FW: Myofascial Pain: Use of Botulinum Toxin

[Guest guest]

The Use of Botulinum Toxins in the Management of Myofascial Pain and other

Conditions Associated with Painful Muscle Spasm

Mike A. Royal, M.D.

Objectives

* Discuss the pharmacology and potential side effects of botulinum toxin.

* Discuss traditional approaches to the treatment of myofascial pain

syndrome.

* Discuss the potential applicability of botulinum toxin in the treatment

of refractory cases of myofascial pain (including a review of currently

available literature ).

* Discuss injection techniques and dosing of botulinum toxin for

myofascial

pain.

Introduction

     Botulinum toxins (BTs) are potent neurotoxins produced by Clostridium

botulinum that are able to block acetylcholine release at the neuromuscular

junction producing a flaccid paralysis. The resulting temporary

chemodenervation (lasting several months) occurs with minimal risk of

systemic adverse effects. BTs can provide symptomatic improvement in a

variety of conditions associated with muscle spasm or hypertonicity1,

including focal dystonia2, cervical dystonia (torticollis)3, spasmodic

dysphonia4, oromandibular drstonia (Meige's syndrome)5, temporomandibular

disorder6, tension-type7 and migraine8 headache and refractory myofascial

pain syndrome9. Although the cosmetic use (reducing facial wrinkles10) is

perhaps the best known application for BTs, there has been tremendous

interest and clinical study into their potential for therapeutic efficacy in

chronic pain syndromes, 11,12,13,14,15,16 though the mechanism of analgesia

in such conditions is probably not entirely due to a reduction in focal

muscle spasm. This chapter will summarize the clinical studies evaluating

botulinum toxins as potential therapeutic agent in refractory cases of

myofascial pain or other conditions associated with painful muscle spasm.

      The recent addition of the Elan Pharmaceutical product, Myobloc™

(BTB)

also raises the important issue of choice. Although the net effect of each

BT

is to block acetylcholine release, one cannot take data derived from

clinical

studies of BTA and apply it to BTB by making some adjustment for potency

differences. Each BT has a different structure, different mechanism of

action

(although the net effect may be the same), different formulation, different

storage and handling guidelines, different FDA-approved uses, different

dosing concerns, and possibly different antibody development concerns.

BTAhas

been around much longer and all of the published pain and headache clinical

research used BTA

Myofascial Pain Syndrome

     Myofascial pain syndromel7 (MPS) is a regional pain syndrome defined

by

the presence of a localized, hyperirritable trigger point, a palpable knot

or

mass (usually 3- 6mm in diameter), in a taut band of muscle associated with

tenderness and referred pain into well-defined areas remote from the trigger

point area. 18,19 Myofascial pain syndrome (MPS) is characterized by

chronic,

focal muscle pain, associated with stiffness, tenderness and fatigue.20 A

myofascial trigger point has been defined as a well-localized, highly

irritable taut band of skeletal muscle fibers that responds with a twitch

response and referred pain distribution pattern to palpation.21 Unlike

active

trigger points, a latent trigger point is clinically silent until activated,

typically by trauma, but may cause pain on palpation. Laboratory testing,

radiographic studies or other standard tests are not helpful in making a

diagnosis of MPS.22 Diagnostic ultrasound has not been found to be useful.23

Testing appears only to be useful for excluding other diagnoses.

     Just as one should not lump fibromyalgia (FM) and MPS into the same

diagnostic basket, myofascial trigger points should be distinguished from

fibromyalgia tender points that are in characteristic locations and may be

clinically silent unless stimulated by palpation.24 By the American College

of Rheumatology 1990 Criteria25, FM is a more widespread pain condition

(three or more body regions above and below the waist) lasting for 3 or

months associated with pain in at least 11 or 18 tender point sites on

digital palpation with a force of approximately 4 kg. Tender points are not

associated with a " twitch " on palpation and are usually clinically silent

unless stimulated by palpation. Tender points typically do not cause a

referred pain pattern on palpation.26 Patients with FM tend to have more

constitutional symptoms than those with MPS.

     Without a well-understood pathophysiological etiology and the lack of

specific diagnostic tests and the paucity of objective physical signs, the

diagnosis of MPS has become suspect for some and overly diagnosed for

others.28 The pathogenesis of trigger points is unknown but several

hypotheses exist.29 The energy crisis model proposes that direct injury or

repetitive overloading of muscle results in sustained release of

intracellular calcium and focal muscle hypercontraction, possibly due to

disruption of the sarcoplasmic reticulum.30 The localized spasm induces

release of nociceptive and inflammatory mediators that produces a positive

feedback process leading to focal ischemia (depletion of ATP), lactic

acidosis and eventual fibrosis. However, pathological and histological

analyses do not support this theory .31

     The dysfunctional muscle spindle and the irritable motor endplate

models

grew out of different interpretations of electromyographic (EMG) evaluations

of trigger points. Durette et al studied 21 patients with MPS and found no

evidence of spontaneous fibrillation or positive sharp wave potentials.32 In

contrast, Hubbard and Berkoff examined EMGs in the upper portion of the

trapezius muscle in individuals with fibromyalgia or tension-type

headaches.33 Trigger points were identified with digital palpation of the

taut muscular band and characteristic pain referral pattern. A monopolar EMG

needle was inserted directly over the trigger point and advanced

incrementally until the patient described his typical pain and referral

pattern. One mm adjustments in the needle were enough to make the

pain/referral disappear. A second control needle was placed 1 cm away.

Sustained spontaneous EMG activity was found at the trigger point, but not

at

the control point. This low level electrical activity was not blocked by

tubocurarine (blocking cholinergic motor activity) but was by sympatholytics

such as phentolamine (blocking muscle spindle afferents). Latent trigger

points showed similar findings, but to a lesser degree. No fibrillation

potentials or positive sharp wave potentials were noted in trigger points or

control points. The authors hypothesized that the EMG activity was generated

from sympathetically stimulated intrafusal muscle fibers. Simons et al. used

a similar technique and found active loci of spontaneous EMG activity much

like that seen in the end plate region.34 He postulated that the electrical

activity was due to abnormally increased motor endplate activity with

excessive release of acetylcholine at the neuromuscular junction resulting

in

extrafusal muscle contraction in the immediate vicinity of the extrafusal

motor endplates.

     The peripheral sensitization model proposes that peripheral silent

afferents become activated after injury by the release of peripheral

nociceptive mediators.35 Whereas the central sensitization model proposes

that the repetitive incoming nociceptive traffic induces neuroplastic

changes

in the dorsal horn (NMDA-mediated process).36 It is likely that many of

these

proposed processes are occurring simultaneously.

     Overall treatment goals are directed toward interrupting the

pain/spasm

cycle, treating underlying conditions if MPS is a secondary process, and

working on maladaptive behaviors by using cognitive-behavioral approaches37.

Travell and Simons popularized the spray and stretch technique as the

mainstay of treatment for MPS.38 The purpose is to desensitize the trigger

point and stretch and relax the taut band of muscle. Ice may be used instead

of vapocoolant sprays. Authors disagree on how effective the treatment is

compared with trigger point injections, but it certainly makes sense to use

this noninvasive technique as an adjunct to other therapies especially where

the patient and family can be trained in the technique and the patient is

cooperative and willing to do the post treatment exercises.

     Along with spray and stretch techniques, physical therapy39 (PT) and

PT

modalities are probably the most commonly used approaches in early MPS.

Therapeutic heat and cold therapy40, transcutaneous nerve stimulation,

electrical muscle stimulation, ultrasound, iontophoresis, myofascial

release,

massage, hydrotherapy, stretching and strengthening exercises (passive and

active) and acupuncture I can be very helpful.

     Borg-Stein and Stein reviewed the medical literature of trigger point

injections and concluded that although such injections have widespread

clinical acceptance, evaluating their efficacy is hindered by difficulties

in

definitions as well as variations in technique.42 Gerwin et al. noted that

although interrater reliability in identifying trigger points is somewhat

suspect, it improves significantly with a few hours of training.43

Obviously,

training in injection technique is important as well in ensuring that

whatever is injected is delivered to the trigger point region.

     Short-terrn efficacy has been demonstrated with dry needling,44

sterile

water,45 lidocaine (plain 1 and 2%),46 bupivacaine,47 diclofenac,48 and

prednisone. It appears that the nature of the injected substance is not a

critical factor and it is unclear whether any therapeutic substance injected

provides more benefit than dry needling alone.49 The needle is presumed to

cause a mechanical disruption of the trigger point zone and stretch of

adjacent muscle fibers. Local anesthetics when injected do reduce post

injection soreness and for that reason are most commonly used. All local

anesthetics have the potential for myotoxicity with lidocaine 0.5-1.0%

having

less potential for this than bupivacaine 0.25-0.5%, but the problem rarely

occurs absent excessive use of this modality .Epinephrine may prolong the

block from the local anesthetic, but is not necessary for trigger point

release. Most authors feel that steroids are not needed unless there is an

associated inflammatory process such as bursitis, tendonitis, or scar

neuroma. Trigger point injections should be part of a comprehensive

treatment

program and not a sole treatment inititative.

     Pharmacotherapy for MPS has included skeletal muscle relaxants

(although

many of these produce unwanted sedation and side effects), antispastic

agents

(such as baclofen and tizanidine), antidepressants (especially tricyclic

antidepressants), anticonvulsants (especially those producing reduction in

muscle spasm such as the benzodiazepines clonazepam and diazepam and

gabapentin), and traditional analgesics.50 None of these agents are

particular effective, but may be useful as adjuncts to other treatments.

Unfortunately, much of the published literature discussing pharmacotherapy

optioins lumped MPS and FM together and does not speak specifically to the

response of MPS.

Botulinum Toxins in Myofascial Pain and Conditions with Muscle Spasm:

Clinical Developments

     When conservative therapies fail to improve refractory myofascial

pain,

BTs may be quite helpful in reducing the spasm to a point where conservative

measures can be reinstituted with greater effect to resolve the process.

There seems little doubt that BT injections can produce a much longer

duration response than local anesthetic or steroid + local anesthetic

trigger

point injections. However, it was only relatively recently that this fact

was

firmly established.

     Lalli et al. looked at lidocaine vs. BTA in the treatment of

myofascial

pain in a double-blind randomized trial of 20 patients (15 female) who

received 50 units of BTA (Botox®) or 1% lidocaine.51 Botulinum toxin-treated

patients showed statistically significant improvement at 2 and 4 weeks as

measured by visual analog scales and palpable muscle spasm. No major side

effects were seen.

     Porta et al. looked at lidocaine/methylprednisolone versus BTA

(Botox®)

in 40 patients with MPS in the psoas, piriformis, and scalenus anterior

muscle in a single-blind, randomized trial.52 Patients receive BT (80-150

units) or similar volume of steroid/local anesthetic as a compartment

injection into the affected muscle. The reduction in pain scores was better

in the BT-treated group at 30 days (p=0.0598) but did not reach significance

until 60 days (p0=.0001). No major side effects were observed.

     Patel et al. presented their preliminary results from a randomized

double-blind, placebo controlled study comparing trigger point injections

with saline, bupivacaine or BTA (Botox®).53 Twelve patients had completed

the

study at the time of the poster presentation. The preliminary data with this

small number of patients showed a trend toward significance for the BTA

group.

     It was in 1994 that initial clinical reports hinted at the potential

of

BT in improving myofascial pain. As seems to be the case in other new areas

for use of a product, initial reports were either anecdotal case reports or

flawed by small numbers of patient participants.

     Acquadro and Borodic reported on the use of BTA (Botox®) in 2 female

patients with refractory trapezius and splenius capitis myofascial pain.54

The first injection of 50 units provided the patients with slight

improvement

and the second of 150 units 4 weeks later provided what was reported as

dramatic improvement

     Cheshire et al. described responses to BTA (Botox®) trigger point

injections in six patients with chronic myofascial pain in a randomized

double-blind, placebo controlled study.55 Cervical paraspinal or shoulder

girdle trigger points were injected with either saline or 50 units of BTA

reconstituted in 4 ml of preservative-free saline injected equally into two

or three sites. Responses were measured over 8 weeks by verbal pain

descriptors, visual analog scales, pressure algometer and palpable muscle

spasm or firmness. Four of six subjects experienced reduction in pain and

spasm following BT, but not saline, injections. Onset of responses occurred

within the first week following BT injections with a mean duration of 5-6

weeks.

     In 1997, Alo and colleagues reported on their prospective but

uncontrolled study of 52 patients (29-83 years old) with refractory MPS

(cervicothoracic 33, low back/gluteal 19) who received

fluoroscopically-directed injections of BTA (Botox®) 10u/cc in

preservative-free saline (10-300 units BTA were used in the cervicothoracic

MPS patients and 90-300 units BTA were used in the low back/gluteal MPS

patients).56 Up to 3 treatments were given 4 weeks apart if persistent spasm

and pain were noted.57 Greater than 50% reduction in spasm and symptoms were

achieved in 63% of the cervicothoracic and 43% of the lumbar/gluteal

patients. A very mild, short-lived flu-like syndrome was seen in 62% of

patients with the first injection and not observed subsequently to this

extent and only one patient suffered transient dysphagia. The rather high

incidence of flu-Iike syndrome has not been reported by other authors and

may

have been due to the use of contrast for targeting the injections under

fluoroscopy.

     Grana reported on 5 patients with cervical MPS who received BTA

(Botox®)

50 units in 4cc preservative-free normal saline in divided doses into the

upper and middle trapezius, scalene, levator scapulae and

sternocleidomastoid

muscles after achieving less than a week of relief with standard trigger

point injections with local anesthetics.58 All 5 patients reported improved

VAS pain scores 2 weeks post BTA and 4/5 still had VAS reductions at 3

months.

     In the first large controlled study of BTA in muscular pain, Knusel et

al. presented data on the use of BTA (Botox®) in chronic low back muscular

pain (without prior surgery or other identifiable spine pathology) in 70

patients randomized into four groups (placebo, 120, 180 or 240 units of

BTA).59 Patients in all groups improved in all outcome measures. The BTA 240

unit group showed statistical significance over placebo at weeks 6, 9 and 12

for muscle spasm and weeks 6 and 12 for physician global assessment. No

adverse events of significance were noted.

     These data and subsequent unpublished data derived from other studies

conducted by Allergan on low back pain point to the difficulty of assessing

a

new modality of treatment in a rather amorphous condition. Low back pain is

a

rather broad diagnostic category that makes it difficult to be sure that any

patient group is relatively homogenous. Additionally, recruiting patients

who

have not had surgery , have no spine pathology , have no pending litigation,

disability or workers' compensation claims and have had no significant

interventions whatsoever will recruit a group of patients that pain

physicians see infrequently and such patients are likely to respond to even

simple modalities, such as trigger point injections, creating the potential

for high placebo response rates. Perhaps if different inclusion/exclusion

criteria and a higher total dose were used similar to that used by Jabarri

et

al. (see below), better results might have been seen.

     Porta et al. performed a preliminary trial of BTA (Botox®) and

physical

therapy on 38 patients (24 women, 14 men; age range 18-73 years; 3 with

fibromyalgia) with piriformis (27), iliopsoas (9) and scalenus (2)

myofascial

pain.60 Injections into the piriformis and iliopsoas were performed with CT

-guidance while other injections were done by palpation alone. Efficacy and

safety were evaluated at 1 month. Seventeen patients (45%) reported pain

relief and 6 (16%) reported improvement. Eight of the 15 who had no impr

ovement admitted to failing to comply with the therapy requirements showing

that BT treatments do not work in a vacuum but must be part of a treatment

continuum.

     Wheeler et al. reported the lack of efficacy of BTA (Botox®) over

placebo in when injected into trigger points in 33 patients with

cervicothoracic myofascial pain in a randomized, double-blind study.61

Participants were divided into 3 groups receiving 50 or 100 units of BTA

diluted in 2 ml of preservative- free normal saline or normal saline and

were

evaluated over a 4 month period in a standard fashion. The most tender

trigger point (if there were several) was chosen as the injection site.

Participants were followed regularly and algometer measurements of the

trigger point injected as well as subjective assessment of improvement,

visual analog scale measurements, and physical examinations were performed.

A

second injection of 100 units of BT in 2 ml of normal saline was given to 11

patients in the same site and to 2 patients in an adjacent symptomatic site.

     Although by their strict criteria for improvement (absence of pain

simultaneously on three different measures -Neck Pain and Disability Scale,

pressure algometer, and patient's global assessment), similar clinical

improvement rates across the 3 groups were seen, there were notable

differences among the groups in response to the second injection. The number

of patients determined to be asymptomatic was higher in the BT groups. The

authors noted that further investigation with higher doses and sequential

injections might have reached clinical significance. Certainly the use of 50

units while reasonable for a single injection site, is not sufficient if

several muscles are involved. Additionally, the the study design of

injecting

only the most tender trigger point even if several active trigger points

were

identified seems to run counter to typical approaches to myofascial pain

treatment of trying to " deactivate " all of the active trigger points in

order

to give the patient better relief.

     Royal et al. presented their retrospective data on 81 patients (age

range 21 to 84 years old) with cervical (73 injections), thoracic (17

injections), lumbar and/or gluteal (20 injections) and extremity (4

injections) MPS who had previously failed traditional conservative measures

and had only short-term improvement with standard trigger point

injections.62

The 81 patients received 109 BTA (Botox®) injections (average of 131 units

per session) over an approximately 18-month period. Six patients were

excluded from analysis due to insufficient follow up information.

Sixty-three

patients (84 injections; 21 male, 42 female) experienced a fair to excellent

response. Areas of MPS involvement were: cervical- 73, thoracic-17,

lumbar/gluteal-20, and extremity-4. BTA dosing ranges for specific muscle

groups were as follows: Trapezius: 20-100 units; Levator scapulae: 15-40

units; Splenius capitis: 20-50 units; Sternocleidomastoid: 25-100 units;

Quadratus lumborum: 20-60 units; Piriformis: 30-100 units; Rhomboid: 20-120

units; Thoracic and lumbar paraspinals: 20-40 per segment.

     The BTA injections were performed as standard trigger point injections

with the Botox® reconstituted in local anesthetic, typically bupivacaine

0.5%, in a, final concentration of 10 units per cc. Each trigger point

received 2-4 cc of total volume infiltrated in a standard fashion under

direct digital palpation using a 25 Ga 1.5 inch needle with 1-2 cc directly

into the trigger point and additional amounts in the surrounding taut band

of

muscle. Patients received 100 to 300 units of BT A (the majority received

100

units for unilateral pain and 200 for bilateral) at any injection session

with the dosing amount determined by the number of involved muscles and

severity of spasm. Only patients with a good to excellent response were

offered repeat BTA injections when the first wore off. The complication rate

was exceedingly low. One patient had transient neck muscle weakness within

the first week that resolved completely after a few days. One patient

developed transient tension-type headache symptoms in the first few days of

the injection that was felt to be due to the injection itself.

     A positive response was defined as at least a 30% reduction in

symptoms

from baseline. An excellent response was defined as at least 70% reduction

from baseline. A good response was defined as 50-69% reduction and a fair

response as 30-49% reduction. No relief or minimal relief was defined as a

response less than 30% from baseline. The breakdown of responses are

reflected in Table 2. Ten percent of the patients injected were " cures " with

complete resolution of symptoms at one year follow up. The breakdown for

patient insurance coverage was workers compensation (34%), private insurance

(30.5%), medicare (19%) and personal injury (16.5%).

     Freund and Schwartz reported on the treatment of whiplash-associated

neck pain with botulinum toxin in a randomized, double-blind, placebo

controlled trial of 26 patients.63 Fourteen of the patients received 100

units of BTA (Botox®) in 1ml of saline while twelve received placebo (1ml of

saline). Five trigger points received 0.2ml each via a 30 GA needle. The

treatment group showed a trend toward improvement in range of motion and

reduction in pain at 2 weeks post injection. At 4 weeks post, the treatment

group was significantly improved (p<0.01).

     Bahman Jabarri and colleagues at the Department of Neurology,

Uniformed

Services University, Bethesda, MD have studied the use of 200 units of BTA

(Botox®), 40 units/site, versus saline placebo at five lumbar paravertebral

levels on 28 patients with chronic unilateral low back pain using a

randomized, double blind design.64 Visual analogue scores (VAS) and the

Oswestry's Low Back Pain Questionnaire (OLBPQ) were used to follow the

patients. At three weeks, 11 of 14 patients who received BTA (78%) showed

significant (>50%) pain relief versus 4 of 14 (28%) in the NS group

(p=0.021). At eight weeks, 9 of 14 in the BTA group (61%) and 2 of 14 (14%)

of NS group reported relief (P=0.018). Repeat OLBPQ at eight weeks showed

improvement in 10 of 14 (70%) in the BTA group versus 3 of 14 (21% ) in the

NS group (P=0.022). No patient experienced side effects.

     Lang published her data on 72 patients receiving 95 BTA (Botox®)

injections for MPS using a novel grid pattern into the mid belly of the

muscles.65 The median BTA dose was 200 units. Outcomes were good to

excellent

in 65%, fair in 24% and poor in 12%. There were 2 cases of transient

weakness

and 1 case of transient flu-like syndrome. Insurance type seemed not to be

predictive of outcome.

     Inhahl and Holm injected 36 patients (19-78 years) many of whom had

undergone surgery with BTA (Botox®) into painful or tender muscles

(iliopsoas, quadratus lumborum, multifidus, and piriformis) based upon

palpation.66 Injections were performed with CT (iliopsoas and piriformis) or

EMG-guidance (quadratus and multifidus ). Twenty percent of patients

reported

excellent pain reduction, 40% were good and 25% fair .

     Although the data on BT use in myofascial pain and conditions

associated

with painful muscular spasm can be challenged on the basis that most of the

studies were retrospective or uncontrolled, the sheer number of studies

showing positive results along with similar findings in the few controlled

prospective studies that have been done suggest that there is something of

value to consider.

Antinociceptive Mechanisms

     Brin proposed that the mechanism of action for BT in migraine is less

likely to be due to blocking muscle contraction and thus removing a migraine

trigger and more likely to be due to blocking release of pain-mediating

neurotransmitters or peptides or some other central effect. There is

considerable supporting data from the cervical dystonia and spasticity

literature for the position that BTs reduce pain from some mechanism other

than effects on alpha motor neurons even before the chemodenervation effects

occur. Jankovic and Schwartz noted that pain consistently improved, often

within hours after the BTA injection, well before any reduction in muscle

spasm could be detected in their large series of cervical dystonia

patients.67 Most clinicians treating cervical dystonia with BTA have

observed

that pain relief typically outweighs the degree of spasm reduction seen.68

Fillippi et al. demonstrated that gamma motor endings of isolated rat

masseter muscles could be blocked within 80 minutes by BT thereby reducing

the Ia afferent signal from the muscle spindles and muscle tone via a reflex

mechanism.69 Subsequent intrafusal and extrafusal atrophy from

chemodenervation prolongs the effect.70 Giladi also postulates thata central

reorganization takes place due to the prolonged reduced spindle feedback.71

      In the 1970s, Wiegand et al. demonstrated retograde axonal spread of

radiolabeled BT injected near the sciatic nerve within 48 hours.72 The

authors noted that they could not confirm whether the retrograde

radioactivity was unchanged toxin or breakdown products. Aoki confirmed the

findings of Wiegand et al. in a study in which rats were injected

unilaterally in the gastrocnemius muscle with radiolabeled BTA.73

Radioactivity remained at the injection site for at least 2 hours and

disappeared by 48 hours, having appeared in the sciatic nerve and spinal

cord. However, Aoki was able to show that the retrograde radioactive spread

was due to breakdown products and not intact toxin transport.

     Since co-localization of vasoactive intestinal peptide and

neuropeptide

Y with acetylcholine has been demonstrated in parasympathetic neurons,

inhibition of SNAP-25 or VAMP by BT could block neurotransmitter exocytosis

and reduce pain.74 In a study of rat dorsal root ganglia neurons and

isolated

rabbit iris spincter and dilatory muscles, BTA was shown to inhibit

neuropeptide release.75 Additionally, BTA can block the in vitro release of

substance P and acetylcholine but not norepinphrine from rabbit ocular

tissue.76 Aoki and Cui demonstrated that BTA (3.5 or 7.0 units/kg/paw)

blocked the neuropathic pain component (rat hind paw formalin model) in a

dose-dependent fashion.77 Rats were challenged with subcutaneous 5% formalin

in one hind paw at 5 days and in the opposite hind paw at 12 days post BTA.

BTA efficacy was slightly less at day 12 than 5. The animals showed no

obvious motor weakness or weight loss. These data provide interesting topics

for discussion, but answers must await further study.

Dosing Considerations

     Once the decision is made to consider BT for the treatment of MPS or

other muscle spasm conditions, the key questions are which patient will best

benefit from this therapy, what dose to administer (in what concentration

and

in what diluent) and how to do it. Unfortunately, the answers to many of

these questions are still uncertain. Until more studies are performed, only

general guidelines are available from the currently available literature.

     1. Whom to inject?

     As with any new therapy, especially one that is expensive, it makes

sense to use BTs only in more refractory cases until the treatment becomes

established and pharmacoeconomic data is supportive. In MPS, especially in

the cervical and thoracic region, the potential for significant reduction in

medication use and complete resolution of symptoms in a substantial portion

of refractory cases is a strong argument in support of BT use. Quality of

life and functional improvement can be measurably improved in many patients.

In the lower back, conditions that " look " more like spasticity or focal

dystonia, such as piriformis syndrome or unilateral back spasm, seem to

respond better than more diffuse amorphous conditions. Several researchers

are conducting additional studies on the use of BT in low back pain and we

should have better guidelines on patient selection soon.

     2. Where to inject?

     With MPS, most investigators have injected active trigger points

directly or used a grid pattern (Lang's method) around them to get more

diffuse spread through the involved muscle. Yue also has demonstrated that

scalene or psoas compartment injections under fluoroscopic guidance can be

used with success to target adjacent muscles.78 In the lower back, trigger

points in deeper paraspinals are not as easily felt and the limited studies

that have been published have either chased tenderness or spasm as their

guide for which muscles to inject.

     3. How much to inject?

     Cervical and VIIth nerve dystonia data has been used as a starting

point

for BTA dose calculations with adjustments depending upon the size of the

muscle and degree of spasm. Clinical experience with BTA would seem to

support this extrapolation to MPS/headache, but with BTB it will be

important

to be cautious at first and start at a maximum of 2,500 to 5,000 units and

move upward depending upon clinical response until data from current studies

provides dose-response information.79

     The total maximum dose per visit for BTA (Botox®) typically should

not

exceed 300-400 unit range (although many have gone as high as 600- 700

safely

for numerous involved muscles as in diffuse spasticity/dystonia) and

intervals between doses should be no more frequent than every 3 months.

Following these general guidelines will reduce adverse events (primarily

weakness) and antibody formation. Little data is available to help one

decide

on BTB dosing outside of cervical dystonia. It appears to be about 40-50

times less potent than BTA with very few patients having received doses at

or

above 20,000 units, though these doses appear to be well tolerated. In the

cervical dystonia data, BTB produced a duration of action between 12 and 16

weeks similar to that seen with BTA.

     Larger volumes of injectate and doses of neurotoxin may influence the

tendency for excess BT to diffuse to nontargeted sites (adjacent muscles or

remote sites). This becomes a concern especially with anterior neck

injections where EMG guidance and low volumes of injectate (BTA l00 units/cc

or BTB 5,000 units/cc) should be used. The technique of using multiple

injection sites (grid pattern) within the muscle appears to reduce unwanted

side effects as does using EMG guidance to target motor end plates thus

allowing one to use less toxin.

     4. What to use as diluent?

     Allergan recommends that only preservative-free saline (PFNS) be used

as

the diluent and once it is added to reconstitute Botox® it should be used

within 4 hours due to dual concerns of protein denaturation and infection

risk. Elan Pharmaceuticals also recommends that PFNS be used if one desires

a

more dilute concentration of Myoblocâ„¢ than 5,000 units/cc and, although the

toxin is stable for months at room temperature, if the vial is violated, the

toxin should be used within 4 hours due to infection concern. Since the pH

of

5.6 in the Myoblocâ„¢ preparation might cause local injection discomfort,

perhaps more than that seen with the more neutral pH of BTA, the author re

commends that preservative free lidocaine be used to dilute the BT to

provide a local anesthetic effect.

     The use of preservative-free local anesthetic as a diluent, though

outside of labeling from the manufacturers, does not denature the protein

(as

long as bicarbonate is not added to neutralize the acidic pH of the local

anesthetic) and certainly seems to help with local injection pain with the

BTB formulation.80In MPS, numerous studies have documented that local

anesthetics seem not to interfere with toxin efficacy, although studies

comparing local anesthetics versus PFNS have not been done. Additionally,

whether volume of diluent makes a difference in efficacy is not known,

although studies are in progress to answer this question.81

      5. Is targeting of injections needed?

      The use of fluoroscopic or EMG guidance to identify the muscle or

localize the motor endplate prior to injections appears to be a benefit in

some situations (particularly in the anterior neck and the deep paraspinal

muscles and possibly to reduce unwanted remote spread by targeting motor end

plates with lower toxin doses ), but other clinicians have not shown that

this technique is necessary when the muscles and trigger points are easily

palpable. Fluoroscopic or CT guidance with or without EMG can be very

helpful

for injections of the piriformis, multifidus or psoas muscles. EMG guidance

is typically used when targeting extremity muscles or neck muscles that

cannot reliably be identified with palpation.

Conclusion

     BTs appear to be a useful treatment in refractory MPS and other

conditions with muscle spasm. Presumably BTs work by breaking the spasm/pain

cycle giving the patient a " window of opportunity " for traditional

conservative measures to have a greater beneficial impact, but several

studies suggest that a direct antinociceptive effect distinct from any

reduction in muscle spasm may be at play. The major benefit of BTs compared

with standard therapies is duration of response. We do not advocate that BTs

be used as a first line treatment for MPS. However, in refractory cases

where

nothing else has worked, it may offer a chance for improvement or cure not

otherwise available. In the year 2001 we should have some very good data

from

studies presently being conducted to help us decide where to place BT in our

pain treatment continuum. For now, it remains an off-label, but increasingly

accepted, approach in patients with refractory myofascial or muscular pain,

who despite multidisciplinary approaches, continue to suffer .

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Table 1

Distinguishing Fibromyalgia from Myofascial Pain Syndrome

Characteristic Fibromyalgia syndrome Myofascial Pain Syndrome

Prevalence 4-6%of general medical patients 30-60%of pain clinic patients

Sex 10:1 female 1:1

Onset 50% idiopathic; 20% physical trauma; 20% viral; 10% emotional

Trauma or strain

Sleep disorder, fatigue Always Often

Pain Diffuse Localized

Pain referral (trigger point) ? Localized

Tenderness (tender point) Multiple spots at tendon insertion, in muscle

belly or over bone Few spots in muscle belly only

Palpable taut band with twitch response ? Present

Interrater reliability Good for palpation or algometry Good for tenderness

to palpation, poor for other features

Fatigue Common Uncommon

Irritable bowel symptoms Common Uncommon

Treatment Medications, exercise Local myofascial release

Local injections Uncertain Good results in case series

Outcome Usually chronic Usually self-limited

Table 2

103 injections in 76 patients # of injections % M:F (# patients)

Response duration (months)

Excellent 56 54.4 25:10 3.6

Good 16 15.5 12:4 2.5

Fair 12 11.7 5:7 2.4

No/minimal 19 18.4 6:7

Table 3

Recommended Dose Ranges for BTA (Botox®)

Frontalis: 6:10 Trapezius: 25-100 Iliopsoas: 50-100

Corrugator: 3-5 Levator scapulae: 25-50 Lumbar paraspinals: 50/segment

(300-400)

Procerus: 3-5 Latissimus dorsi: 50-100 Quadratus lumborum: 50-100

Obicularis (crows feet): 3-5 Teres major: 25-75 Piriformis 50-100

Temporalis: 6-10 Brachioradialis: 25-75 Medial hamstrings: 50-150

Sternocleidomastoid: 50-100 Biceps: 75-125 Gastrocnemius: 50-100

Scalene: 25-50 Brachialis: 25-50 Lateral hamstrings: 75-150

Splenius capitis: 10-30 Flexor carpi radialis: 10-50 Soleus: 25-75

Semispinalis capitis: 10-30 Flexor carpi ulnaris: 10-50 Tibialis posterior:

75-125

Splenius cervices: 10-30 Iliocostalis thoracis: 100-200 Tibialis

anterior: 50-100