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CLINICAL QUESTIONS

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Botulin-urntoxinMore than just a pretty faceby Gordon D. Ko, MD

CASE PRESENTATION

Mrs. K., a 46-YEAR-OLD church worker and married mother of two, wasseen with fibromyalgic syndrome, irritable bowel syndrome, and migraineheadaches. She was taking belladonna/ergotamine/phenobarbitol tablets,codeine, and pinaverium bromide. Supplements included ginger, echinacea,milk thistle, garlic, vitamin E, and coenzyme QlO. She had been abused inchildhood by alcoholic parents and was an intravenous drug abuser (hepa-titis C diagnosed in 1995). She was in a car acddent in 1989, incurringwhiplash and a right frozen shoulder.

Initial examination Oune 2000) findings in-

cluded: height ='163 em, weight = 52 kilos, noanemia or jaundice, and BP 134/99 nun Hg.She was treated with hydrotherapy (in addi-tion to active physiotherapy) and gabapen-tin (slowly up to 2,400 mg/day). She wasweaned off codeine and belladonna/ergot-

amine/phenobarbitol.On her September 2000 visit, she had a

better appetite and her weight had increasedto 54 kilos. In December 2000, she began

receiving injections of botulinum toxin typeA (BTX-A):25 units for headaches (withsupraorbital nerve blocks) and 75 units forupper trapezii and splenii cervids. At the post-injection in January 2001 she described "anexcellent response." Her headaches resolved(not to mention her wrinkles!) [see Table 1].

She returned in March 2001 for an injectionof 300 units of BTX-A.Her 22nd set of injec-tions was done on January 15, 2008 with400 units as follows: 25 units (2:1 dilution)

into bilateral pectoralis minor, pectoralis major,

TABLE1

Data from Mrs. K's case study- Outcome measure Post-injection

September20004/1013/4518/70

Pre-injectionJune 2000

5/1025/4530/7057/10018/18

PVASSFMPOIFIQTeP count 18/18

January 20013/107/4511/7014/1008/18

PVAS= Pain visual analog scale, SFM= short-form McGillQuestionnaire, POI= Pain DisabilityIndex, FIQ= FibromyalgiaImpact Questionnaire, TeP = tender point

-- -----

Gordon Ko, MD,

CCFP(EM), FRCP(C),

DABPM&R, DABPM,

heads the Canadian

Centre for Integrative

Medicine in Markham,

ON and is a consultant

in Rehabilitative

Medicine at Sunnybrook

Health Sciences Centre,

levator scapulae, upper trapezius muscles;50 units (4:1 dilution) into bilateral subscap-ularis muscles; 10 units (2:1) into bilateralmasseters, splenius capitus muscles and60 units total into the frontalis, procerus, cor-rugator, occipitalis muscles (following the_Silberstein protocol for migraine). With thesetreatments, she continues to work full-time,exerdses 3x/week, and requires no oral anal-

MAY2010. PARKHURST EXCHANGE. 41

gesic agents. She has experienced no adverseeffects over these past 9 years with regards tocardiac, liver, renal and endocrine ftmction.

Botulinum toxin was first used in the 1950s

by ophthalmologist Dr. Alan Scott (and sub-sequently approved by the FDAin 1989) forthe treatment of eye movement disorderssuch as strabismus and blepharospasm. Itsuses have subsequently expanded to includeneurological movement disorders includingfocal muscle dystonia and spasticity. Botuli-num toXin type-A (BTX-A)prevents spasticitythrough its prolonged blockade of acetylcho-line. When injected into muscle, BTX-Abindswith high specificity and affinity to presynapticcholinergic axon terminals.

This inhibits calcium-activated release of

acetylcholine,a blockade which leads to muscle

relaxation or paralysis. Within 4 days, collat-eral terminal sprouting will occur, as thebody attempts to reinnervate the neuromus-cular junction. These temporary ftmctionalsynapses bring partial recovery of muscleftmction after about 28 days.Byabout 2 monthspost-injection, the original nerve terminalswill begin to recover their ability to releaseacetylcholine as original connections arerestored. Sprouting then stops and the tem-porary synapses lose their function. Withinroughly 3 months, the original neuromuscularjunctions recover full, normal function.

Other potential targets are cholinergic para-

TABLE2

Trigger points andmyofascial pain syndrome criteria*

Major criteria. pain localizedto region, usually unilateral,asymmetric tenderness. taut band is palpable. pain in known referred zone. exquisite spot tenderness. restricted range of motion due to tight muscle

Minor criteria

. reproduction of pain/altered sensation by pressure on TrP

. local twitch response on snapping the taut band

. pain alleviated by stretching muscle or by injecting TrP

Diagnosis requires aii the major criteria and at least one minorcriteria; TrP = trigger point.* Source: fur Uro/2006;49:S28-3S.

sympathetic and postganglionic sympatheticnerve synapses of the autonomic nervoussystem. For example, intradermal injections ofBTX-Aleads to denervation of eccrine glands(useful for hyperhidrosis and sialorrhea).lCurrent research includes treatment of over-

active bladders2 and prostatic hypertrophy.3Patients are usually advised that the onset

of action occurs around day 3, and the peakeffect (in muscle relaxation) after 3 weeks.The average duration of response is 3 months.Pain relief, however, may last longer thanthe muscle relaxation effect.4 Injections arespaced at least 3 months apart to minimizethe rare risk of antibody formation to theprotein (as this would prevent BTX-Afromworking the next time).

Post-injection electrical stimulation of the

injected muscle has been reported to augmentthe response. Targeted injections of the nerveterminal endplate (with electromyographic[EMG]guidance) appear to be more effectivethan anatomical approaches.

. The safety of botulinum toxinsBotulinum toxin type-A comes in vials of 100units. A unit of BTX-Ais defined as the lethaldose for 50%(ill-50) of mice. The ill-50 for

monkeys is 39 U/kg. Extrapolated to a 70 kghuman, this would mean a lethal dose is about

2,700 units. The typical maximum dose atone injection setting is 400 units.

BTX-Ashould be stored in the freezer and

reconstituted with preservative-free normalsaline.When stored in saline, it loses potency by35%after one week and 44% after two weeks.

Reported side effects include post-injectionmuscle 'soreness, stiffness (typically lastinga week), and rarely, a flu-like illness, whichmay last a few days to a month. Inadvertentweakness is generally near the site of injection,e.g. eyelid ptosis for injections in the peri-cranial frontal muscles, and difficulty withswallowing for anterior neck muscle injections.Case reports of serious adverse effects haveled to recent FDAand Health Canada safetyreviews. Such incidents are largely dependent

42 . PARKHURST EXCHANGE. MAY 2010

on operator technique, e.g. concomitant gen-eralanesthetic,and dose used.Aretrospective .

review of 929 patient encounters involvingchildren with cerebral palsy documented nosevere adverse effects or botulism.s Other

supportive studies document safety and ameta-analysis has supported the overall safetyof BTX-A.6

Contraindications tobotulinum toxinsRelative contraindications to BTX-Ainclude

generalized muscular weakness (myopathiesand neuromuscular junction diseases suchas myasthenia gravis), profound atrophy ofthe target muscle, aminoglycoside antibiotictherapy, nursing and pregnancy.

.Botulinum toxin and headacheIt was first observed by Jankovic in work oncervical dystonia that there was a noticeablereduction in pain. Subsequent reports by theCarruthers (a Vancouver-based dermatologist-ophthalmologist couple who were the first toreport the anti-wrinkle effects from blephar-ospasm treatment) documented relief ofheadaches with injections done for wrinkles.

Though there were earlier supportivestudies for the use of botulinum toxin type-Afor headache treatment (migraine, tension,and cervicogenic types), more recent, largermulti-centre trials found no good evidencefor a role in tension-type headache. Resultswere more positive in specific subgroups ofmigraine and chronic daily headaches. But arecent neurology consensus panel did notfind sufficient evidence at this time for head-ache.? The results Qfa large multi-centre

phase ill trial for migraine (PREEMPT),however,concluded this therapy was safe and effective.

Laboratory pain studiesMore recent lab research has also indicated

that BTX-Amay also have a more centraleffect in pain control by blocking calcium-mediated release of substance P in dorsal root

ganglion neurons, as well as in the brain and

TABLE3

ABCD starting dose guidelinesll

Active Trigger Point: five to 10 units - if local anesthetic providesjust short-term relief.

BiomechanicaJapproach: 25 to 50 units, e.g. injectingtight pectoralsto correct anterior shoulder protraction and head forward posture.Dosing may be titrated up higher for larger muscles, e.g. piriformiswith 100 units, iliopsoas with 150 units.

Combination of the above: care must be taken to not over-injecttrigger points that are in weakened muscles under biomechanicaltension.

Dystonia: higher starting doses are administered and often withelectromyographic guidance.

trigeminal nerve emling. Lab studies suggestthat botulimun toxin type-A may also inhibitother pain neurotransmitters. It reducescapsaicin-evoked pain and neurogenic vaso-dilation in human skin as well.

In our clinic, we've observed effectivenessin focal neuropathic pain control with intra-dermal injections of BTX-A.This may alsoapply for the 27%to 38%of fibromyalgia (FMS)patients with marked skin allodynia, in whomthere are higher levels of cytokines in theskin. Patients with marked hypersensitivityshould first try intradermal injections (usinga 4:1 dilution), as they may actually have gen-eralized neuropathic pain disorder and aremore likely to flare up if injected too deeplyand in too many areas initially. BTX-Acan beinitiated successfully in fibromyalgia patientswho suffer from migraine headaches andlower back pain.

Botulinum toxin and myofascialpainjfibromyalg iaOneproposed theory for such pain relief isthat BTX-Aresolves muscle trigger points[TrPs].It's important to distinguish triggerpoints from fibromyalgia tender points. Thecriteria for trigger points are listed in Table 2.Studies are conflicting on the use of BTX-Ainmyofascial pain. Successful randomized trialswere published for chronic piriformis painsyndrome and chronic mechanical back pain.

It's been reported that 72%of FMSpatientshave trigger points.8 Tender points don't

usually respond to injections of local anes-thetic, but trigger points in fibromyalgia do.9Current theories as to the pathophysiologyof TrPs include the dysftmctional motor end-plate where excessive acetylcholine is releasedand where higher levels of inflammatorymediators have been found. Such mediators

are often co-localized with acetylcholine andmay explain how BTX-Aworks for recalci-trant TrPs.

One previous published study on BTX-Afor FMSfound it to be ineffective. 10 This was

a small study of 10 patients who underwentalternate injections of lidocaine or BTX-Asolely into the upper trapezii muscles. Onlyone patient reported relief of pain for twoweeks with lidocaine. In our experience, injec-tions into the trapezius may exacerbate painin FMSpatients, particularly in the presenceof a head-forward posture with depressedscapula and TOSsymptoms (painful paresthe-sias in the arm). Weakening this scapulaelevator will aggravate the tension on thebrachial plexus. Instead, injections into thetight pectoralis minor!levator scapulae mus-cles combined with daily stretching of thesemuscles and scapular stabilization exercises -strengthening the trapezii and rhomboids- results in a much better clinical response.

Botulinum toxin and otherpainful conditionsStudieshavealsobeen publisheddemonstrat-ingeffectivenessforother conditionsincluding:. TMJpain syndrome. tendinopathies (tennis elbow). plantar fasciitis. osteoarthritis, rheumatoid and psoriatic

arthritis .

. post-motor vehicleaccidentwhiplashsyndrome

. cancer pain, including post-radicalneck dissection and radiation fibrosis

syndrome. surgicalwound healing. post-amputation and phantom limb pain. sports overuse injuries

Continued on page 49

44 . PARKHURST EXCHANGE. MAY 2010

PERSPECTIVESON PAINBOTULINUM TOXINContinuedfrom page 44

We recommend when injecting BTX-Afor pain touse the ABCDrecommendations, found in Table 3.

Patients who comply well with their exerciseregimen (strengthening of weak core muscles anddaily stretching of injected tight muscles), oftenseem able to go for longer periods in between BTX-Ainjections. Treatment should always be integratedwith lifestyle changes, including adequate physicalactivity level, stress management, detoxification,and sleep hygiene. An interdisciplinary care andpolypharmacy approach will be required for morecomplex chronic pain patients, in which BTX-Ahelpsto contribute to the overall rehabilitation. FE

For more information:

· Dr. Ko's physician education website atwww.NeuropathicPain.ca·General education website at

www.l_www.DrKoPRP.com:a·For physician training, contact theCanadian Society for Neurotoxins in Pain

Selected references

1. Nawnann M.J NeuroI2001;248:131-3.

2. Kalsi V et al. Eur UroI2006;49:528-35.

3. Maria G et al. Urology 2003;62:259-64.

4. Freund B, Schwartz M. J Pain 2003;4:159-65.

5. Willis AW et al. Develop Med Child NeuroI2007;49:818-22.

6. Naumann M,Jankovic J. Curr Med Res Opin 2004;20:981-90.

7. Nawnann M et al. Neurology 2008;70:1707-14.

8. Gerwin RD. J Musculoske Pain 1995;3 (Suppll):121.

9. Hong ez, Hsueh TC. Arch Phys Med RehabilI996;77:1161-6.

10. Paulson GW, Gill W. Movement Disorders 1996;11:459.

n. Erbguth Fj. Pain and Headache 2003;14:54-70.

For a coinplete list of references, please go toparkhmstexchange.com and click Botulinum toxinon the May 2010 contents pages.