Botulinum Neurotoxin in

Chronic Pain Management

P. Prithvi Raj, MD, FIPP

Chairman, World Institute of Pain, Section of Pain Practice, Antioch, California

Chronic pain creates an enormous individual and soci-

etal burden and has a detrimental effect on quality of

life (QOL), impacting physical functioning, general

health, vitality, social functioning, emotional well-being,

and mental health.1 Indeed, studies suggest a virtual

inverse “dose–effect relationship” between the severity

of pain and the quality of a patient’s life. The direct and

indirect costs of chronic pain are huge, and chronic pain

is associated with an estimated 4 billion lost workdays

in the United States each year.2 In this supplement, we

have attempted to: (1) provide an overview of the epi-

demiology of chronic pain and its effects on the indi-

vidual and society; (2) describe the neurophysiology and

neuroanatomy of chronic pain within the same context;

and (3) review the management and design of thera-

peutic targets for chronic pain treatment. Overall, our

goal has been to detail the need for, and approaches to,

the aggressive diagnosis and management of chronic

pain.

Acute pain serves as a protective warning system to

help individuals avoid potentially harmful interactions

with the environment; for chronic pain, however, any

such physiologic usefulness becomes overshadowed by

the disability and disruptions the pain causes. Thus, in

the context of modern physiology and medicine, chronic

pain should be considered a disease.

With increasing appreciation of the severe conse-

quences of chronic pain on QOL, and the development

of treatment strategies for managing patients with

chronic pain, the discipline of pain management has

emerged as a recognized medical specialty. In the past,

patients who had chronic pain with no obvious etiology

may have been denied effective treatment as a result of

prejudicial categorization by some as “drug seekers,”

“hypochondriacs,” and victims of some form of psy-

chiatric impairment. Patients with chronic pain should

no longer be subjected to such misconceptions or believe

that pain is something they must simply endure. Despite

recent advances in our understanding of its nature and

importance, the management of chronic pain often

remains a challenge, even to experienced clinicians.

The physician whose patient continues to be

burdened by pain, despite conventional therapy, is

confronted by a considerable variety of pharmacother-

apeutic interventions, most of which, however, are not

indicated primarily for analgesia. In this supplement, we

have reviewed current strategies for the management of

chronic pain, including treatment with systemically

acting agents such as the tricyclic antidepressants and

anticonvulsants, the application of topical preparations

such as capsaicin, and most recently, the administration

of injectable and locally acting agents such as the botu-

linum neurotoxins (BoNTs). In this supplement, we

have sought to highlight the use of the BoNTs as a new

therapeutic development in chronic pain management.

While BoNT now plays an established role in myo-

genic disorders such as strabismus, cervical dystonia,

and facial rhytids, the discovery of its primary antinoci-© 2004 World Institute of Pain, 1530-7085/04/$15.00Pain Practice, Volume 4, Issue 1S, 2004 S68–S72

Address correspondence and reprints requests to: P. Prithvi Raj, MD, FIPP, 4748 Matterhorn Way, Antioch, CA 94531, U.S.A. E-mail: Prithvi-raj@comcast.net

Botulinum Neurotoxin in Chronic Pain Management • S69

ceptive activity has been fortuitous. Early work sum-

marized by Binder et al. found that 89% of migraineurs

treated with botulinum neurotoxin type A (BoNT/A) for

cosmetic indications or dystonia demonstrated remis-

sion or significant relief of migraine.3 Following these

initial experiences with BoNT/A in patients who had

migraine, Tsui et al. performed a randomized, double-

blind, placebo-controlled study whose results suggested

that the pain relief produced by this agent in patients

with cervical dystonia was independent of its effect on

muscular contractions.4 Although it was reasonable to

posit that the analgesic effects of BoNT on pain were

primarily the result of its effect at the myoneural

synapses, considerable evidence has since accumulated

to suggest a more complex mechanism of action.

The etiology of the analgesic efficacy of BoNT/A is

under investigation. As discussed in this supplement,

there are several potential explanations for the drug’s

antinociceptive utility:

1. BoNT/A may relax spastic muscles by directly

inhibiting the release of acetylcholine at the

myoneural junction.

2. BoNT/A may diminish the release of sensitiz-

ing mediators. Substance P is an important

neurogenic effector of inflammation that ac-

companies myofascial pain syndromes and has

been associated with migraine. Experimental

studies indicate that BoNT inhibits substance

P release through an acetylcholine-mediated

mechanism.5–7

3. BoNT/A may work multisynaptically to decrease

sensory input by disrupting positive feedback

loops between the a- and g-motor neurons.8

4. BoNT/A may facilitate the remodeling of central

pain processing independent of its effects on the

elements of the stretch reflex.9 Because it also

decreases the release of glutamate, a principal

excitatory neurotransmitter involved in synaptic

plasticity, there may be effects on downstream

long-term potentiation of major pain pathways.

5. There may be some evidence for the direct

analgesic action of axonally transported BoNT/A

on sensory neurons synapsing at the dorsal horn

of the spinal cord,10 although this is poorly

understood.

With the confirmation of early findings of its clinical

efficacy and mechanism of action through in vitro

experimental work and observational case studies and

randomized clinical trials, BoNT/A has emerged as a

novel pharmacotherapy potentially providing significant

analgesic activity to patients with a variety of chronic

pain syndromes.

HEADACHE

The article in this issue that addresses headache pain,

written by Stuart J. Tepper, MD, documents the impact

of headache on QOL and productivity on the indi-

vidual as well as the pharmacoeconomic burden of

headache pain on society. The significant number of

comorbidities associated with headache, particularly

migraine, and including depression, epilepsy, and

stroke, underscore the neurophysiologic and neuro-

chemical interrelationship between headache and

other conditions. Presently, abortive medications, such

as analgesics, nonsteroidal anti-inflammatory drugs

(NSAIDs), barbiturates, ergots, antiemetics, and

opioids, allow the successful management of migraine

as well as the more common tension-type headache

(TTH). While prophylaxis may be preferable to man-

agement with abortive medications for individuals who

suffer from chronic headache pain, many of the pro-

phylactic agents currently used are associated with

adverse events that may limit their utility. Recent studies

have shown BoNT/A, and potentially BoNT/B, to be

effective for prophylactic treatment, reducing the pain

and frequency of migraine and TTH. In prospective

studies of migraine treatment with BoNT/A, 51% of

patients reported complete improvement of symptoms

for a mean of 4.1 ± 2.6 months and 38% of patients

reported partial response for a mean of 2.7 ± 1.2

months.3 Other studies of BoNT/A for headache pain

also yielded positive results.11–15 Additionally, in one

study, the use of acute conventional migraine treatments

(NSAIDs and triptans) was significantly reduced.15 Both

patient and investigator global effectiveness evaluations

also showed a marked improvement for the majority of

BoNT/A patients. The injections were safe and well

tolerated, with only one adverse event reported (frontal

asymmetry of approximately 30 days).15 Effective pro-

phylaxis with BoNT may not only decrease the need for

abortive and prophylactic drugs, but decrease the inci-

dence of the many comorbidities associated with

headache.

NECK AND SHOULDER PAIN

Neck and shoulder pain are among the most common

of the musculoskeletal disorders and are a major cause

of morbidity and disability. International studies esti-

mate that at least 67% of the population will experi-

S70 • raj

ence acute neck pain and that 10% to 14% of adults

have chronic neck pain.16–18 Neck and shoulder pain,

including cervical dystonia as well as nondystonic pain,

may arise from a variety of etiologies. Cervical dystonia

is a sustained, involuntary contraction of the neck

muscles, which is almost always accompanied by some

degree of pain in the neck or shoulder region. Disabil-

ity due to this condition is common, and early treatment

is important to prevent progression and cervical spondy-

losis and myelopathy. In its early stages, this disorder

can be managed with anticholinergic agents, benzodia-

zepines, and g-aminobutyric acid; pharmacotherapy

may be augmented by physical therapy, electrical stim-

ulation of the cervical muscles, or muscular feedback.

However, the above pharmacotherapies are frequently

associated with adverse events that may limit their use.

For acute nondystonic neck and shoulder pain, oral

anti-inflammatory agents may be used; for chronic pain,

antiepileptic agents, tricyclic antidepressants, intra-

articular steroid injections, physiotherapy, and surgery

are options.

The high degree of pain relief afforded by BoNT/A

in patients who had cervical dystonia led to the clinical

trials of BoNT in patients with nondystonic neck and

shoulder pain associated with muscle stiffness or spas-

ticity. Excellent results have also been obtained with

BoNT for conditions as diverse as whiplash, cervico-

thoracic myofascial pain, upper limb motor neuron

spasticity, spasmodic voice disorders including stutter-

ing, and limb and oromandibular dystonias.

LOW BACK PAIN

Low back pain is a disorder suffered by millions of

Americans and is responsible for a significant loss

of productivity and impaired QOL. Various strategies

to manage low back pain include physical therapy,

behavior modification, massage, heat/cold treatments,

and acupuncture, in addition to standard, systemi-

cally acting orally administered medications, such as

NSAIDs, nonopioid analgesics, opioid analgesics, anti-

convulsants, tricyclic antidepressants, a-adrenergic

agents, muscle relaxants, and n-methyl-d-aspartate

receptor antagonists.19 Nerve or spinal blockade, estab-

lished with parenterally administered analgesics such as

lidocaine, has been used in conjunction with steroids to

provide localized pain relief. Surgery, including fusion

of spinal elements, may be indicated in patients who do

not respond to more conservative, nonsurgical thera-

pies.20 The demonstrated safety and long-term efficacy

of BoNT/A in patients with myofascial pain and muscle

spasm resulting in low back pain provides a treatment

option that is straightforward and practicable. When

used appropriately, BoNT/A can provide successful

management of back pain and its associated comor-

bidities, obviating the need for surgery and the con-

tinuous use of analgesic agents.

ADVERSE EVENTS

Adverse events from BoNT therapy are generally not

serious and may include localized pain, tenderness, and

bruising at the injection site, weakness of adjacent mus-

culature through neurotoxin diffusion, dysphagia and

associated upper respiratory infection, and in the case

of BoNT/B, an increased tendency for remote effects

such as hemifacial ptosis due to enhanced systemic dif-

fusion. Although BoNT therapy is well tolerated, it may

lead to the generation of neutralizing antibodies, the for-

mation of which is influenced by the unique genetic dis-

position of the host as well as the dose and frequency

of injection.22

POTENCY OF BoNT

With regard to the effects of dose, the total protein load

delivered per injection will differ among BoNT prepa-

rations because differences exist within dosing parame-

ters. These differences are related to the amount of

nonactivated vs. activated BoNT in various prepara-

tions. Nonactivated BoNT will contribute to the total

amount of protein in the dose, but not its effectiveness.

For example, although preparations of BoNT/A contain

more total protein per unit than BoNT/B,22,23 the usual

dosage range of BoNT/A is much lower than that of

BoNT/B. A dose of BoNT/A proven efficacious for

cervical dystonia (236 units)22 contains approximately

12ng of protein, while a dose of BoNT/B (5,000 to

10,000 units) can contain up to 100 ng of protein.23–25

Accordingly, patients treated with BoNT containing

higher doses of protein are more likely to develop neu-

tralizing antibodies.26

BoNT is a nonsystemic, pharmacologically benign,

long-acting antinociceptive agent that, unlike commonly

prescribed oral analgesic agents, does not require fre-

quent dosing. Patients are thus freed from regimens of

multiple oral analgesics and muscle relaxants. Further-

more, the associated complications of some systemic

agents, such as gastrointestinal intolerance and bleed-

ing, renal insufficiency, constipation, and cognitive

deficits, are avoided. Because the most effective level of

chronic pain control requires continuous analgesia,

numerous difficulties are created by symptom-driven

Botulinum Neurotoxin in Chronic Pain Management • S71

dosing with systemic agents, a problem obviated by the

continuous, long-term level of analgesia achieved with

locally injectable agents.

Along with the benefits conferred by nonsystemic

antinociception, BoNT/A has a wide safety margin con-

ferred by a high ratio of the median lethal dose to the

median effective dose (14 :1 in a murine model), demon-

strating that effective doses are an order of magnitude

lower than toxic doses. Additionally, the long-term

effectiveness of BoNT obviates the need for frequent

administration necessary with other locally acting

antinociceptive agents, such as capsaicin. BoNT/A pro-

vides antinociceptive effects for 6 to 8 weeks, and in

some cases, relief has been sustained for 3 to 4 months.

Reduction in pain is progressive after BoNT injections,

although this effect does not result in tachyphylaxis.

Therapy with BoNT should be tailored to the individ-

ual patient, using multiple injection sites and treatment

models individualized for each patient’s needs.

FUTURE EXPECTATIONS

Anecdotally and in small open studies, BoNT has been

used for patients suffering from excessive salivation,

tearing, and sweating. Rare reports are published

describing the efficacy of BoNT in complex regional

pain syndrome, stroke, and sphincter spasm and pain.

Can it be that injection over peripheral nerves (eg,

brachial plexus, sciatic nerve, lumbosacral plexus) and

sympathetic afferent pain fibers (eg, sphenopalatine gan-

glion, stellate ganglion, splanchnic plexus, celiac plexus,

hypogastric plexus) may show pain relief and, thus,

provide further options for persistent chronic pain? One

looks forward to future investigations in these areas

with optimism.

Acknowledgment

This work was supported by an unrestricted educational

grant from Allergan, Inc.

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