Review Article
`TheScientificWorldJOURNAL (2008) 8, 229–236
`ISSN 1537-744X; DOI 10.1100/tsw.2008.33
`
`
`
`Complex Regional Pain Syndrome
`(CRPS/RSD) and Neuropathic Pain: Role of
`Intravenous Bisphosphonates as
`Analgesics
`
`Jennifer Yanow, Marco Pappagallo, and Letha Pillai
`The Mount Sinai School of Medicine, Department of Anesthesiology, 5 East 98th, Street,
`6th fl., Box # 1192, New York, NY 10029
`
`E-mail: yanowj01@med.nyu.edu, letha.pillai@mssm.edu, Marco.Pappagallo@mountsinai.org
`
`Received November 1, 2007; Revised January 13, 2008; Accepted January 20, 2008; Published February 25, 2008
`
`Neuropathic pain is a sequela of dysfunction, injuries, or diseases of the peripheral
`and/or central nervous system pain pathways, which has historically been extremely
`difficult to treat. Complex regional pain syndrome (CRPS) types 1 and 2 are neuropathic
`pain conditions that have a
`long history
`in the medical
`literature but whose
`pathophysiology remains elusive and whose available treatment options remain few.
`While an exact animal model for CRPS doesn't yet exist, there are several animal models
`of neuropathic pain that develop behaviors of hypersensitivity, one of the hallmark signs
`of neuropathic pain in humans.
`Bisphosphonates have been used for pathologic conditions associated with
`abnormal bone metabolism, such as osteoporosis, Paget’s disease and cancer-related
`bone pain for many years. More recently, results of clinical trials have indicated the
`potential role of bisphosphonates in the treatment of CRPS/RSD.
`In this paper we will review the preclinical studies regarding the use of
`bisphosphonates as analgesics in animal models of neuropathic pain, and also
`summarize the clinical trials that have been done to date. We will give an overview of
`bisphosphonate pharmacology and discuss several potential mechanisms by which
`bisphosphonates may be analgesic in CRPS/RSD and bone pain of noncancer origin.
`
`KEYWORDS: neuropathic pain, CRPS 1, CRPS 2, RSD, causalgia, bisphosphonates
`
`
`NEUROPATHIC PAIN AND COMPLEX REGIONAL PAIN SYNDROME (CRPS/RSD)
`
`Neuropathic pain is a sequela of dysfunction, injuries, or diseases of the peripheral (post-thoracotomy,
`HIV, diabetes) and/or central (stroke, multiple sclerosis, shingles) nervous system pain pathways. The
`pain signal is thought to be generated ectopically in small afferent fibers (A-delta, C-nerve fibers) and
`abnormally modulated by the central nervous system (CNS). Patients will exhibit several features
`classically used to describe neuropathic pain, such as hyperalgesia (exaggerated response to a mildly
`noxious stimulus) or allodynia (pain from non-noxious stimuli). Neuropathic pain continues beyond the
`
`*Corresponding author.
`©2008 with author.
`Published by TheScientificWorld; www.thescientificworld.com
`
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`Grun. Exh. 1011
`PGR for U.S. Patent No. 9,707,245
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`Yanow et al.: Bisphosphonates and Neuropathic Pain
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`TheScientificWorldJOURNAL (2008) 8, 229–236
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`time of normal tissue healing and is a considerable source of disability. Historically, it has been extremely
`difficult to treat and combinations of pharmacological agents, including antidepressants, anticonvulsants,
`and opioids, have often been used to alleviate suffering and pain in patients affected by neuropathic pain
`syndromes.
`Complex regional pain syndrome (CRPS) type 1, formerly known as reflex sympathetic dystrophy
`(RSD), is a debilitating neuropathic pain disorder that has been recognized for more than a century. In
`1993, the International Association for the Study of Pain (IASP) revised the IASP taxonomy by
`redefining and reclassifying RSD as CRPS type 1, and causalgia as CRPS type 2[49]. CRPS type 1 occurs
`following a period of immobilization or noxious event, and involves the development of continuing pain,
`allodynia, or hyperalgesia out of proportion to the initial event. CRPS type 2 occurs after a definable
`nerve injury, with the resultant pain, allodynia, or hyperalgesia not necessarily localized to the
`distribution of the injured nerve. Despite the long history of this disorder, the pathophysiology of
`CRPS/RSD has remained elusive. Of interest are the regional skeletal changes observed in several cases
`of CRPS/RSD. Although it has lost diagnostic purposes, a three-phase bone scintigraphy is still used in
`the evaluation of CRPS/RSD. Bone scintigraphy utilizes a technetium-99 radiolabeled bisphosphonate as
`an intravenous marker. The old RSD literature indicated a 50% diagnostic sensitivity and 90% diagnostic
`specificity for bone scintigraphy when performed in cases of RSD with duration of less than 6
`months[1,2]. The typical RSD bone scan findings consisted of a homogeneous unilateral marker uptake
`(hyperperfusion) within the bone of the affected limb at both phase 1 (or “perfusion phase”) occurring 30
`sec after the marker injection and phase 2 (or “blood pool phase”) occurring 2 min after the marker
`injection. During phase 3 (or “mineralization phase”) at 3 h after injection, a characteristic uptake of the
`radiolabeled bisphosphonate is only observed in and around the joints of the affected limb. The
`significance of the bone scintigraphy findings in CRPS/RSD is unclear. Also undetermined is the
`potential role of bone pain mechanisms in CRPS/RSD. However, it is conceivable that a subgroup of
`patients with CRPS/RSD may suffer from a pathological pain state occurring in the bones of the
`symptomatic limb. For simplicity, we are going to use the term “neuropathic bone pain” to indicate this
`potential bone mechanism.
`
`PHYSIOLOGIC MECHANISMS OF “NEUROPATHIC BONE PAIN”
`
`Immunohistochemical studies have revealed an extensive network of nerve fibers in the vicinity and
`within the skeleton[3]. Peptidergic sensory fibers, as well as sympathetic fibers, occur throughout the
`bone marrow, mineralized bone, and the periosteum. Both the periosteum and the bone marrow receive
`the highest degree of innervation. Multiple algogenic factors, such as a low pH, local synthesis of nerve
`growth factor (NGF), and release of proteases and inflammatory substances, such as cytokines and
`prostaglandins (PGs), might act synergistically to activate the extensive network of nociceptors
`innervating the periosteum, the cortical and trabecular bone, as well the bone marrow.
`Activated osteoclasts produce an acidic microenvironment via the release of protons through vacuolar
`H+-ATPase[4,5]. A potential mechanism of bone pain may be the activation of two main groups of acid-
`sensing nociceptors[6]. Acid-sensing ion channels (ASICs) and the capsaicin receptor transient receptor
`potential vanilloid subtype 1 (TRVP1) are involved in proton-transduction mechanisms and in pain signal
`transmission[7,8,9]. ASIC-expressing nociceptors may also be involved in the transduction and
`transmission of mechanical pain[10]. It follows that some of the antinociceptive properties of agents that
`ameliorate bone pain, including bisphosphonates, may be attributed to inhibition of osteoclast activity
`and, in turn, to a decrease in proton concentration of the bone microenvironment.
`NGF induces hyperalgesia by up-regulating the transcription for genes encoding pain receptors, such
`as capsaicin receptor or TRPV1, neuropeptides such as calcitonin gene-related peptide (CGRP), and the
`transmitter substance P. NGF was recently found to have a relevant role in bone pain. NGF-expressing
`cells and nociceptors with high-affinity tyrosine kinase receptors for NGF are found in bone[11,12,13].
`NGF is produced by many cellular elements, including mast cells, macrophages, endothelial cells,
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`osteocytes, osteoblasts, and bone marrow stromal cells[12,13], and its expression is enhanced in bone
`inflammation, bone cancer, trauma, and fractures. Therefore, inhibitors of osteoclasts or other cells that
`acidify the bone microenvironment or express NGF may prevent or reduce chronic bone pain. It is
`postulated that as neuropathic bone pain mechanisms are set in motion, pain becomes chronic and
`refractory to treatment.
`There is evidence that tumor cells, endothelial cells, and activated macrophages, when directly
`exposed to bisphosphonates in vitro or in vivo, can suffer from bisphosphonate-induced toxic effects and
`even undergo apoptosis[14,15]. It is unknown, but possible, that the analgesic properties of
`bisphosphonates may not only be attributed to inhibition of osteoclast activity, but also to inhibition of
`NGF-expressing cells. Neuropeptides (CGRP and substance P) can activate mast cells (potent source of
`NGF) and endothelial cells to cause vasodilatation and plasma extravasation. Moreover, the presence of
`receptors for CGRP and substance P has recently been described on osteoclasts and osteoblasts. CGRP
`and substance P appear to regulate osteoclast formation, bone formation, and resorption[3].
`It is hypothesized that bone pain mechanisms may have a more important clinical role than originally
`thought, and this may be relevant to subgroups of patients with chronic back pain and CRPS/RSD (Marco
`Pappagallo, oral communication, 2006).
`
`BISPHOSPHONATES: AN OVERVIEW
`
`The pharmacological agents called bisphosphonates were initially developed as analogues of
`pyrophosphate, an agent commonly used as an antitartar agent
`in
`toothpaste. Traditionally,
`bisphosphonates have been used not only as analgesics for oncological bone pain, but also in the
`treatment of hypercalcemia of malignancy, osteolytic bone metastases, Paget’s disease of bone, and
`osteoporosis. Earlier bisphosphonates, such as etidronate and clodronate, have been largely replaced by
`second-generation bisphosphonates, including pamidronate, as well as third-generation bisphosphonates,
`including zoledronic acid and ibandronate.
`Bisphosphonates all have the P-C-P structure in common, which is similar to the P-O-P structure of
`native pyrophosphate. The bisphosphonates differ from one another at the two “R” groups. The ability of
`bisphosphonates to inhibit bone resorption depends on two specific properties of the bisphosphonate
`molecule. The two phosphonate groups plus the hydroxyl group at the R1 position result in high affinity
`for bone mineral, allowing efficient targeting of bisphosphonates to bone mineral surfaces. Once the
`bisphosphonate molecule is within the bone, the phosphorus groups and the R2 side chain determine the
`biological activity of the molecule and influence the ability of the drugs to interact with their targets.
`The P-C-P moiety of the bisphosphonate molecule is responsible for its strong affinity for
`hydroxyapatite. The ability of the bisphosphonate to bind to hydroxyapatite crystals and to prevent
`growth/dissolution is enhanced when the R1 side chain is a hydroxyl group rather than a halogen atom.
`The P-C-P structure is also responsible for the ability of bisphosphonates to inhibit bone resorption. By
`altering the R2 side chain, more potent antiresorptive bisphosphonates (for example, pamidronate and
`alendronate) are produced. These bisphosphonates have an R2 side chain that contains a basic primary
`amino-nitrogen atom in an alkyl chain and are 10–100 times more potent than etidronate and clodronate.
`Compounds containing a tertiary amino-nitrogen, such as ibandronate, are even more potent, and those
`containing a nitrogen atom within a heterocyclic ring (risedronate, zoledronate) are up to 10,000 times
`more potent than etidronate[16].
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`FIGURE 1. Chemical structure of
`the nitrogen-containing and non-nitrogen-containing
`bisphosphonates. Adapted from Russell, 2007[16].
`
`
`
`Non-nitrogen-containing compounds, such as clodronate and etidronate, exert their effects by leading
`to the intracellular accumulation of metabolites that inhibit osteoclast function and cause their cell death.
`Nitrogen-containing bisphosphonates, such as alendronate, risedronate, and zoledronate, have bulkier side
`chains and are not metabolized. Instead, they interfere with metabolic reactions in the mevalonate
`biosynthetic pathway, protein prenylation, and ultimately the signaling functions of key regulatory
`proteins[16].
`Bisphosphonates are available as oral or intravenous preparations. The major disadvantage of the
`orally utilized bisphosphonates is their extremely poor absorption in the gastrointestinal tract. Less than
`1% of the oral dose is absorbed, and absorption is suppressed by food intake. In order to obtain a rapid
`and more considerable effect, a relatively high dose of bisphosphonates must be given by intravenous
`(IV) infusion. The pharmacokinetics of bisphosphonates is complex. These drugs remain in the bone,
`attached to hydroxyapatite crystals, for weeks to months.
`Some of the bisphosphonates’ biological effects are mediated through actions on the osteoclasts and
`likely on their cell precursors and other related cells, such as macrophages, CNS dendritic cells, and
`microglia. Bisphosphonates suppress osteoclast-mediated bone resorption via an intracellular effect on
`osteoclasts, and cause inhibition of osteoclast activity and reduction of the osteoclast life span. Of note,
`IV bisphosphonate treatment is associated with a rapid relief of bone pain[17,18], e.g., “immediately after
`the first infusion”[19], “within 10–14 days”[20], “within a matter of days”[21], and “within 1 month of
`infusion”[22].
`When appropriately administrated, IV bisphosphonates are generally well tolerated and only
`associated with transient and manageable side effects (flu-like symptoms or acute phase reaction during
`the first 3 days following the infusion; symptoms usually respond to anti-inflammatory agents).
`Nevertheless, more recently and primarily in the oncology field, a serious condition known as
`osteonecrosis of the jaw (ONJ) has emerged as a potential treatment complication. ONJ may affect a
`subgroup of patients undergoing chronic IV bisphosphonate treatment for multiple myeloma, bone
`metastases from breast, prostate, or lung cancer. Some authors have reported a 5–10% incidence
`occurring after prolonged IV bisphosphonate treatment[25,26]. Tissue biopsies of the affected jaw lesions
`have revealed findings consistent with osteomyelitis[25]. Major risk factors include prolonged treatment
`with potent bisphosphonates (i.e., monthly IV administration for more than 1 year), poor oral hygiene,
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`existing periodontal disease, periodontal surgery, dental implants, and a history of recent dental
`extractions.
`There is a question about whether bisphosphonates inhibit fracture repair, although recent studies
`have shown no adverse bone healing in animals treated with ibandronate[26,27], as well as improved
`osseointegraion of metal implants[28].
`
`PRECLINICAL STUDIES: BISPHOSPHONATES IN NON-BONE-RELATED PAIN
`MODELS
`
`Multiple lines of evidence gleaned from preclinical studies corroborate the analgesic action of
`bisphosphonates. Several preclinical studies revealed central and peripheral prolonged analgesic
`properties of the bisphosphonates for non-bone-related pain states[29,30]. These studies have also
`revealed a dose-dependent analgesic effect in animal models of both inflammatory and neuropathic
`pain[31,32,33,34].
`There are several animal models of peripheral nerve injury and neuropathic pain produced by varying
`degrees of spinal nerve ligation, resulting in an incomplete denervation of the sciatic nerve territory
`through selective damage of certain contributing spinal nerves[35]. Three commonly used models are the
`Bennett model (loose ligation/chronic constriction of the entire sciatic nerve), the Chung model (tight
`ligation of an entire spinal segmental nerve close to the dorsal root ganglion), and the Seltzer model (tight
`ligation of a portion of the proximal sciatic nerve)[36]. These animals develop certain behaviors
`indicative of hypersensitivity, one of the hallmark signs of neuropathic pain in humans They display
`mechanical hypersensitivity to hair stimulation, mechanical pin-prick hyperalgesia, cold allodynia, and
`reduced latency to withdrawal in response to a heat stimulus; behaviors that persist for a prolonged period
`of time following the nerve ligation.
`Walker et al. examined the analgesic efficacy of zoledronic acid in a rat model of neuropathic pain
`and mechanical hyperalgesia induced by partial ligation of the sciatic nerve. A reversal of mechanical
`hyperalgesia was observed 30 min following zoledronic acid administration[35]. Liu et al. investigated
`the effects of IV liposome-encapsulated clodronate in a rat model of neuropathic pain induced by sciatic
`nerve ligature. The authors showed that clodronate not only reduced the Wallerian nerve fiber
`degeneration and the recruitment of macrophages infiltrating the injured nerve, but also mechanical
`hyperalgesia[37]. Goicoechea et al. showed a dose- and time-dependent analgesic effect from
`intraperitoneal aledronate in the abdominal constriction test in mice[38]. Bonabello et al. showed both a
`peripherally and centrally mediated analgesic action of four bisphosphonates (clodronate, alendronate,
`pamidronate, and etidronate). The authors used two mouse pain models, the tail-flick test for thermal pain
`and the writhing test for chemical pain. The bisphosphonate effect was compared to those from morphine
`and acetylsalicylic acid. To study the peripheral effects of bisphosphonates, the medications were given
`intravenously. A dose-dependent antinociceptive effect was observed following administration of
`pamidronate, clodronate, and acetylsalicylic acid. Etidronate and alendronate also produced an analgesic
`effect, but only at the highest dose tested. To study the central effect of clodronate and pamidronate, the
`medications were administered intracerebroventricularly. Both bisphosphonates showed a dose-dependent
`antinociceptive effect[29].
`
`CLINICAL EXPERIENCE: BISPHOSPHONATES IN CRPS/RSD TRIALS
`
`A review of the literature reveals multiple studies of bisphosphonates for CRPS/RSD. To date, four trials
`of intravenous pamidronate for CRPS/RSD have been published. In 1995, Maillefert et al. reported on
`seven of 11 patients with CRPS/RSD, who experienced clinically significant improvement from
`pamidronate therapy[39]. In 1997, Cortet et al. reported on 10 women and 13 men with CRPS/RSD, who
`showed highly significant pain reduction and physical functional improvement[40]. In 2001, Kubalek et
`
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`al. treated 29 patients with CRPS/RSD[41]. Twenty-five of the patients experienced excellent pain relief
`from IV pamidronate at a dose of 60 mg/day for 3 consecutive days. Lastly, in a double-blind,
`randomized, placebo-controlled trial of IV pamidronate (n = 27), the active treatment group (n = 14)
`reported significant improvement in pain and physical function at 3 months postinfusion[42]. In a
`controlled trial of clodronate, 32 CRPS/RSD patients were randomized to receive either IV clodronate
`(300 mg daily) for 10 consecutive days or placebo[43]. This trial demonstrated significant efficacy of the
`clodronate treatment over placebo. Adami et al. reported that among 20 patients with CRPS/RSD, IV
`alendronate relieved pain by at least 50% in 13 patients, and those who received two infusions performed
`better than those who received one[44]. Finally, Manicourt et al. conducted a randomized controlled trial
`of oral alendronate (40 mg daily) for 8 weeks vs. placebo in patients (n = 40) with post-traumatic
`CRPS/RSD of the lower extremities[45]. The alendronate-treated patients exhibited a significant and
`sustained improvement in levels of spontaneous pain, mechanical pressure, and joint mobility. Several
`lines of evidence suggest that a subgroup of patients with CRPS/RSD might have bisphosphonate-
`responsive bone pain. Therefore, it is conceivable that bisphosphonate-responsive pain mechanisms might
`be involved in maintaining some of the symptoms of CRPS/RSD.
`
`CONCLUSION
`
`The use of bisphosphonates for pathological conditions associated with abnormal bone metabolism, such
`as cancer bone pain, osteoporosis, and Paget’s disease, has been well documented. More recently, results
`of clinical trials have indicated the potential role of bisphosphonates in the treatment of the neuropathic
`pain syndrome known as CRPS/RSD. In this review, we have discussed several potential mechanisms by
`which bisphosphonates may be analgesic in CRPS/RSD and bone pain of noncancer origin. More
`research will be necessary to help elucidate these mechanisms. Some important information could be
`ascertained from studying the effects of IV bisphosphonates in patients with early CRPS/RSD. If the
`progression of disease was shown to be halted following therapy, in theory it may be possible for IV
`bisphosphonate treatment to lessen or even prevent the chronic neuropathic pain that eventually develops
`in CRPS/RSD.
`
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`intravenous bisphosphonates as analgesics. TheScientificWorldJOURNAL 8, 229–236. DOI 10.1100/tsw.2008.33.
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