1 / 61

Bisphosphonate Therapy for Non-Cancer Pain

Bisphosphonate Therapy for Non-Cancer Pain. Marco Pappagallo, MD Director, Pain Medicine Research & Development Professor, Department of Anesthesiology Mount Sinai School of Medicine, NY. Bone Pain.

cassius
Download Presentation

Bisphosphonate Therapy for Non-Cancer Pain

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Bisphosphonate Therapy for Non-Cancer Pain Marco Pappagallo, MDDirector, Pain Medicine Research & DevelopmentProfessor, Department of AnesthesiologyMount Sinai School of Medicine, NY

  2. Bone Pain bisphosphonates widely used in the battle against cancer-related bone pain

  3. What is Bone Pain?

  4. What we were taught BONE INNERVATION ONLY IN THE PERIOSTIUM !? Adapted from: Patrick Mantyh, PhD, The mechanisms and pharmacology of bone pain AAPM 2005 Annual Meeting Lecture

  5. REVISITING BONE INNERVATION Adapted from: Patrick Mantyh, PhD, The mechanisms and pharmacology of bone pain AAPM 2005 Annual Meeting Lecture

  6. REVISITING BONE INNERVATION Adapted from: Patrick Mantyh, PhD, The mechanisms and pharmacology of bone pain AAPM 2005 Annual Meeting Lecture

  7. calcitonin gene-related peptide (CGRP) nerve fibers In bone, small nerve fibersexpress • Transient Receptor Potential Vanilloid Subtype 1 (TRPV1) – i.e., the capsaicin receptor • High affinity Tyrosine Kinase Receptors (Trka) for NGF (nerve growth factor)

  8. BONE PAIN MECHANISMS role of NGF • expression enhanced in bone inflammation, bone cancer, trauma, fractures • produced by many cellular elements • induces hyperalgesia via upregulation of transcription for genes encoding pain receptors (e.g. capsaicin receptor TRPV1)

  9. BONE PAIN MECHANISMS role of NGF Adapted from: Patrick Mantyh, PhD, The mechanisms and pharmacology of bone pain AAPM 2005 Annual Meeting Lecture

  10. Bone Pain Mechanismsrole of protons (H+) • Acidic microenvironment (pH 4.0) due to release of protons from activated OSTEOCLASTS • Low pH activates TRPV1 and ASICs (Acid-Sensing Ion Channels)

  11. From Osteoclasts to Bisphosphonates

  12. HISTORY OF BISPHOSPHONATES • Designed as synthetic analogues of pyrophosphate • Initially used in industry as water softening agents in irrigation systems

  13. PYROPHOSPHATE • blocks precipitation of calcium phosphate in plasma, urine, and soft tissues • commonly used as an anti-tartar agent in toothpaste • In the body, rapidly hydrolyzed by alkaline phosphatase

  14. Pyrophosphate Generic Bisphosphonate

  15. HISTORY OF BISPHOSPHONATES • Etidronate, first bisphosphonate for medical use • In 1969, bisphosphonates discovered as bone loss inhibitors

  16. Etidronate Clodronate Tiludronate Pamidronate Alendronate Risedronate Ibandronate Zoledronate

  17. FDA approved indications • Hypercalcemia of Malignancy • Osteolytic Bone Metastases • Osteoporosis • Paget’s disease of bone

  18. BISPHOSPHONATES • chemical adsorption onto hydroxyapatite • cellular uptake by osteoclasts, macrophages, tumor cells, etc

  19. Bioavailability • Less than 1% of the oral dose absorbed • GI absorption suppressed by food intake • For a more rapid and effective action, bisphosph can be given by IV infusion.

  20. PHARMACOKINETICS • transient distribution to liver and other organs • as a sponge, metabolically active bone adsorbs IV dose • pharmacokinetics is complex; bisphs remain attached to bone for weeks to months • amount of drug released in plasma related to rate of bone metabolism and turnover

  21. Non-nitrogen-containing Bisphosphonates • First generation bisphos, such as ETIDRONATE, TILUDRONATE, and CLODRONATE • accumulation of a cytotoxic ATP analogue compound

  22. Nitrogen-containing Bisphosphonates • Most recent bisphos, e.g., ALENDRONATE, PAMIDRONATE, ZOLEDRONATE, RISEDRONATE, and IBANDRONATE • Block addition of hydrophobic molecules to proteins ; important for cell membrane function and sub-cellular protein trafficking

  23. Anti-Osteoclast Effect • Inhibition of osteoclast activity, and reduction of their life span • Bisphos may affect other cellular elements present in bone (e.g., endothelial cells, ostocytes, mast-cells, macrophages)

  24. BISPHOSPHONATES AS ANALGESICS

  25. Preclinical Studies DOSE DEPENDENT ANALGESIC EFFECT in animal models of inflammatory pain, cancer pain, neuropathic pain • Goicoechea et al., J Pharmacol, 1999; • Cui et al., Pain, 2000; • Oelzner et al. Inflamm Res,2000; • Bonabello et al., Pain, 2001; • Walker et al., Pain , 2002; • Harada et al., Inflamm Res,2004; • Kawabata et al., Neuropharmacology, 2006; • Bianchi et al., European Journal of Pain, 2007;

  26. IV Pamidronate as Analgesic • Metastatic bone pain • Ankylosing spondylitis • Paget’s disease • Rheumatoid arthritis • CRPS/RSD • Chronic back pain Hortobagyi et al., 1996; Lipton et al., 1994; Maksymowych et al., 1998; Van Offel et al., 2001; Maccagno et al., 1994; Kubalek et al., 2001; Fulfaro et al., 1998; Varenna et al., 2000; Pappagallo et al,. 2003

  27. IV BISPHOSPHONATES for metastatic bone pain IV bisphos treatment for hypercalcemia due to bone metastases associated with a quick relief of severe cancer bone pain Fulfaro et al., 1998; Hortobagyi et al., 1996; Purohit et al. 1994; Coleman et al. 1997

  28. IV Bisphosphonates for Ankylosing Spondylitis Two open-label trials and a RCT indicate that IV pamidronate can reduce morning stiffness and back pain in patients with NSAID-refractory ankylosing spondylitis (AS) Maksymowych et al J Rheumatol 1998; Maksymowych et al., J Rheumatol 2001; Maksymowych et al., Arthritis Rheum 2002;46:766–73.

  29. IV Bisphosphonates for Paget’s Disease of Bone Bisphos play a relevant therapeutic role in modifying the disease course, and improving pain and mobility Walsh et al. Bone 2004;34:747–54., Bombassei et al., Am J Med Sci 1994. Vasireddy et al., Clin Rheumatol 2003;22:376–80.

  30. IV Bisphosphonates for Rheumatoid Arthritis Some evidence of benefit, in the management of pain and prevention of bone erosions Rovetta et al. Minerva Med 2003; Jarrett et al., Arthritis Rheum 2006; Romas E. Best Pract Res Clin Rheumatol 2005;

  31. IV Pamidronate for Chronic Mechanical Back Pain • Patients (n=25) with NSAIDs-refractory chronic LBP and with no osteoporotic fractures or metastatic disease • Average pain decreased from baseline by 3.6 points (on 0–10 NRS) • Bisphosph-related pain relief not associated with an increase in opioid analgesics . Pappagallo et al., J Pain Symptom Manage 2003;

  32. A Pilot Trial of IV Pamidronate for Low Back Pain ClinicalTrials.gov - Identifier:NCT00101790Sponsored by the National Institute of Neurological Disorders and Stroke • Four study groups, each group with subjects randomly assigned to pamidronate (n=7) or to placebo (n=4) • Dosage: 30 mg of PAM in the 1st group, 60 mg in the 2nd group, and 90 mg in the 3rd group • Subjects in the 4th group will receive 2 treatments of best tolerated / more effective PAM dose

  33. CRPS/RSD Marco Pappagallo, MD

  34. CRPS / RSD IASP DIAGNOSTIC CRITERIA • Inciting Noxious Event (e.g.,trauma) or a Cause of Limb Immobilization (e.g., cast, stroke) • Pain, Allodynia / Hyperesthesia disproportionate in severity to any inciting noxious event • At some point in time, evidence of regional abnormal skin color / To changes, edema, sudomotor activity • CRPS 1:Diagnosis of Exclusion

  35. Technetium-99 Bisphosphonate in Bone Scintigraphy • May show regional skeletal changes in several cases of CRPS • Utilizes a technetium-99 radio-labeled bisphosphonate (medronate, oxidronate) as an intravenous marker

  36. 3 phase BONE SCAN FINDINGS 1. HYPERFUSION in theblood pool phase(2 min after infusion) 2.INCREASED PERIARTICULAR TRACER UPTAKE during the mineralization phase (3 hrs after infusion) Reportedly 50% sensitivity 90% specificity The BONE SCANtracer is a bisphosphonate mixed with radioactivetechnetium and injected for detecting abnormal bone metabolism and disease. Higher Sensitivity inCRPS of < 6 mo.

  37. IV PAMIDRONATE • Maillefert et al., 1995; open label • Cortet et al., 1997; open label • Kubalek et al., 2001; open label • Robinson et al., 2004; RCT IV CLODRONATE 5. Varenna et al., 2000; RCT IV, ORAL ALENDRONATE 6. Adamiet al., 1997; open label 7. Manicourt et al., 2004; RCT

  38. IV PAMIDRONATE FOR CRPS • Maillefert et al. 1995: improvement in 7 of 11 patients • Cortet et al., 1997: improvement in pain and physical function in 10 women and 13 men • Kubalek et al., 2001: excellent pain relief in 25 of 29 patients from IV pam at 60 mg/day for 3 consecutive days • Robinson et al, 2004: RCT (n=27) of IV pam 60 mg as a single dose vs. placebo; significant improvement in pain and function at 1 and 3 months postinfusion (active treatment group n=14)

  39. IV Clodronate • Varenna et al, (2000): RCT (N=32) of IV clodronate, efficacy at 6 mo, after 300 mg daily for 10 days (active tx group, n=15);urine NTx as predictive factor for efficacy IV / Oral Alendronate • Adami et al.,(1997): IV alendronate relieved CRPS by at least 50% in 13 patients out of 20 • Manicourt et al.,(2004): in a RCT (N=40) of oral alendronate, efficacy (improvement in pain and joint mobility) for post-traumatic CRPS of the lower extremity at 3 mo after 40 mg daily for 8 wks (alendronate-treated group, n = 19)

  40. Open label pilot trial of IV ibandronate for CRPSBreuer B, Pappagallo M, Goldfarb R, et al., The Journal of Pain, 2007 • Objectives: • assess safety of IV ibandronate 6mg daily for 3 days in patients with CRPS • evaluate analgesia • explore correlation between tx response and bone scan findings

  41. IV Ibandronate for CRPS/RSD:Results (N=10) at 3 mo Post-intervention • Patient Global Impression of Change: • 4 subjects with much improvement • 6 subjects with minimal improvement • Brief Pain Inventory: significantly lower than baseline for average pain p = 0.007; worst pain p = 0.004 • Neuropathic Pain Scale:descriptors significantly improved for • unpleasantness, sensitivity, depth, intensity, surface, heat, cold, sharpness, and dullness.

  42. IV Ibandronate for CRPS/RSD • Aside from transitory flu-like symptoms, ibandronate was well tolerated • No hypocalcemia or delayed adverse events reported

  43. IV Ibandronate for CRPS/RSD: Bone Scan Findings in the Affected Limb • Uptake (compared with contralateral limb) • 5 subjects with an increased uptake • 2 subjects with a decrease uptake • 3 subjects with no difference • Subjects (N=5) with positive bone scans improved more than those having decreased uptake (N=2) in neuropathic pain qualities (p≤0.03)

  44. IV Ibandronate for CRPS/RSD - Conclusion • A subgroup of patients with CRPS appear to have bisphos-responsive pain • Bone pain mechanisms maintaining some of the symptoms of CRPS

  45. IV Bisphosphonates CONTRA-INDICATIONS & SIDE-EFFECTS

  46. IV Bisphosphonates CONTRA-INDICATIONS • Pregnancy • Renal, Hepatic mod-severe Disease • Hypocalcemia • Poor Oral Hygiene and Active Endodontic / Periodontal Disease

  47. SIDE EFFECTS • IV Bisphosphonates well tolerated when appropriately administrated • associated with transient and manageable (e.g., acute phase reaction)side effects • However, there is an emergent concern about a complication known as osteonecrosis of the jaw (ONJ)

  48. toothpaste with pyrophosphate should probably be discouraged in patients with exposed bone

More Related