item on our drug plan.

I would be interested in an comments or experience with this treatment.