1Morphological Madrid Research Center (MoMaRC), Ultradissection Group, Madrid, Spain
2Anesthesiology, Palliative Care and Pain Clinic, National Institute of Cancerology, Colima, México
3Anesthesiology, Dr. José Penna General Interzonal Hospital, Bahía Blanca, Buenos Aires, Argentina
4Anesthesiology, Portuguese Institute of Oncology Francisco Gentil, Porto, Portugal
5Anesthesiology, México Hospital, San José, Costa Rica
6Anesthesiology, Móstoles Universitary Hospital, Móstoles, Spain
7Outcomes Research Consortium, Cleveland, Ohio, USA
8Anesthesiology Clinical Research Office, Ataturk University, Erzurum, Turkey
9Anesthesiology, University Hospital 12 de Octubre, Madrid, Spain
10Rheumatology and Pain Management, Fisiotech Lab Studio, Firenze, Italy
Neuropathic pain has different causes including surgery, trauma, viral infections, cancer, vascular
malformations, alcoholism, neurological conditions such as multiple sclerosis, and metabolic conditions such
as diabetes. Although there are various medical treatments for chronic neuropathic pain, these treatments
may have limited or weak evidence, as well as interventional treatments, which have short-term efficacy
and therefore require repeated interventions over time. Botulinum toxin type-A (BT-A) has been used for its
analgesic effects in different pain situations. There are several potential mechanisms of action of BT-A, which
are currently being researched. We report a series of three cases where ultrasound-guided intraneural infiltration
with BT-A was administered as compassionate use for successful treatment of persistent neuropathic pain. This
method may be effective for patients with persistent neuropathic pain and provide long-lasting effects. More
studies, including randomized and controlled trials, are required to confirm the effectiveness of the treatment.
Until more evidence arrives, intraneural injection of BT-A can be considered when conventional treatment has
botulinum toxin-A, neuropathic pain, palliative care
Neuropathic pain has different causes, including surgery, trauma, infections, cancer, alcoholism, neurological conditions, or metabolic conditions . Although there are various medical treatments for chronic neuropathic pain, these may have limited or weak evidence, and off-label drug prescription is a common practice in palliative care  or in unresponsive chronic pain conditions .
Conventional management of chronic neuropathic pain starts with non-opioid based therapies, including non-steroidal anti-inflammatory drugs, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, or anticonvulsants . Opioids have been shown to be beneficial in some cases and are also of ten used in clinical practice, despite limited evidence in their favor .
Since in most cases the evidence is either weak or limited, the clinical experience becomes fundamental when deciding medical treatment for chronic neuropathic pain or cancer associated neuropathic pain is needed.
Interventional pain management, like nerve blocks, may be indicated, with results that are often effective, with less adverse effects than conventional treatments, but commonly limited in time and to be repeated or with the need to place catheters, which often present complications and which may not be easy to manage [6,7].
An ideal strategy would be to achieve the same analgesic effect as a peripheral block but with a longer duration. Although adjuvants are commonly used in nerve blocks to increase this parameter, to date, none of the available drugs has ever been shown to obtain a sufficiently long effect to make it usable for the management of intractable or unresponsive chronic pain [8,9].
Botulinum toxin is a family of proteins produced by Clostridium botulinum of other species of its genera, which prevents the release of acetylcholine in the neuromuscular joint, causing paralysis. There are 7 main types of botulinum toxin, named type A–G, of which the types A and B are medically used. Although the only FDA-approved use of botulinum toxin type-A (BT-A) in pain management is the prevention of chronic migraine, there currently is a growing interest in its potential applications to other pain types, including chronic neuropathic pain . There have been several reports of favorable outcomes in chronic perineal pain , post-herpetic neuralgia, diabetic neuropathy , and there are even some clinical trials with promising results  and long-lasting effects .
Herein, we report a series of three patients with unresponsive chronic neuropathic pain that was successfully treated with ultrasound-guided intraneural injection (INI) of BT-A.
Authorization for off-label and compassionate use of BT-A was requested for all three cases. Patients were informed of the expected benefits and potential risks secondary to both the procedure and the drug and signed informed consent.
A 56-year-old man underwent supracondylar amputation for osteosarcoma of the femur. Two months after surgery, the patient complained of excruciating pain in the entire left lower limb, with numbness and a sensation of constant muscle contraction and fatigue in the stump of the amputated leg, despite being treated with a dose of tramadol of 50 mg every six hours and with an additional 50 mg as rescue analgesia, gabapentin 600 mg twice daily, and duloxetine 60 mg daily.
His pain score was greater than 7/10 on the visual analog scale (VAS). It was proposed to perform ultrasound-guided INI BT-A of the sciatic nerve. A sciatic nerve block with ultrasound-guided INI BT-A was performed in the gluteal and in the popliteal region using 150 U per site (Figure 1A and 1B). Treatment was adjusted to tramadol 100 mg if the pain was severe, gabapentin 600 mg at night, and duloxetine 60 mg in the morning.
The control at the third week after the INI showed the complete disappearance of the permanent severe pain with sporadic mild pain referred in the sole of the amputated foot with a VAS of 2–3/10.
At 8 weeks after INI of the sciatic nerve, the patient did not correlate any sensation of any kind in the left leg distal to the stump (no phantom limb syndrome), and the VAS was 0/10 (no pain at all) on the residual limb.
A 33-year-old woman was diagnosed with desmoplastic fibroma of the lower left limb 8 months earlier (Figure 1C). The VAS was 6/10 at rest and 10/10 with movement that did not respond to conventional treatments and for which ultrasound-guided INI BT-A of the sciatic nerve at the gluteal level was proposed (Figure 1D). With the patient in the lateral decubitus position, an ultrasound-guided INI was performed with 300 IU of BT-A INI. After the procedure, the patient was managed with duloxetine 60 mg in the morning and gabapentin 300 mg in the evening and 1 mg of morphine intravenously as rescue therapy.
Within just 24 hours after the procedure, the VAS was 0/10. After a further 4 days, she reported mild pain in her left buttock, so she took half a 5 mg morphine tablet at night. Six weeks after INI BT-A, the patient underwent total tumorectomy and placement of a prosthesis in the left lower limb, under spinal anesthesia with 12 mg bupivacaine and 100 mcg of morphine.
After surgery, the patient maintained a VAS of 0/10, fully recovered function, and only a slight numb sensation in the left pelvic area persisted.
A 21-year-old patient suffered a below-knee amputation of his right lower limb in a motorcycle accident. The patient was referred to the pain clinic 1 month after the amputation, for a constant tingling in the plantar region of the amputated limb (phantom limb) and no benefit from the conventional treatment with pregabalin 300 mg. VAS intensity was 8–9/10 for which an ultrasound-guided INI with 100 UI of BT-A was performed in the sciatic nerve at the popli-teal level (Figure 1E and 1F), with an immediate and significant reduction in pain and numbness of the limb (VAS of 2/10). The pain then progressively decreased until the disappearance (VAS 0/10) on the third day after injection and remained unchanged at the control 1 month after the treatment.
Figure 1. Subgluteal Sciatic Nerve Ultrasound-Guided (USG) Botulinum Toxin Type-A (BT-A) Injection for Desmoplastic Bone Fibroma
Case 1: Subgluteal sciatic nerve (A) USG subepineural BT-A injection (B). Case 2: computed tomography (C) and X-ray (D) of the desmoplastic
bone fibroma of the lower left limb. Case 3: USG sciatic nerve at popliteal fossa (E) with subepineural BT-A injection (F).
Intractable neuropathic pain can be defined as a pain for which its cause cannot be removed or otherwise treated, and relief has not been found after reasonable efforts in the generally accepted course of medical practice. Although often used indiscriminately from chronic pain, intractable pain represents an additional challenge for the physician, with the need to use off-label drugs, both in terms of another indication and in a different dosage or route of administration. Unfortunately, this is not an uncommon situation for pain or palliative care doctors, who in addition to treating complex patients, face the bureaucracy and legal issues associated with this condition .
In pain and palliative care, the main reasons for off-label are the lack of interest for the pharmaceutical companies to investigate in these specialties because the registration is time-consuming and high costly ; therefore, it is essential to register and publish off-label treatments to support our daily practice with scientific evidence.
Nowadays, in addition to the only approved indications in chronic migraine as pain treatment, the BT-A has been reported to be effective in several neuropathic conditions, such as trigeminal, posttraumatic, or postherpetic neuralgia. However, there is still not sufficient scientific basis to obtain the indication of use of BT-A in these conditions .
Although BT-A is reported to enter the nerve predominantly at the synaptic level , a study showed that direct application of BT-A to the proximal stump of a severed sciatic nerve resulted in a significant reduction in axotomy-induced loss of perisomatic cholinergic terminals at 1 week and 2 months after excision, and the attenuation of the synaptic deficit has been associated with increased motor recovery, indicating that BT-A, when applied directly to the nerve, exhibits also a regenerative effect . The mechanism of action of BT-A is still under investigation, and there are several potential peripheral and central effect sites where BT-A can act in vitro, and studies are currently ongoing to clarify this aspect .
A characteristic of BT-A is its long-lasting action, which is most likely related to its intracellular action and on the SNAP-25 protein, generating temporary chemical denervation that can recover in a two-phase period that lasts for approximately 90 days , enabling the long-lasting effects that we saw with a single injection.
In our cases, we preferred the ultrasound-guided nerve block with INI of BT-A (Figure 2; Video 1). Although INIs have been strongly discouraged, they do not necessarily cause neurological problems . Indeed, it has been shown that INI of BTA does not cause any alteration of the nerve architecture, nor cellular infiltration or demyelination . It has recently been further demonstrated that not only is it possible to inject intraneurally, but it is also very difficult to damage the nerve fascicles .
In conclusion, an ultrasound-guided INI of BT-A can be considered a new optional intervention in unresponsive neuropathic pain or in palliative care when conventional treatment has failed. More studies, including randomized controlled trials, are required to confirm the effectiveness of the treatment.
Figure 2. Ultrasound-Guided Subepineural Botulinum Toxin Type-A (BT-A) Injection
Ultrasound image of the nerve before (A) and after (B) subepineural BT-A injection. The swelling of the nerve and the almost absent perineural
diffusion confirm the success of the injection.
We thank the patients who underwent the treatment and who generously allowed us to publish their data and images. All contributors were included among the authors.
The authors declare that there is no conflict of interest related to this article.
No funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
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