The Neurotoxin Institute

Advisory Editor
F. Michael Ferrante, MD, FABPM
Medical Director, Pain Medicine Center
Professor of Clinical Anesthesiology and Medicine
Department of Anesthesiology
UCLA School of Medicine
University of California, Los Angeles
Los Angeles, California

Introduction

Acute or chronic pain has a deleterious impact on every aspect of patients' lives and imposes a tremendous burden on society and healthcare resources. A recent study (Pain News, 2002) estimated that the economic cost of pain to United States employers is $80 billion per year, with the majority of the cost ($64 billion) attributable to loss of productivity.

There has been considerable interest in the efficacy of botulinum neurotoxin (BoNT) in managing pain, particularly in musculoskeletal pain conditions in which the muscle-relaxing effect of BoNT is likely to be of therapeutic benefit. There have also been a number of recent advances in the research and development related to therapeutic uses of non-botulinum neurotoxins for pain.

Part I. Botulinum neurotoxins for pain management

Mechanism of action of BoNT in pain reduction

See “Botulinum Neurotoxin Mechanism of Action” Module for in-depth discussion of BoNT mechanism of action

The irreversible presynaptic blockade of the release of acetylcholine at the motor endplates caused by BoNT and the resulting relaxation of the muscle is well established and is the underlying mechanism for its therapeutic effect on hyperactive muscle disorders. Other processes and pathways that are thought to contribute to reduction of pain sensation with BoNT therapy include altered afferent input to the central nervous system produced by the effect of BoNT on muscle spindles; inhibition of the release of neurotransmitters and neuropeptides involved in peripheral pain and somatosensory pathways such as glutamate, substance P, and calcitonin gene-related peptide; and direct antinociceptive effects in the central nervous system (Gobel et al, 2001; Guyer, 1999; Hallett, 2000; Sheean, 2002). For example, BoNT injection has been shown to block formalin-induced release of glutamate in the paws of rats (Cui et al, 2002). Inhibition of glutamate release was associated with reduced neuronal activity in the dorsal horn in the tonic nociceptive phase of the formalin response. Cui et al speculated that their results demonstrate a pathway by which suppression of the glutamate-mediated peripheral neurotransmitter release by BoNT inhibits peripheral and central sensitization and thereby reduces the sensation of pain (Cui et al, 2002). Figure 1 illustrates some of the putative pathways of chronic muscle pain and potential sites where BoNT might act to alleviate pain.

Figure 1. Pathophysiology of chronic muscle pain. ACh-acetylcholine; BK-bradykinin; BTX (BoNT)-botulinum toxin; CCK-cholecystokinin; CGRP-calcium gene-related peptide; Glu-glutamate; PG-phosphate glutamate; SP-substance P. Sheean G. Reproduced with permission from Sheean G. Botulinum toxin for the treatment of musculoskeletal pain and spasm. Curr PainHeadache Rep. 2002;6:460-469.

Clinical applications of BoNT in managing pain

The use of BoNT in pain management is a relatively new area of investigation. As a result, there are few randomized, placebo-controlled, double-blind trials. In addition to the well-studied effects of BoNT on pain in dystonia and spasticity, the range of other painful, nonneurologic muscle conditions that are potential targets for BoNT therapy include neck and low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular pain and other facial pain disorders, and headache. See The Use of Botulinum Neurotoxins in Headache

Spasticity

Spasticity caused by cerebral palsy, stroke, and a variety of upper motor neuron disorders is frequently painful. Wissel et al evaluated the effect of BoNT type A (mean dose, 165.7 U) on pain in 60 patients with acute or chronic spasticity in a prospective multicenter study (Wissel et al, 2000). Patient-assessed pain improved in 54 of 60 patients with or without associated subjective functional improvement. Thus, BoNT was found to be an effective treatment modality to reduce spasticity-related local pain (Wissel et al, 2000).

Back pain

Back problems account for 16.5% of all disability in the United States (Centers for Disease Control and Prevention, 1999). Estimates of the number of adult Americans who experience low back pain at some point range from 13.8% to 80% (Hourigan et al, 1989; Loney and Stratford, 1999). Accordingly, safe and effective treatments for back pain are an important public health need.

Foster et al investigated the efficacy of BoNT type A in 31 patients with chronic low back pain

(Foster et al, 2001). Patients were randomized to double-blind treatment with 200 U of BoNT type A (40 U/site at five lumbar paravertebral levels on the side of maximum discomfort) or placebo. Pain and degree of disability were assessed at baseline and at 3 and 8 weeks, using a visual analogue scale (VAS) and the Oswestry Low Back Pain Questionnaire (OLBPQ). At 3 and 8 weeks, a significantly greater proportion of BoNT type A-treated patients experienced >50% pain relief (73.3% and 60% at 3 and 8 weeks, respectively ; P≤0.01) compared with placebo-treated patients (25% and 12.5% at 3 and 8 weeks, respectively). The degree of disability due to back pain measured with the OLBPQ at 8 weeks also showed improvement in more patients in the BoNT group (66.7%) compared with the placebo group (18.8%; P=0.011). These results confirmed the observations of open-label and uncontrolled studies.

Neck pain

Freund and Schwartz studied BoNT type A treatment of whiplash-associated neck pain in a randomized, double-blind, placebo-controlled study of 26 patients with chronic neck pain subsequent to a motor vehicle accident (Freund and Schwartz, 2000). Fourteen of the patients received 100 U BoNT type A while 12 received saline. Outcome measures included total subjective neck, shoulder, and head pain based on VAS scores. Follow-up assessments were carried out at 2 and 4 weeks posttreatment. At 4 weeks postinjection, the treatment group was significantly improved from preinjection pain levels (P<0.01). The placebo group showed no statistically significant changes at any posttreatment time.

Myofascial pain syndrome

Myofascial pain syndrome (MPS) is a condition of acute or chronic muscle pain and stiffness characterized by the presence of localized, hyperirritable trigger points. A trigger point is a palpable knot or mass (usually 3-6 mm in diameter) in a taut band of muscle, associated with tenderness and referred pain into well-defined areas remote from the trigger point area (Reilich et al, 2004; Sheean, 2002). MPS can develop in any skeletal muscle, tendon, or fascia, typically resulting in persistent regional pain including neck pain, shoulder pain, chronic tension headache, or orofacial pain (Graff-Radford, 2004). Myofascial pain is extremely common, with prevalence among patients presenting to pain management centers estimated at approximately 85% to 93% (Borg-Stein, 2002), and severe chronic forms are often refractory to pharmacological treatment and physical therapy (Reilich et al, 2004).

The etiology of myofascial pain syndrome is uncertain. The current leading endplate hypothesis, known as the “integrated trigger point hypothesis,” proposes that an initial muscular overload due to overuse or trauma causes dysfunction at the neuromuscular endplate (Reilich et al, 2004). This action results in excessive release of acetylcholine, prolonged depolarization, and sustained muscle contraction, leading to compression of small blood vessels, local tissue ischemia, release of bradykinin, and excitation of nociceptors (Figure 2) (Mense, 2004; Reilich et al, 2004). The postulated sustained muscle contraction thus provides the rationale for treatment with BoNT (Mense, 2004; Reilich, 2004; Sheean, 2002).

Figure 2. The endplate (or “integrated”) hypothesis of the formation of myofascial trigger points. The trigger point formation starts with an excessive release of acetylcholine from the presynaptic portion of the endplate following a trauma to the muscle. Reproduced with permission from Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J Neurol. 2004;251(suppl 1):I1-I7, which modified it after Simons DG. Clinical and etiological update of myofascial pain from trigger points. J Musculoskeletal Pain. 1996;4:93-121.

A number of small clinical trials that have examined the efficacy of BoNT in the treatment of MPS have produced variable results. In 1994, Cheshire et al used a crossover strategy in a small (N=6) double-blind, placebo-controlled trial of BoNT in patients with chronic myofascial pain (Cheshire et al, 1994). Six patients were injected with 50 U of BoNT type A or saline into 2 or 3 trigger points in the cervical paraspinal or shoulder girdle muscles. Eight weeks later, patients were injected with whichever treatment they did not receive originally (Cheshire et al, 1994). Four of the six patients experienced a statistically significant reduction in pain (defined as a 30% reduction from baseline, measured on a VAS) in response to BoNT type A but not to saline; one patient did not respond to either treatment and one patient responded to both treatments. Mean duration of the response to BoNT was 5 to 6 weeks.

In a randomized, double-blind study, Wheeler et al treated 33 MPS patients with 50 or 100 U of BoNT type A or placebo (normal saline) (Wheeler et al, 1998). Significant changes from baseline in the posttreatment assessment at 4 months were noted in all treatment groups, without significant differences among treatment groups. However, there were notable increases in clinical improvement in patients given a second injection of BoNT type A (100 U) in the same site compared with those who received placebo followed by an injection of BoNT type A (100 U).

Porta conducted a comparative trial of BoNT type A and methylprednisolone in patients suffering from chronic myofascial pain (Porta, 2000). Although both treatment groups experienced significant reductions in pain 30 days after receiving injections, the reduction in the mean pain score between baseline and 30 days postinjection was greater for the BoNT type A group compared with the steroid group. Furthermore, the reduction in pain severity score at 60 days postinjection was significantly greater for the BoNT type A group than for the steroid-treated group. The beneficial effects of BoNT-A therapy were continuing to increase at 60 days postinjection, whereas the effects of steroid therapy had begun to wane at 60 days.

Wheeler et al used a comprehensive set of outcome measures in a randomized, double-blind, 4-month study that compared the therapeutic efficacy of BoNT type A to normal saline in 50 patients with chronic neck pain originating from muscle spasm or myofascial dysfunction (Wheeler et al, 2001). At each follow-up visit (at 4, 8, 12, and 16 weeks), patients completed the neck pain and disability (NPAD) instrument, which uses a VAS to measure neck pain and disability, and used a diary to record adverse events. Patient and physician global assessments of improvement were also recorded. Results showed significant benefit in both treatment groups, with significant decline in pain and disability and an increased ability to withstand pressure on trigger points. Patients in the BoNT type A treatment group reported more adverse events than did those in the placebo group.

Lang reported an open-label, exploratory pilot study (N=72) for treatment of MPS (Lang, 2000). Treatment consisted of one or more injections of BoNT type A into the cervicothoracic and/or lumbosacral regions using a novel injection technique. The injections were either unilateral or bilateral and spread evenly throughout the mid-belly of surface muscles in a grid-like pattern. Most patients received injections into multiple muscles (total dose range, 20-600 U; mean total dose, 236 U; mean volume/treatment, 10 mL; mean U/mL = 20 ). Seventy-two of the first 95 follow-up visits occurred during the first 21 days postinjection. For these visits, physician global outcome ratings based on assessment of range of motion and reported subject symptomatic improvement were “excellent” for 13 treatments (18%), “good” for 34 treatments (47%), “fair” for 18 treatments (25%), and “poor” for 7 treatments (10%). Twenty of the 95 follow-up visits occurred between days 22 and 60 postinjection. For these visits, physician global outcome ratings were “excellent” for 2 treatments (10%), “good” for 10 treatments (50%), “fair” for 4 treatments (20%), and “poor” for 4 treatments (20%).

Ferrante et al conducted a 12-week, randomized, double-blind, placebo-controlled trial to assess the effect of 10 U, 25 U, and 50 U BoNT type A injections in 132 patients with cervical and/or shoulder myofascial pain and active trigger points (Ferrante et al, 2005). Patients treated with BoNT type A demonstrated improvement in three variables associated with quality of life (SF-36 Vitality, SF-36 Social Functioning, and SF-36 Role Emotional) compared with control (placebo) patients, but no significant effect on pain scores was observed.

De Andrés et al analyzed the efficacy of BoNT type A treatment in an open-label interventional prospective study of 77 patients with refractory MPS resistant to conservative management and physical therapy (De Andrés et al, 2003). Outcome measures included a VAS to assess pain reduction, the Oswestry low back pain questionnaire to determine degree of improvement in disability, and the hospital anxiety and depression scale to evaluate psychologic status. Analysis of VAS scores demonstrated significant pain improvement, which was maintained during the 3 posttreatment determinations, with a positive correlation between VAS scores before treatment and those at 15, 30, and 90 days. This study, however, did not include a control group.

A prospective, single-blind study by Kamanli et al compared injection of trigger points with BoNT type A to dry needling and lidocaine injections in 29 patients with MPS (Kamanli et al, 2004). Outcome measures included cervical range of motion, trigger point pain pressure threshold, pain scores, and VAS scores for pain, fatigue, and work disability at the end of the fourth week. Secondary measures included evaluation of anxiety and depression and quality-of-life assessment. The results showed significant improvement in pain pressure thresholds and pain scores in all 3 treatment groups, significant improvements in quality of life scores in the lidocaine and BoNT type A groups, and significant improvement in depression and anxiety scores only in the BoNT type A group.

An open-label chart review by Lang compared the efficacy and tolerability of two BoNT serotypes, type A and type B, in the treatment of MPS (Lang, 2003). The charts of 91 patients who received BoNT type A (n=56; mean dose, 256.9 U; range, 100-600 U) or BoNT type B (n=35; mean dose, 9000 U; range, 2500-20,000 U) were included in the review. Patients rated the intensity of their pain using a VAS before and after receiving injections of BoNT type A or BoNT type B. Patients who received BoNT type A experienced significantly greater reductions in VAS pain scores, significantly longer durations of pain relief, and fewer and milder adverse events than those who received BoNT type B.

Botulinum neurotoxin is not FDA-approved for the treatment of myofascial pain. Studies of BoNT in MPS have been limited in number and typically small in scale. Although some preliminary studies indicate that BoNT has efficacy in the management of MPS, others failed to show a therapeutic benefit. Further large, randomized, double-blind studies will be needed to establish the safety and efficacy of BoNT in the treatment of myofascial pain.

Temporomandibular and other facial pain disorders

Temporomandibular disorders (TMD) affect the face and jaws and cause chronic pain and dysfunction in many people. Freund and Schwartz evaluated the effect of BoNT type A therapy in 60 patients with temporomandibular pain in an open-label study. Both masseter muscles were injected with 50 U each and both temporalis muscles with 25 U each under electromyographic guidance. Of the 60 subjects, 38 (63%) reported a 50% improvement in facial pain during the follow-up period; 46 who met the International Headache Society criteria for chronic tension headache reported a ≥ 50% improvement in headache pain as well (Freund and Schwartz, 2002).

Nixdorf et al evaluated the efficacy of BoNT type A in the treatment of chronic moderate-to-severe jaw pain (myogenous orofacial pain) in a double-blind, placebo-controlled, crossover trial. They injected 25 U into each temporalis muscle and 50 U into each masseter muscle. Data were collected at baseline, 8, 16, and 24 weeks, with crossover occurring at 16 weeks. Primary outcome variables were pain intensity and unpleasantness measured by horizontal VAS. Neither of the primary outcome variables was significantly different between the two treatments (P=0.10). However, only 10 of the 15 enrolled subjects completed the study and it is likely that there were too few subjects to provide sufficient statistical power to detect treatment differences (Nixdorf et al, 2002).

Hemifacial spasm

Poungvarin et al conducted a double-blind crossover study of BoNT type A in 55 patients with hemifacial spasm (Poungvarin et al, 1995). In response to BoNT type A treatment, 81% of patients rated their response as excellent, 7% reported moderate improvement, 9.6% reported mild improvement, and 2.4% reported no response. In contrast, when given the saline injection, 0% rated their response as excellent, 2% reported moderate improvement, 12% reported mild improvement, and 86% reported no response to treatment. These results confirm the findings of previous uncontrolled studies of BoNT type A in hemifacial spasm.

Summary and conclusions

BoNT consistently reduces the musculoskeletal pain associated with dystonia and spasticity and other disorders characterized by focal muscle overactivity. Clinical trials of BoNT in a variety of other pain disorders have yielded encouraging results, but there have been few controlled trials and some inconsistent findings. There is emerging evidence suggesting that BoNT may alleviate pain through a series of complex pathways that extend beyond the muscle-relaxing effect achieved by inhibition of neuromuscular transmission. Further study is needed to enhance our current understanding of the pathophysiology of chronic pain disorders and the mechanisms by which BoNT may modify pain, as well as to quantify the benefits of BoNT therapy in these disorders.

Part II. Non-botulinum neurotoxins in pain reduction

Introduction

A wide array of neurotoxins derived from plant and animal sources are under investigation for their therapeutic application to pain. Clinical research regarding several of these compounds has advanced sufficiently to indicate substantial promise. Included in this category are neurotoxins derived from the cone snail (conotoxins), potent capsaicin analogues derived from the euphorbia plant, and tetrodotoxins found in marine organisms and amphibians.

Cone snail neurotoxins

There are more than 500 species of predatory cone snails within the genus Conus (Jones and Bulaj, 2000). Cone snails are tropical marine mollusks that envenomate their prey with a complex mixture of neuropeptide active compounds. The mechanism of action of these venoms on the cone snail's prey is that they target specific ion channel and receptor subtypes (McIntosh et al, 2000). Each Conus venom contains a unique combination of 50 to 200 neuropharmacologically active peptides; however, the structure and function of only a small number of these peptides have been established. Three classes of targets of these peptides have been determined: voltage-gated ion channels, ligand-gated ion channels, and G-protein-linked receptors (Table). The combination of peptides contained in the venom of the cone shell snail effectively and immediately immobilizes its prey by targeting a diverse array of voltage-sensitive ion channels and N-methyl- d-aspartate, glutamate, vasopressin, serotonin, and acetylcholine receptors (Adams et al, 1999).

Adapted from McIntosh JM, Corpuz GO, Layer RT, et al. Isolation and characterization of a novel conus peptide with apparent antinociceptive activity. J Biol Chem. 2000;275:32391-32397.

Among the many conotoxins from a variety of Conus species that have been isolated, several have demonstrated considerable clinical potential in pain reduction. The characteristics of these conotoxins that make them attractive for therapeutic application in human disease are their high potency and selectivity (Adams et al, 1999). The biological actions of many of these conopeptides can be classified into three distinct categories: production of excitotoxic shock, paralysis, and inhibition of sensory circuits (McIntosh et al, 2000). The basis for the therapeutic use of neurotoxins isolated from cone shell venoms is that the active peptides specifically target components of neural transmission by way of their effects on ion channels and receptor types (Adams et al, 1999; McIntosh et al, 2000).

One of the Conus peptides that has advanced to clinical trials for the treatment of pain is ω-conotoxin MVIIA, an N-type calcium channel blocker isolated from Conus magus. Ziconotide (SNX-111) is a synthetic ω-conotoxin that blocks the entry of calcium ions into nerve cells (Jain, 2000; Wang et al, 2000). Several types of voltage-gated calcium channels have been identified in the sensory pathways known to play a role in nociceptive signaling; the N type appears to be the predominant channel and is particularly important at the spinal level (Chong et al, 2002; Jain, 2000; Wang et al, 2000). The ω-conotoxins block neuromuscular transmission by preventing the voltage-activated entry of calcium into the nerve terminal (Shon et al, 1995). This conotoxin produces analgesia by blocking neurotransmitter release from primary nociceptive afferents and thereby prevents the propagation of pain signals to the brain (Bowersox and Luther, 1998; Jain, 2000). The N-type selective inhibitors such as ω-conopeptide and its derivatives such as ziconotide are antinociceptive in several animal models of neuropathic pain (Jain, 2000). In human studies, ziconotide effectively reduced both malignant and nonmalignant chronic pain (Chong et al, 2002). In an open-label feasibility study of 31 patients, ziconotide, administered intrathecally, produced partial to complete pain relief in a patient population previously found to be opioid-resistant. Another study demonstrated that 150 patients with cancer pain treated with ziconotide experienced a 30% reduction in pain measured by VAS scores compared with placebo (Chong et al, 2002).

A New Drug Application was approved by the United States FDA for the use of ziconotide as an investigation drug for the treatment of chronic pain. Ziconotide is used for continuous intrathecal infusion after injection of the local anesthetic through the catheter. The rationale for intrathecal administration is that ziconotide binds in the human spinal cord at the site where pain signals originate (Atanassoff et al, 2000). Clinical studies of ω-conotoxin MVIIA indicated that it is roughly 1000 times more potent than morphine but does not produce the tolerance or addictive properties of opiates (McIntosh et al, 2000; Jain, 2000; Wang et al, 2000). Most neurological adverse effects related to a delay in clearance of ziconotide from the neural tissues were manageable with dose reduction, although a few are serious and slow to resolve due to the delay in clearance of the drug from the neural tissues. (Jain, 2000).

Another Conus peptide in clinical development, contulakin-G, isolated from Conus geographus, is an agonist of neurotensin receptors but appears to be significantly more potent in inhibiting pain than is neurotensin in in vivo assays (McIntosh et al, 2000; Craig et al, 1999). Preclinical studies of contulakin-G support its efficacy in pain inhibition (Craig et al, 1999). It is being investigated as a potential therapy for postsurgical pain (McIntosh et al, 2000).

Livett et al reported preliminary results of another conotoxin, ACV1, on chronic pain at the Venoms to Drugs 2002 conference (Holmes, 2002; Major, 2002, University of Melbourne Web site). ACV1 appeared to inhibit pain and also accelerate the recovery of injured nerves, which may also facilitate recovery from chronic pain. Experiments using ACV1 in a standard rat model for chronic pain suggested that ACV1 suppresses the transmission of pain sensations through the nervous system by blocking nicotinic acetylcholine receptors that are involved in pain transmission (Holmes, 2002; Livett et al, 2004). ACV1 is a much smaller molecule compared with the ω-conotoxins, and, unlike ziconotide, which must be injected into the spinal column, ACV1 can be injected into the muscle or fat layer. (Livett et al, 2004; Major, 2002, University of Melbourne Web site)

Plant-derived neurotoxins and pain

The neurotoxin capsaicin, the active ingredient in hot chili peppers, has been studied extensively in vivo and in vitro as a modulator of the nociceptive function in primary sensory neurons. Capsaicin-sensitive neurons are peptidergic sensory neurons with unmyelinated C fibers. These neurons participate in the transmission of nociceptive information to the central nervous system, while their peripheral terminals release a number of proinflammatory mediators (Szallasi and Blumberg, 1996; Szabo et al, 1999; Szallasi and Blumberg, 1990). Resiniferatoxin, which is a potent capsaicin analogue, is a neurotoxin derived from the Euphorbia resinifera plant (Szallasi and Blumberg, 1996; Szallasi and Blumberg, 1990; Szolcsanyi et al, 1991). Although resiniferatoxin has been studied mostly in relation to its therapeutic potential in urology, it produces long-lasting desensitization of nociception by way of its effects on C-fiber sensory neurons and therefore has potential analgesic properties in other tissues (Szabo et al, 1999; Szallasi and Blumberg, 1990; Szolcsanyi et al, 1991). After an initial activation of the VR1 receptor, capsaicin and related compounds desensitize VR1 to subsequent stimuli (Szabo et al, 1999). This desensitization and a refractory state of primary dorsal root ganglion after exposure to the vanilloid provide an opportunity to induce an analgesic response to subsequent pain stimuli (Szabo et al, 1999).

In an animal model Szabo et al evaluated the analgesic effect of resiniferatoxin administered epidurally or systemically on the response to a thermal stimulus in rats (Szabo et al, 1999). Compared with vehicle, resiniferatoxin by both routes of administration produced profound thermal analgesia; however, by the epidural route the analgesic effects were selective for the spinal cord region, while subcutaneous administration produced generalized analgesia. Epidural treatment was 25 times more effective than subcutaneous treatment with respect to back paw withdrawal latency but no different from the subcutaneous route with respect to the front paw response. This finding is consistent with the regional selectivity of the lumbar epidural route, which induces a potent segmental desensitization to C-fiber–mediated pain in the rat (Szabo et al, 1999). Moreover, resiniferatoxin was also shown to suppress substance P synthesis, which is likely to contribute to its analgesic properties (Szallasi et al, 1999).

C-fiber sensory afferent neurons mediate the responses to a variety of pain stimuli, including chemogenic pain and thermal (cutaneous) and neurogenic inflammation. Accordingly, this provides a theoretical basis for the therapeutic effectiveness of resiniferatoxin and clinical application in a number of human pain disorders (Biro et al, 1997).

Other non-botulin um neurotoxins in pain reduction

A wide variety of neurotoxins from plant and animal origins (poisons and venoms) are under investigation for potential application in the treatment of pain and other neurological conditions. In addition to cone snails, venoms from tarantula spiders, poison-dart frogs, and predatory marine snails are being studied by the biopharmaceutical industry.

The development of new and more effective agents to reduce pain is a high priority because of the deleterious impact of chronic pain on physical well-being and quality of life. Because of advances in recent years in our understanding of the mechanisms underlying a variety of different painful conditions, specific therapies targeted to the underlying pathophysiology and with fewer side effects will be possible.

Neurotoxin-based therapies are in development for the following 3 types of pain (Hall, 2003):

Conus venoms are a potential source for neuropathic pain therapies, one of the most difficult types of pain to treat. The venom from the Chilean pink tarantula, currently only a research tool, may provide a useful model for the synthesis of more stable derivatives (Hall, 2003). A derivative of the neurotoxin produced by dart frogs may be a therapeutic product as effective as morphine in reducing pain but without the side effects (Hall, 2003). The Epipedobates tricolor, a type of poison frog, secretes epibatidine, a neurotoxin with anesthetic properties; moreover, a less toxic analogue of epibatidine, called ABT-594, holds promise for pain therapy (Fisher et al, 1994; Traynor, 1998). Epibatidine does not exert its analgesic effect through opioid receptors, as demonstrated by the lack of an inhibitory effect of naloxone, an opioid antagonist (Traynor, 1998). Epibatidine (and its analogues) interact with nicotinic acetylcholine receptors, a type of ligand-gated ion channel whose endogenous ligand is acetylcholine (Traynor, 1998; Barrantes, 2004; Gerzanich et al, 1995). Furthermore, the analgesic effects of epibatidine are blocked by mecamylamine, a noncompetitive nicotinic antagonist (Badio and Daly, 1994; Traynor, 1998). One of the challenges in the development of a therapeutic product from epibatidine is that although it is a potent analgesic, it is highly toxic at doses only slightly higher than the effective therapeutic dose (Traynor, 1998). This challenge also applies to a number of other neurotoxins.

The application of the array of venom-derived neurotoxins to controlling pain is based on the same actions on nerves that make them effective for defending against and/or preying upon other animals.

References and Further Reading

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Atanassoff PG, Hartmannsgruber MW, Thrasher J, et al. Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. Reg Anesth Pain Med. 2000;25:274-278.

Badio B, Daly JW. Epibatidine, a potent analgetic and nicotinic agonist. Mol Pharmacol.1994;45:563-569.

Barrantes FJ. Structural basis for lipid modulation of nicotinic acetylcholine receptor function. Brain Res Brain Res Rev. 2004;47(1-3):71-95.

Biro T, Acs G, Acs P, Modarres S, Blumberg PM. Recent advances in understanding of vanilloid receptors: a therapeutic target for treatment of pain and inflammation in skin. J Investig Dermatol Symp Proc. 1997;2:56-60.

Borg-Stein J. Cervical myofascial pain and headache. Curr Pain Headache Rep. 2002;6:324-330.

Bowersox SS, Luther R. Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus. Toxicon. 1998;36:1651-1658.

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Cheshire WP, Abashian SW, Mann JD. Botulinum toxin in the treatment of myofascial pain syndrome. Pain. 1994;59:65-69.

Craig AG, Norberg T, Griffin D, et al. Contulakin-G, an O-glycosylated invertebrate neurotensin. J Biol Chem . 1999;274:13752-13759.

Cui M, Li Z, You S, Khanijou S, Aoki KR. Mechanisms of the antinociceptive effect of subcutaneous Botox ®: inhibition of peripheral and central nociceptive processing. In: Abstracts of the International Conference 2002: Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins. Naunyn Schmiedebergs Arch Pharmacol. 2002;365(suppl 2):R17.

De Andrés J, Cerda-Olmedo G, Valía JC, Monsalve V, Lopez-Alarcón MD, Minguez A. Use of botulinum toxin in the treatment of chronic myofascial pain. Clin J Pain. 2003;19:269-275.

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Hourigan CL, Bassett JM. Facet syndrome: clinical signs, symptoms, diagnosis, and treatment. J Manipulative Physiol Ther. 1989;12:293-297.

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MUSCLE PAIN

Neurotoxins in the Treatment of Muscle Pain

Introduction

Part I. Botulinum neurotoxins for pain management

Mechanism of action of BoNT in pain reduction

Clinical applications of BoNT in managing pain

Spasticity

Back pain

Neck pain

Myofascial pain syndrome

Temporomandibular and other facial pain disorders

Hemifacial spasm

Summary and conclusions

Part II. Non-botulinum neurotoxins in pain reduction

Introduction

Cone snail neurotoxins

Plant-derived neurotoxins and pain

Other non-botulin um neurotoxins in pain reduction

References and Further Reading