CLINICAL REPORT

Subcutaneous Botulinum Toxin

for Chronic Post-Thoracotomy

Pain

Gustavo Fabregat, MD; Juan M. Asensio-Samper, MD; Stefano Palmisani, MD;

Vicente L. Villanueva-Perez, MD; Jose De Andres, MD, PhD

Department of Multidisciplinary Pain Management, General University Hospital, Valencia,Spain

n Abstract: Objective: Botulinum toxin is a neurotoxin

that has been widely used in chronic pain for the treatment

of multiple conditions with a component of localized

muscle spasm. Recent studies suggest that botulinum toxin

is effective in the treatment of neuropathic pain syndromes

such as post-herpetic neuralgia.

Case Report: We report the case of a 67-year-old man

who underwent atypical segmentectomy of a right lower

lobe lung nodule. The patient was referred to our pain

management department with a of 2-year history persistent

pain along the thoracotomy scar having a predominantly

neuropathic component, refractory to standard treatments.

He was successfully treated with subcutaneous botulinum

toxin type A.

Discussion: On the basics of our own experience and on

the analysis of the reports published in the literature,

fractioned subcutaneous injections of botulinum toxin may

be useful for the treatment of various chronic localized pain

conditions including chronic post-thoracotomy pain. n

Key Words: botulinum toxin, neuropathic pain, subcuta-

neous, chronic post-thoracotomy pain

Chronic post-thoracotomy pain (CPTP) is a common

entity in clinical practice. It is defined as pain that

recurs or persists along a thoracotomy incision for at

least 2 months following surgery.1 The incidence of

chronic post-thoracotomy pain ranges between 26%

and 67%2 and can persist in 38% of the cases 3 years

after surgery.3

The etiology of chronic post-thoracotomy pain

remains unclear; however, it is believed that both noci-

ceptive and neuropathic components may play a role.

Indeed, neuropathic components may be present in

nearly 50% of the patients who develop chronic post-

thoracotomy pain.3 Multiple therapies have been

attempted for conditions involving neuropathic pain.

The most frequently used drugs include tricyclic

antidepressants, ligands of the a2d subunit of voltage-

dependent calcium channels, lidocaine patches and

opioids.4 However, in spite of the wide range of thera-

peutic options, neuropathic pain remains poorly con-

trolled in many patients.

Botulinum toxin is a neurotoxin that has been

widely used in chronic pain for the treatment of multi-

ple conditions with a component of localized muscle

spasm, such as focal dystonia, cramps or isolated

spasms and chronic myofascial pain syndromes.5

Address correspondence and reprint requests to: Gustavo Fabregat,MD, Department of Multidisciplinary Pain Management, General Univer-sity Hospital, Avda. Tres Cruces s/n, 46014, Valencia, Spain. E-mail:gfabregat@gmail.com.

Submitted: June 21, 2011; Revision accepted: May 14, 2012DOI. 10.1111/j.1533-2500.2012.00569.x

� 2012 The Authors

Pain Practice � 2012 World Institute of Pain, 1530-7085/12/$15.00

Pain Practice, Volume ••, Issue •, 2012 ••–••

Recent studies suggest that botulinum toxin is effective

in the treatment of neuropathic pain syndromes such

as post-herpetic neuralgia,6 even if its mechanisms of

action are not fully understood.

We present the case of a 67-year-old patient treated

with subcutaneous botulinum toxin type A (BTX-A)

for chronic post-thoracotomy pain with a predomi-

nantly neuropathic component.

CASE REPORT

We report the case of a 67-year-old man with a history

of smoking 40 cigarettes per day, with emphysematous

COPD treated with beta-2 agonists, inhaled steroids

and tiotropium. The patient underwent atypical seg-

mentectomy of a right lower lobe nodule that was path-

ologically confirmed to be a squamous cell carcinoma.

The patient was referred to our Pain Management

Department with a 2-year history of persistent pain along

the thoracotomy scar. The pain was described by the

patient as oppressive, stabbing, and intermittent, with

electric shock sensations and radiation into the breast.

The pain involved 2 intercostal spaces at the level of the

thoracotomy and the intercostal space below (intercostal

spaces 6 and 7). The reported severity of his pain was 8

on the visual analogue scale (VAS; 0 to 10). Upon physi-

cal examination, the patient exhibited tenderness of the

dermatomes involved with mechanical dynamic allo-

dynia and pin-prick hyperalgesia. The remainder of the

neurological examination was within normal limits.

With these findings, the patient was diagnosed with

neuropathic pain secondary to thoracic surgery.7

The patient had been treated with multiple anti-

inflammatory drugs, paracetamol and metamizole

sodium. At the time of his first visit to our Pain Manage-

ment Department, he was being treated with gabapentin

2400 mg/day and sustained-release oral morphine

(60 mg/day), with little effectiveness. Duloxetine treat-

ment was initiated at 60 mg/day and intercostal nerve

blocks were performed at the affected levels, with almost

no improvement. Topical capsaicin was added, and the

scar was injected with neurolytic solution, resulting in

partial improvement (VAS 6). Given the persistence of

his symptoms and the lack of results, we decided to per-

form subcutaneous infiltration of the painful area with

BTX-A (Botox�; Allergan, Irvine, CA, U.S.A.).

For these purposes, the affected area was thor-

oughly examined and the areas of hyperalgesia and

allodynia were defined using a sharp stick and a swab

brush, respectively (Figure 1).

After marking these areas, a grid covering the

affected zone was drawn with divisions of approxi-

mately 1 square centimeter. We then deposited 2.5 IU

of BTX-A in the center of the squares that most closely

corresponded to the painful area. A maximum of 40

squares were infiltrated with a total dose of toxin

amounting to 100 IU.

Five days after the treatment, the improvement in

pain was about 50% as measured on the VAS. The

patient reported having experienced some restlessness

in the afternoon after the infiltration, in addition to

discomfort associated with the puncture.

At 15 days after infiltration, the improvement

reported by the patient was approximately 80% (VAS

1). This improvement persisted at 12 weeks after

infiltration.

DISCUSSION

The precise mechanism by which BTX-A relieves neu-

ropathic pain remains unclear, while the number of

papers reporting a significant improvement in pain is

increasing. Encouraging improvements have been

reported in a variety of situations that exhibit a neuro-

pathic pain component such as post-herpetic neural-

gia,6,8–10 central pain syndrome,11 chronic postsurgical

pain (hernia repair, hysterectomy or carpal tunnel syn-

drome),12 post-traumatic neuralgia,12 trigeminal neu-

ralgia, and chronic facial pain.13,14 Other situations in

which BTX was administered successfully include

diabetic neuropathy,15,16 complex regional pain syn-

drome17 and occipital neuralgia.18

Figure 1. Detail of the areas of hyperalgesia (white arrow) andallodynia (black arrow).

2 • FABREGAT ET AL.

In addition to amputation of a limb, thoracotomy is

considered by some authors to be the procedure entail-

ing the highest risk of severe chronic postoperative

pain.19 Little is known about the etiology of chronic

post-thoracotomy pain. The proposed causes include

intra-operative intercostal nerve injury causing neuro-

pathic pain;20 however, chronic postoperative pain

seems to encompass both nociceptive and neuropathic

components.21

We found only one case of chronic post-thoracotomy

pain treated with subcutaneous BTX-A in the literature.

In this report, a decrease of 50% in the VAS score was

obtained after the treatment.12 In our patient, the

improvement was approximately 80%, from an initial

VAS score of 8 to a VAS score of 1 at 4 weeks; the

improvement persisted at 12-week follow-up.

It is certainly known that BTX-A proteolytically

degrades the SNAP-25 protein, a type of SNARE pro-

tein. The SNAP-25 protein is required for vesicle fusion

that releases neurotransmitters from the axon endings

(in particular, acetylcholine). BTX selectively blocks

cholinergic transmission at the neuromuscular junction

(proteolytic activity directed specifically on SNARE

proteins, essential for vesicle fusion). This mechanism

of action makes BTX useful in clinical practice.

It seems, nonetheless, that the effect of BTX is not

limited to the local activity. Some studies have shown

that active BTX-A spreads to neighboring, non-

injected muscles. Indeed, Yaraskavitch et al. injected

BTX-A intramuscularly in an experimental study in

cats. Four weeks after BTX-A injection in the target

muscle, force production was decreased in non-target

neighboring muscles. The decreases in forces were not

associated with the differences in the muscle masses

for target and neighboring agonist muscles (ie this is

not the result of functional disuse).22

It has also been observed that BTX-A may inhibit

peripheral sensitization of nociceptive fibers as well as

neurogenic inflammation by inhibiting the release of

local nociceptive neuropeptides/agents via vesicle-

dependent exocytosis (calcitonin-GRP, substance P,

bradykinin, glutamate) or by other mechanisms

(TRPV1, ATP receptor P2X3).23–26

It is widely assumed that BTX-A remains at the syn-

aptic terminal and its effects are confined to the injec-

tion sites. However, Antonucci et al.27 demonstrated,

in a series of experiments in rats, that catalytically

active BTX is retrogradely transported by central neu-

rons and motoneurons and is then transcytosed to

afferent synapses, in which it cleaves SNAP-25. Detec-

tion of cleaved SNAP 25 is the most sensitive test to

monitor the presence of BTX-A in vivo because a sin-

gle toxin molecule can proteolyze a large number of

SNAP 25 target molecules. These authors found SNAP

25 cleavage in distant areas such as the contralateral

hemisphere when they administered BTX-A in the hip-

pocampus of rats. Similarly, administration of BTX-A

in the optic tectum led to emergence of BTX-A trun-

cated SNAP-25 in the retina, thereby demonstrating

that the substance is transported unchanged to the

neuron’s soma and is subsequently released in second-

order neurons. This spread was not only seen in the

central nervous system. When using BTX-A in rat

whisker muscles, cleaved SNAP 25 also appeared in

the facial nucleus. These experiments demonstrate axo-

nal migration and neuronal transcytosis of BTX-A.

This retrograde spread was blocked by colchicine,

pointing to an involvement of microtubule-dependent

axonal transport.

Some studies in humans point to CNS changes in

patients treated with intramuscular BTX-A.28 These

changes are attributed to denervation or alterations of

sensory inputs after toxin treatment. Perhaps the retro-

grade neuronal transport of unaltered toxin could

explain distant effects of botulinum toxin. However,

this would warrant further research.

One of the drawbacks of case reports is to rule out

the placebo effect. Although the placebo effect because

of needle insertion could explain the improvement

experienced by our patient, having received previous

unsuccessful interventional therapies as well as the

coincidence in time with the activity of the toxin

makes this possibility less likely.

Based on the analysis of the reports published in the

literature, it would appear that fractioned subcutane-

ous injections of botulinum toxin may be useful for

the treatment of various chronic localized pain condi-

tions with minimal side effects, including CPTP syn-

drome. The mechanism by which this new route of

administration is effective remains unknown and may

constitute the focus of futures studies. Multicenter tri-

als are needed to establish indications, dosages, and

routes of administration, whereas longer follow-up

periods are warranted to determine the safety of such

treatments.

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