(1)
Botulinum Toxin Treatment Program, Yale School of Medicine, New Haven, CT, USA
Abstract
Neuropathic pain (NP) is a common form of human pain, often poorly responsive to analgesic medications. This chapter discusses the pathophysiology and conventional treatment of common categories of neuropathic pain and reviews the literature on botulinum neurotoxin (BoNT) efficacy in neuropathic pain. The level of efficacy for BoNT treatment in each category is defined according to the published guidelines of the American Academy of Neurology. The data on type A toxin (mostly onabotulinumtoxinA, onaA) indicates efficacy in postherpetic neuralgia and probable efficacy in post-traumatic neuralgia, and painful diabetic neuropathy. Retrospective studies and anecdotal observations suggest efficacy in residual limb pain of amputees, complex regional pain syndrome, and chemotherapy-induced allodynia. Controlled studies are necessary to assess the efficacy of BoNTs in these conditions. Much remains to be learned about the most effective dosage and technique of injection, optimum dilutions, and differences among BoNTs in the treatment of neuropathic pain.
Electronic supplementary material
The online version of this chapter (10.1007/978-1-4939-2501-8_3) contains supplementary material, which is available to authorized users.
Keywords
Botulinum toxinBotulinum neurotoxinNeuropathic painPainAllodyniaPostherpetic neuralgiaPost-traumatic neuralgiaDiabetic neuropathyComplex regional pain syndromePhantom painResidual painIntroduction
Neuropathic pain (NP) is defined as a pain caused by lesion or disease of the somatosensory system (Treede 2012). The site of disturbance or damage can be peripheral (peripheral nerve, plexus, or root) or central (spinal cord, brain stem, or thalamus). Typically, the pain has a burning, jabbing, and searing quality. Skin areas of allodynia (touch perceived as pain), hyperalgesia (enhanced pain after exposure to painful stimuli), and hyperesthesia or dysesthesia (enhanced or altered sensations to touch) are common.
The pathophysiology of neuropathic pain is yet to be fully elucidated; the peripheral neuropathic pain (PNP) is currently believed to result from damage to peripheral nervous system with irritation of nerve endings and accumulation of nociceptive transmitters and modulators (substance P, glutamate, bradykinin, calcitonin gene- related peptide, and others). Accumulation of these agents produces local inflammation. Together, these two phenomena lower the sensory threshold of peripheral nerve endings to nociceptive stimuli (peripheral sensitization). Peripheral sensitization increases the number of nociceptive volleys into the spinal cord and leads to sensitization of sensory spinal cord neurons (central sensitization). The interplay between peripheral and central sensitization contributes to pain chronicity (Aoki and Francis 2011).
A number of mechanisms are now considered contributors to neuropathic pain (Table 3.1). Modifying these mechanisms is the basis of treatment strategies for NP treatment.
Table 3.1
Pathophysiological mechanisms of neuropathic pain
Level of the nervous system | Pathophysiological mechanisms |
|---|---|
PNS | |
Peripheral nerve | Release of pain-related mediators (BK, PG, TNFα, ILs, His, ATP, and potassium ions) |
Upregulation of TRP proteins in uninjured C fibers | |
Dysregulation of the synthesis or the functioning of voltage-gated sodium channels | |
Dysregulation of the synthesis or the functioning of potassium channels | |
Dorsal root ganglion | Increased activity in dorsal root ganglions |
Dorsal root ganglion infiltration by activated macrophages | |
Increased synthesis of proinflammatory cytokines in dorsal root ganglions | |
CNS | |
Spinal cord neurons | Functional reorganization (neuroplasticity) of dorsal horn nociceptive |
Neurons | |
Increased release of glutamate and substance P | |
Increased expression of Nav1.3 in dorsal horn second-order neurons | |
Increased activity in voltage-gated calcium channels | |
Selective apoptotic loss of GABA-releasing interneurons | |
Reduction of KCC2 in lamina I neuron | |
Intracellular changes induced by the activation of NMDA receptors or other receptors (i.e., glutamate metabotropic receptors) by excitatory amino acids released by primary afferents | |
Microglial activation | |
Brain stem (descending pain-controlling systems) | |
Loss of function in descending inhibitory opioidergic, serotonergic, and noradrenergic pathways | |
Changes in the modulatory control of nociceptive pathways | |
Brain | Functional reorganization (neuroplasticity) of thalamic and cortical (prefrontal and somatosensory) nociceptive neurons |
OnabotulinumtoxinA (onaA) has shown the potential to influence neuropathic pain in animals through a number of mechanisms: blocking the release of pain mediators from peripheral terminals and from dorsal root ganglia (Meng et al. 2007; Lucioni et al. 2008), decreasing local inflammation around nerve terminals (Cui et al. 2004), inhibiting sodium channels in peripheral and centred nervous system (Shin et al. 2012) discharge of muscle spindles (Filippi et al. 1993), and decreasing sympathetic transmission (Rand and Whaler 1965). The muscle spindle discharge can enhance central sensitization; increased sympathetic activity can maintain pain. The details of BoNTs’ effects (particularly onaA) on experimental pain of animals and healthy human subjects are presented in Chap. 2.
Five examples of peripheral neuropathic pain (PNP) for which prospective and controlled data are available on BoNT efficacy are presented in this chapter. These include postherpetic neuralgia, post-traumatic neuralgia, painful diabetic neuropathy, complex regional pain syndrome, residual limb pain, and phantom pain. Case reports and videotapes are provided from the author’s experience.
In this chapter and throughout the book, the level of efficacy for BoNTs is defined according to the guidelines of the therapeutics and assessment subcommittee of the American Academy of Neurology (AAN). These guidelines require two class I studies for level A evidence (effective or not effective). For level B evidence (probably effective/ineffective), one class I or two class II studies are required. Presence of only one class II study denotes level C (possibly effective/ineffective) evidence. Level U means efficacy is undetermined. Appendices 3.1 and 3.2 provide a summary of the AAN guidelines with descriptions of the study class and level of evidence (French and Gronseth 2008; Gronseth and French 2008). The Yale Medical Library’s search system was used for literature search which encompasses a number of search programs including PubMed and Ovid.
Among the seven BoNT serotypes (A, B, C, D, E, F, and G), only types A and B have clinical utility. Three type A toxins (onabotulinumtoxinA, onaA; incobotulinumtoxinA, incoA; abobotulinumtoxinA, aboA) and one type B toxin (rimabotulinumtoxinB, rimaB) are approved by the FDA for use in the USA (Fig. 3.1). Table 3.2 illustrates the generic and trade names of these toxins, their manufacturer’s name, and number of units/vial.
Fig. 3.1
FDA-approved botulinum neurotoxins (From Chen and Dashtipour 2013 © 2013 Wiley Publications, reprinted with permission from Wiley)
Table 3.2
FDA-approved botulinum neurotoxins
Name given by FDA | Trade name | Manufacturer | Vial (units) |
|---|---|---|---|
OnabotulinumtoxinA (onaA) | Botox | Allergan Inc. | 100, 200 |
IncobotulinumtoxinA (incoA) | Xeomin | Merz Pharm | 50, 100 |
AbobotulinumtoxinA (aboA) | Dysport | Ipsen Pharm | 300, 500 |
RimabotulinumtoxinB (rimaB) | Myobloc (US) | US WorldMeds | 2,500, 5,000, 10,000 |
Neurobloc (Europe) |
Technical Points
All toxins except incoA require refrigeration. With the exception of rimaA (which comes as an already prepared solution), all toxins need to be prepared with preservative-free saline. A dilution of 1–4 cc can be used in clinical practice. To prepare the solution, saline is drawn with a 20 or 21 gauge needle into a 2 or 4 cc syringe and then introduced into the vial. The vial is then gently shaken for a few seconds. In the case of incoA, it is recommended to invert the vial two to three times. The solution is then drawn with the same needle into a 1, 2, or 4 cc syringe. For injection, a 27.5 or 30 gauge needle is used. Depending on the depth of injection, the length of the needle may vary from 0.5 to 1.5 in.; for subcutaneous injection, a 0.5-in.-long needle suffices. Per manufacturer’s recommendations, the prepared toxin should be used within 4–6 h.
Botulinum neurotoxins (BoNTs) are now used widely in clinical medicine for a variety of indications such as treatment of dystonias, spasticity, and migraine. In pain medicine, only chronic migraine is an approved FDA indication. All other areas are currently considered off label, although for several of them, the literature strongly suggests efficacy. The four aforementioned neurotoxins are generally considered safe in the recommended doses. Rare and serious side effects, however, have been reported. It is hence prudent before administering any BoNT, to obtain a signed acknowledgement from the patient about having reviewed the list of potential side effects.
Postherpetic Neuralgia
Herpes zoster results from reactivation of varicella-zoster (VZ) virus usually in individuals who previously have had chicken pox and developed cell-mediated immunity after the infection. The reactivation takes place in cranial nerves or dorsal root ganglia with spread of the virus to sensory nerves and corresponding dermatome. Diabetic and immunocompromised patients are more prone to zoster infection.
The extent of pathology varies widely from patient to patient. There is often substantial reduction of epidermal nerve fibers (small unmyelinated fibers) and loss of subepidermal plexus. Reinnervation is slow and skin biopsy, even 10 years after the infection, shows incomplete innervation (Oaklander 2001). In one study, magnetic resonance imaging showed signal changes in the spinal cord and brain stem (56 %), and the cerebrospinal fluid demonstrated inflammatory cells in 61 % of the patients affected by acute zoster infection (Haanpaa et al. 1998). Varicella-zoster vaccination reduces development of PHN by 66.5 % between ages 60 and 80 (Oxman et al. 2005). Antiviral therapy reduces the risk of developing PHN (Wood et al. 1996). Concurrent steroid therapy does not reduce the risk of PHN but alleviates the initial acute pain (Whitley et al. 1996).
Pain associated with zoster infection may manifest before the rash (presymptomatic neuralgia), during the rash, or even later after the rash has cleared up. The typical PHN usually persists beyond 3 months after the zoster infection. The incidence of postherpetic neuralgia increases with age: 5 % for individuals younger than 60, 10 % between 60 and 69, and 20 % for age 80 or older (Yawn et al. 2007). Older age, severity of the initial acute pain (Thyregod et al. 2007), and presence of larger fiber neuropathy (A-beta fibers with loss of vibration) increase the risk of PHN (Baron et al. 1997).
Treatment
PHN is one of the most severe forms of human pain. Affected individuals cope with poor quality of life and are often disabled by severe bouts of pain (Oster et al. 2005). A variety of oral and topical medications are currently in use for treatment of PHN. Gabapentin and pregabalin, due to their safer side effect profiles, are often used as first drugs sometimes in combination with tricyclic agents. More severe forms of pain will require adding opioid agents, corticosteroids, or application of anesthetic patches. Cohen (2013) reviewed the subject of PHN and its treatment in a recent communication (Table 3.3). Most medications depicted in Table 3.3 are also used for treatment of other forms of neuropathic pain. Unfortunately, a large number of patients with PHN fail to respond to currently available medications.
Table 3.3
Medications commonly used for treatment of acute pain associated with herpes zoster
Medication | Dose | Dose adjustment | Maximum dose | Side effects |
|---|---|---|---|---|
Opioid and nonopioid analgesics | ||||
Oxycodone | 5 mg every 4 h as needed | Increase by 5 mg four times daily every 2 days as tolerated | None specified, but should not exceed 120 mg daily except in consultation with a pain specialist | Drowsiness, dizziness, constipation, nausea, vomiting |
Tramadol | 50 mg once or twice daily | Increase by 50–100 mg daily in divided doses every 2 days as tolerated | 400 mg daily; 300 mg daily if patient is >75 years of age | Drowsiness, dizziness, constipation, nausea, vomiting |
Glucocorticoids | ||||
Prednisone | 60 mg daily for 7 days, then decrease to 30 mg daily for 7 days, then decrease to 15 mg daily for 7 days | None | 60 mg daily | Gastrointestinal distress, nausea, vomiting, mood changes, edema, glucose intolerance, increased blood pressure |
Anticonvulsants | ||||
Gabapentin | 300 mg at bedtime or 100–300 mg three times daily | Increase by 100–300 mg three times daily every 2 days as tolerated | 3,600 mg daily | Drowsiness, dizziness, ataxia, peripheral edema |
Pregabalin | 75 mg at bedtime or 75 mg twice daily | Increase by 75 mg twice daily every 3 days as tolerated | 600 mg daily | Drowsiness, dizziness, ataxia, peripheral edema |
Tricyclic antidepressants | ||||
Nortriptyline | 25 mg at bedtime | Increase by 25 mg daily every 2–3 days as tolerated | 150 mg daily | Drowsiness, dry mouth, blurred vision, weight gain, urinary retention |
Topical therapy | ||||
Lidocaine patch (5 %) | One patch, applied to intact skin only, for up to 12 h per day | None | One patch for up to 12 h per day | Local irritation; if systemic, absorption can cause drowsiness, dizziness |
BoNT Studies in Postherpetic Neuralgia
Two double-blind studies have investigated the efficacy of botulinum toxin A in postherpetic neuralgia.
The first study by Xiao et al. (2010) assessed pain relief by visual analog scale (VAS) at 1, 7, and 90 days after subcutaneous injection of BoNT-A in 60 patients with PHN. Quality of life was measured by improvement in sleep hours. Patients were randomized and assigned blindly into three groups: BoNT-A, lidocaine, and placebo (20 in each group). The baseline level of pain and sleep disturbance was comparable between the three groups. The location of herpetic skin lesions was orofacial (n = 11), cervical and upper extremity (n = 14), thoracic (n = 18), and lumbar and lower limbs (n = 17).
A Chinese botulinum toxin A prepared by Lanzhou Institute was used for this study. The injecting solution was prepared by mixing 100 units of this toxin with 2 cc of preservative-free saline (5 units/cc). Injections were subcutaneous, grid-like, 1 cm apart, and into the region of tactile allodynia. Patients in the BoNT group had significantly better pain relief compared to the two groups on lidocaine and saline (P < 0.01). BoNT analgesic response began at days 3–5, peaked at 1 week, and continued for 3 months. The improvement of sleep from BoNT was also superior to the lidocaine and placebo groups (P < 0.05). Patients in the BoNT group also used significantly less opioids (22 % vs. 52 % and 66 %). Side effects consisted only of pain at the time of injection.
Apalla et al. (2013) conducted a prospective, double-blind, parallel study comparing the effect of BoNT-A (onaA) with placebo in 30 adult subjects with PHN. In the BoNT-A group, the toxin was diluted with 4 cc of normal saline and injected subcutaneously via a 30 gauge needle in a “chessboard manner.” The dose per injection site was 5 units. A total of 100 units was used. The severity of pain was assessed by VAS (0–10) at baseline and then daily for the first 2 weeks, every 2 weeks until the 12th week, and every 4 weeks until the 24th week. The primary outcome was 50 % or more reduction in VAS score measured at week 4 compared to baseline. The secondary outcome was improvement of quality of sleep evaluated by a 5-point questionnaire (very bad to very good) recorded at the same time frames.
Maintenance of improved VAS scores beyond the first 4 weeks was also considered a secondary outcome. Significant VAS improvement was reported at 4 weeks and also over subsequent weeks (for the toxin group, P < 0.001). Patients in BoNT also demonstrated significant improvement in quality of sleep and reduction of sleep scores along the same timelines.
The controlled and blinded study of Ranoux et al. (2008) which demonstrated efficacy of onaA in neuropathic pain (rated class I by AAN subcommittee) also included four patients with PHN. The specifics of these four patients, however, were not provided. This study is discussed in detail in the section on post-traumatic neuralgia.
Case Report 3-1
A 62-year-old female was referred to the Yale Botulinum Toxin Treatment Clinic for evaluation of severe right retroauricular pain. Patient specified the onset of pain to 2 years ago. At the onset, the pain involved both inside and behind the right ear. A course of antibiotics was not helpful. Few weeks later, with the appearance of typical skin lesions, zoster infection was diagnosed and treated with acyclovir. The skin lesions gradually improved, but the right retroauricular pain continued and grew in intensity. Some of the bouts of pain ended in severe headaches. The pain was described as jabbing and stabbing resulting in loss of sleep and marked apprehension in anticipation of the next bout. A variety of analgesic medications including gabapentin, pregabalin, and oxycodone were not helpful. The pain was often scored as 10 of 10 on visual analog scale and described as unbearable.
On examination, there was discoloration along with scars of zoster infection behind the right ear. A total of 60 units of onaA toxin was injected in a grid-like pattern behind the left ear subcutaneously at 20 points (3 units/point) using a 30 gauge needle (Video 3.1). The dilution was 100 units per 2 cc. Patient reported a sharp drop in pain frequency and intensity (VAS down from 10 to 3) 5 days after the injections. The pain then disappeared at week 2 postinjection and gradually reappeared at 2.5 months. Over the next 2 years, patient received similar treatments every 3 months. Each treatment resulted in significant reduction in pain. The last injection lasted 6 months with the returning pain reported as subtle (1 in VAS). Patient described no side effects. In an interview 2 years after treatment, the patient was very pleased with the outcome (Video 3.2).
Comment
The author has treated six patients with PHN with subcutaneous injections of onaA. The dose ranged from 60 to 200 units based on the extent of the involved skin. The treatment was very effective in five patients (i.e., case 1). In one patient with extensive zoster infection of the chest, two treatments of onaA with similar doses failed to alleviate the pain.
Based on the above two class I studies, BoNT-A treatment possesses level A efficacy (effective) for treatment of PHN. The role of other BoNTs needs to be investigated. Failure of some patients with PHN to respond to onaA may be related to extensive pathology possibly extending to CNS.
Post-traumatic Neuralgia
Pathophysiology
Peripheral trauma triggers a cascade of events which involve nociceptor receptor sites, peripheral nerve endings, dorsal root ganglia (DRG), spinal cord neurons, and central sensory neurons. Damaged nerve endings often accumulate pain mediators (glutamate, substance P), and new sprouts demonstrate increased density of sodium channels (Katz and Seltzer 2009) which increases peripheral nociceptive firing and generates ectopic discharges. New sprouts show increased sensitivity to cytokines, prostaglandin, and catecholamines. This peripheral sensitization increases the volume of nociceptive volleys which enter the dorsal root ganglia and spinal cord.
Histologic changes which develop after peripheral trauma in DRG and spinal cord indicate increased neural excitation. In DRG, there is overgrowth of sympathetic nerves and abnormal linkage of A and C fibers (McLachlan et al. 1993). In the spinal cord, dark cells appear in dorsal horns which presumably represent dying inhibitory neurons of glycinergic and GABAergic types (Garrison et al. 1991; Todd and Sullivan 1990). Demise of inhibitory neurons leads to enhanced excitation of central neurons. It has also been shown that after peripheral injury, many large alpha/beta afferents (usually ending in Rexed area III) grow and penetrate more superficial levels (Rexed laminae II and I of dorsal horn) and gain access to low-threshold pain afferents (Yaksh and Caplan 1997).
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