Botulinum Toxin in Pain Management Essay

Myofascial pain (MP) is a common, painful disorder that is responsible for many pain clinic visits. MP can affect any skeletal muscles in the body. Skeletal muscle accounts for approximately 50% of body weight, and there are approximately 400 muscles in the body. MP is responsible for many cases of chronic musculoskeletal pain and the diagnosis is commonly missed.Botulinum Toxin in Pain Management Essay

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MP can cause local or referred pain, tightness, tenderness, popping and clicking, stiffness and limitation of movement, autonomic phenomena, local twitch response (LTR) in the affected muscle, and muscle weakness without atrophy. Trigger points (TrPs), which cause referred pain in characteristic areas for specific muscles; restricted range of motion (ROM); and a visible or palpable LTR to local stimulation are classic signs of MP

Botulinum Toxin
What is Botulinum Toxin?
Botulinum toxin is the world’s strongest natural toxin that is created by the growth of clostridium botulinum, an anaerobic bacteria; Botulinum toxin only grows under limited oxygen levels and at temperatures less than 80degreeC. Although botulinum toxin can be ten times more deadly than cyanide and causes botulism, it has many practical medical uses. Botulinum toxin is a protein and has seven structural types. However, only botulinum toxin A and botulinum toxin B have been approved for medical and cosmetic use. Botulinum toxin, most often known for its cosmetic uses such as Botox, has many other medical uses. Some practical uses for botulinum toxin include it being used as a muscle relaxant and pain killer.Botulinum Toxin in Pain Management Essay

Introduction to how BT works?
Botulinum toxin is very effective in reducing pain and muscle spasm. When botulinum toxin is released into the body, it blocks the release of acetylcholine , a neurotransmitter that cuts off the signal between nerves and muscles. When one’s nerves stop transmitting signals to the muscles, one cannot feel pain as strongly, thus reducing pain and one muscles relax.

The phenomenon of phantom limb was first described by a French doctor, Ambroise Pare, in the 16th century however it was not until 1866, after the American Civil War, when Doctor Wier Mitchell published his first account of the malady, coining the term Phantom Limb. Phantom limb is the experience of persisting sensory perceptions after limb amputation and remains one of the best-known, but puzzling phenomena within medical science (Oakley & Halligan, 2002). Phantom limb pain (PLP) is a frequent consequence of the amputation and causes considerable discomfort and disruption of daily activities.

Originally, PLP was thought to have been secondary to nerve damage at the site of amputation but succeeding evidence showed that patients who have undergone regional anesthesia continue to experience phantom limb pain despite the cut-off of pain sensation to the amputated area (Melzack, 1997). This lead to the belief that the pain sensation experienced by patients with PLP may be due to nerve impulses or signals generated at the spinal cord level. This, however, was refuted on the basis that patients with transection of the spinal cord still complain of persisting phantom limb pain.Botulinum Toxin in Pain Management Essay

It has been argued then that the brain areas that correspond to the human body could be the one responsible for the phantom sensations (Melzack, 1997). This was based on the fact that much of the human (and primate) body is represented by distinct brain areas located in the somatosensory and motor cortex on either side of the central sulcus. Consequently, even after limb removal, the brain areas representing those parts remain structurally and functionally intact.

It has been argued that the activation of these bodily disconnected brain areas by adjacent brain areas (representing other intact body parts) may be a partial neurophysiological explanation for the production and maintenance of the continuous perceptual experience that is the phantom limb. This functional remapping results in some cases in the referral of selective sensory information from an intact body area (such as the face or shoulder) to the phantom limb (Halligan, Zeman and Benger, 1999).

The remapping hypothesis is supported by functional imaging (Kew, Halligan, Marshall, Passingham, Rothwell, Ridding, Marsden and Brooks, 1997) and behavioural studies (Ramachandran, Stewart and Rogers-Ramachandran, 1992; Halligan, Marshall, Wade, Davies and Morrison, 1993). Given the magnitude and speed of onset of the reorganization (within 24 hours of amputation) it is unlikely to be a product of neural sprouting but rather the unmasking of existing but previously inhibited neural pathways (Ramachandran and Blakeslee, 1998).Botulinum Toxin in Pain Management Essay

In addition, these abnormal plastic changes in the central nervous system associated with the phantom experience have been used to explain the consistently high incidence of pain attributed to a limb that no longer exists (Ramachandran and Blakeslee, 1998). Several other theories have been proposed to explain the pathophysiological processes behind the PLP phenomenon but despite all of these, the exact cause of PLP remains uncertain. As a consequence, the current treatments for the condition are just as varied as the litany of many possible yet complex mechanism of PLP.

This literary review will assay the possible treatment options available for the management of PLP using information from published literature through searches in research databases using the keywords phantom limb, phantom limb pain, biofeedback, treatment, and phantom limb illusions. Treatments of PLP There are different modalities available in treating PLP ranging from pharmacological agents to psychophysiological therapy. The treatment outcome varies from approach to approach and more even from patient to patient.Botulinum Toxin in Pain Management Essay

A careful evaluation is essential before considering any of of these treatments in order to obtain a more individualized approach in the management of PLP. Thermal biofeedback Biofeedback relies on instrumentation to measure moment-to-moment feedback about physiological processes. It provides patients with information about their performance in various situation (Saddock & Saddock, 2003). Using this electronic feedback, the patient is made aware of certain sensations such as skin temperature and muscle tension.

A case report describing the use of thermal biofeedback combined with electromyogram (EMG) in treating a 69-year-old man suffering from burning and shooting phantom pain suggested that biofeedback is an effective treatment modality for severe phantom limb pain (Belleggia & Birbaumer, 2001). The rationale behind the treatment was based on the premise that most patients complain of intolerance to cold after amputations which tend to aggravate unpleasant or pain sensations in the stump.Botulinum Toxin in Pain Management Essay

The treatment, however, required several sessions and in this particular case, there were 6 sessions of EMG biofeedback followed by another 6 sessions of temperature biofeedback. The patient presented in this case also did not use a prosthesis and did not receive prior treatment for chronic pain and the entire treatment process was done in a controlled environment where everything is calibrated and maintained to avoid external bias.

Although the treatment outcome of the case report was favorable, there is no absolute guarantee that the same beneficial results can be expected to other patients with PLP especially to those who are already using prosthesis and to those who are already refractory to previous chronic pain therapies. Also its efficacy and adaptability in actual clinical settings remains to be studied. Electroconvulsive therapy (ECT) The use of electroconvulsive therapy have been common in patients with psychiatric disorders such as depression.

This involves the utilization of electric stimulation by means of two electrodes placed bilaterally on the temple to produce convulsion. The artificial seizure that followed have shown efficacy in patients with a variety of pain syndromes occurring along with depression (Rasmussen & Rummans, 2000). Using this evidence, 2 patients with severe phantom limb pain refractory to multiple therapies but without concurrent psychiatric disorder were treated using ECT.Botulinum Toxin in Pain Management Essay

One of the patients previous treatments included biofeedback, transcutaneous electrical nerve stimulation, hypnosis, epidural injections, and multiple analgesic medications including non-steroidal anti-inflammatory drugs, opiates, and adjunct analgesics including carbamazepine and nortriptyline. He was referred for ECT by the anesthesia pain service due to previous good responses in depressed patients with a variety of non-phantom limb pain syndromes.

The other patient in the case study also had numerous treatments including transcutaneous electrical nerve stimulation, intra-axillary alcohol injections. Epidural steroid blocks, stellate ganglion blocks, biofeedback, and medications including antidepressants, benzodiazepines, opiates and carbamazepine. After ECT, both patients enjoyed substantial relief of pain with one case in remission from PLP 3. 5years after ECT. From this clinical note, it was concluded that patients with PLP who are refractory to multiple therapies may respond to ECT.

It should be emphasized that ECT have several complications including dental and muscular injuries secondary to the severe muscle twitching accompanying the induced convulsion. The concurrent use of muscle relaxants have been effective in minimizing such injuries. The most troublesome side effect of ECT, however, is memory loss. Some patients report a gap in memory for events that occurred up to 6 months before ECT, as well as impaired ability to retain new information for a month or two after the treatment (Smith, et al, 2003).Botulinum Toxin in Pain Management Essay

You may equate this to the data loss in computers after an unexpected reboot. Hypnotic mirrors and phantom pain Hypnotic procedures have long been used in treating a variety of pain syndromes. This involves the use of suggestion and imagery to alleviate the patients pain experience (Chavez, 1989). A case study reports the use of a hypnotically induced virtual mirror experience which modified long standing intractable phantom limb pain despite generating a qualitatively inferior experience of movement in the phantom limb compared to that produced with an actual mirror (Oakley & Halligan, 2002).

Using hypnosis, two main approaches to modifying phantom limb pain experience were identified in the study: ipsative imagery approach and a simulated movement approach. The ipsative imagery approach takes into account the way the individual represent their pain to themselves and attempts to modify that representation in order to alleviate the pain experience. The movement imagery-based approach encourages the PLP patient through hypnosis to move the phantom limb and to take control over it.Botulinum Toxin in Pain Management Essay

In the study, a case of a 76-year-old woman who had an above-knee amputation of her right leg secondary to peripheral vascular disease was presented. The investigators emphasized that she was pain-free at the time of her operation and that her PLP only begun two years after surgery. There were several components of her pain in her missing limb. She complained of feeling pins and needles in her foot, her toes felt like they were being held in a tight vice, a slicing, cutting pain in the sole of her foot and a chiselling pain in her ankles.

After several sessions using the ipsative imagery approach, the patient claimed significant pain relief of most of her pain but the vice-like pain remained. The movement imagery-based approach also showed notable pain alleviation in another case that was presented, this time of a 46-year-old man who had experienced PLP since suffering from an avulsion of his left brachial plexus some five years prior to the study.Botulinum Toxin in Pain Management Essay

At the beginning of the study, the patient rated his pain at 7 using a scale from 0 to 10, with 0 as pain free and 10 as the worst pain imaginable. During treatment, the patient had 0 rating and immediately after treatment it was 2. 5. The result of the study showed that hypnotic movement imagery is worth investigating further, considering the comparative ease of use and the potential of additional information as to the possible neurocognitive mechanism involved in PLP. Mirror treatment

Mirror treatment uses leg exercises performed in front of a mirror to demonstrate increased motor control over the phantom limb. In contrast to hypnotic imagery techniques which uses hypnotically induced virtual mirror experience, mirror treatment involves the use of a real mirror apparatus to replicate the movements of the real limb with the phantom limb. The first case study of the use of mirror treatment in a person with lower limb amputation who was reporting PLP was presented by MacLaughlan, M. McDonald, D. , & Waloch, J. (2004).Botulinum Toxin in Pain Management Essay

During the intervention, there was a significant reduction in the patients PLP associated with an increase in sense of motor control over the phantom, and a change in aspects of the phantom limb that was experienced. Although this effect was successfully replicated by using hypnotic imagery alone, the significant difference between the two approaches was the qualitatively more powerful experience of movement in the phantom left hand with the real visual feedback.

The case study which was conducted in a conventional clinical setting supports the potential of mirror treatment for PLP patients with lower limb amputations. The investigators, however, emphasized that the case study cannot indicate the extent to which beneficial effects are due to somatosensory cortex re-mapping, psychosocial factors such as individual differences in body plasticity, somatic preoccupation or creative imagination, or to other factors.Botulinum Toxin in Pain Management Essay

Since it is the first case study of the use of mirror treatment in a person with lower limb amputation, similar case studies are needed to ascertain the treatments applicability to other patients with lower limb amputations. Botulinum toxin Pharmacological agents have also been employed in the management of PLP. , Botulinum toxin type A, however, has not been previously used for this indication. In fact, it was only recently that this toxin has been used for medical purposes, especially in the field of cosmetics.

Botox, as it is popularly known, has been beneficial in relieving muscular tension in the face due to its muscle-relaxing effect. Once considered a biological weapon which causes gas gangrene, this toxin inhibits the synaptic transmission of acetylcholine at the motor end plate and muscle spindles of the skeletal musculature and influences nociceptive transmitters. A pilot study on the influence of the agent on phantom pain after amputations was recently reported (Kern, Martin, Scheicher, et al, 2003). Four cases of patients with knee amputations who were suffering from severe stump pain following surgery were presented.Botulinum Toxin in Pain Management Essay


After botulinum toxin injection, significant reduction of pain in the amputation stump was experienced among the patients. Citing a strong correlation between stump pain and PLP and the occurrence of of stump pain without obvious pathology, the study clearly emphasized the need for further investigation into the use of botulinum toxin in the treatment of post amputation pain. Other treatments of PLP Multiple other modalities, adjunct medications and anesthetic/surgical procedures have been used in the treatment of PLP with varying long term success.

Although at least 60 methods of treating PLP have been identified, successful treatment of persistent type is not commonly reported. Tricyclic antidepressants, anticonvulsants, calcitonin and mexilitine have been used with varying success (Delisa, Gans, Bochenek, et al, 1998). Other surgical procedures and drug regimens have also been proposed. Despite all these, an established role of each of these treatments in the management of PLP remains a subject for future investigation. Summary Despite the advances in medical research and treatment, PLP is a phenomenon that continues to perplex the medical field.Botulinum Toxin in Pain Management Essay

Several theories that were proposed to explain the etiology of the condition remain the subject of continued discussion. The pathophysiology involved in PLP could be multifactorial rather than the effect of a single factor. In the United States, there are approximately 1. 6 million people are living with limb loss according to the National Limb Loss Foundation Information Center. Between 1988 & 1999, an average of 133,735 hospital discharges per year was due to amputation. It is estimated that 50%-80% of patients with amputations complain of PLP (Delisa, Gans, Bochenek, et al, 1998).

The actual incidence of this problem is, however, unclear because the condition tends to be underreported because of the complexity and strange nature of the complaint. Finding the most appropriate treatment for PLP has proven to be a difficult challenge for medical practitioners. The current treatment options for the condition are just as varied as the litany of many possible yet complex mechanism of PLP. Thermal biofeedback combined with electromyogram (EMG) have been demonstrated to completely eliminate PLP after treatment.

In a case study, the use of ECT have shown pain relief in patients with PLP refractory to multiple therapies. The use of hypnosis and visual imagery in several case reports has indicated significant success in modifying the pain experience of PLP patients. Interestingly, the success of this technique in treating PLP has given a deeper insight on the psychological aspect of the condition. Botulinum toxin, a drug considered as a very dangerous toxin that causes gas gangrene, has also shown promising results in alleviating stump pain.Botulinum Toxin in Pain Management Essay

Multiple other modalities, adjunct medications and anesthetic/surgical procedures have been used in the treatment of PLP with varying long term success. Establishing an accepted role of each of these treatments in the management of PLP, however, would require further investigation. The highly varied approaches involved in the treatment of PLP present a unique burden especially for the General Practitioners (GPs) who provide the primary health for amputees in the community. A recent study suggests that GPs underestimate the prevalence, intensity and duration of phantom and residual limb pain.

Moreover, inconsistencies in the reasons given for referral to specialist services for the management of phantom pain were reported. These findings have serious implications for the management of phantom limb pain, disability and psychological distress in amputees in that GPs not only provide first line treatment, but are also the gatekeepers for referral to other services (Kern, Martin, Scheicher, et al 2003). The prevalence of case studies presented in this review clearly shows the lack of major clinical trials targeted into identifying the best approach in the management of PLP.

Most of these treatments are already being used for other diseases and there is ample literature to justify their use for PLP yet there is not a single searchable literature involving a bigger study population investigating any of the above methods. It is obvious that the efficacy and cost-effectiveness of these individual treatment methods cannot be ascertained by only a handful of case reports. More comprehensive studies should be done in order to formulate an acceptable protocol for the adequate treatment of PLP.Botulinum Toxin in Pain Management Essay

When people think of new fashion trends they normally think of clothes, but the newest beauty craze that has hit the middle age market is Botox. Botox injection therapy, although not completely new, has come out swinging since being approved for use in cosmetic improvements in 2002. Botox is used to eliminate the look of aging by reducing the appearance of wrinkles on the face, neck and hands. Most commonly, patients use Botox to eliminate crow’s feet around the eyes, wrinkles on the forehead, and frown or laugh lines. It has become such a popular and ‘user friendly’ alternative to traditional cosmetic surgery, many women and even celebrities host Botox parties to share the experience with their friends. Botox parties are held in private homes, in doctor’s suites, at hotels and even spas. Celebrities such as Celine Dion, Cher, Madonna and even Sylvester Stallone are rumored to have gone under the Botox needle; but only a few such as Joan Rivers have credited Botox to helping their skin look younger. Although Botox has been promoted as the miracle cure for aging, for many people who suffer from debilitating disorders or chronic pain, it has proven to be a wonder drug.Botulinum Toxin in Pain Management Essay

So, what is Botox? Botox is the market name for type A botulinum toxin which is a purified form of the toxin produced by the bacteria, clostridium botulinum. This bacteria is commonly associated with food poisoning and is lethal in large doses. The botulism toxin could paralyze vital muscles needed for breathing. Although related to botulism food poisoning, the amounts of Botox given are so minimal and localized, that the toxin will not spread to any other muscles in the body, thus making it a safe and harmless procedure.

Pain is an unpleasant sensory and emotional experience which substantially reduces the quality of life. This subject has attracted attention from scientists as well as philosophers. Charles Darwin described pain as a ‘homeostatic emotion’ which is essential for the survival of species [1]. Philosopher Rene Descartes described the pain as a sensation which is running from skin to brain [2]. Pain is also viewed as protective and beneficial to recuperation. However, in certain conditions, pain becomes a disease itself. In brief, pain can be perceived as a result of complex neuronal processes which are evoked to set up a new balance between excitation and inhibition. Basically, pain is understood as a response of neuronal cells. Recent advances are developing the concept that pain involves immune cells, glial cells, and astrocytes, which form an integrated network with neuronal circuits to modulate pain. Pain research has uncovered several important neuronal mechanisms.Botulinum Toxin in Pain Management Essay

Pain research is a major health problem. Pharmaceutical industries always look for a better drug for pain, partly due to less understanding of its complex mechanism. Pain therapy is not only poorly managed, but they also lack efficacy. A reasonable and effective pain management strategy requires a basic understanding of following things: (i) knowledge of pain inciting stimuli, (ii) involved neural pathways, (iii) response of nervous systems, and (iv) systemic consequences of pain. Having this knowledge, management of pain will be easy and the use of pharmacologic agents and various hypoanalgesic techniques can be optimized for better management of pain and related consequences. Two types of drugs modulate pain: analgesics and anesthetics. Many of the currently available pain therapies are either inadequate or cause uncomfortable to deleterious side effects. The most clinically used drugs are the opioid family, which include morphine and heroin. But these drugs have several significant side effects, including addiction. Scientists are still looking for better medications. Like solution to every problem, mother nature has also provided some alternatives, such as (i) cone snail venom which is 100-times more potent than existing pain medication, (ii) spider venom has a potent compound which blocks voltage-gated sodium channel 1.7 (Nav 1.7), and (iii) poison from the skin of South American Ecuadorean frog, ABT-594, as powerful painkillers with none of the damaging side effects.Botulinum Toxin in Pain Management Essay

One of the naturally existing potent molecules is Botulinum Neurotoxins (BoNTs). Although BoNTs are extremely toxic molecules, these are now increasingly used for the treatment of disorders related to muscle and glandular hyperactivity. Weakening of muscles due to the peripheral action of BoNTs produces the therapeutic effect. Toxin A is approved in the United States for the treatment of cervical dystonia, blepharospasm, and glabellar lines. Although it is too early to establish observations suggesting analgesic property of botulinum toxin, the toxin is known to modify the sensory feedback loop to the central nervous system (CNS). Further, peripheral injection of BoNT A induces nociceptive behavior in animal models of inflammatory and traumatic neuropathic pain [3–7]. Some observations suggest Botulinum Toxin A is effective in neuropathic pain. Neurogenic pain pathways may have a role in neuropathic pain [8–12]. The process relating to various forms of pain is quite complex, but the basic signaling of painful sensations does not require exocytotic signaling in the peripheral nerves. In general, BoNT treatment intervenes pain in two ways: (i) direct way – by abolishing the contractile activity of the muscle (due to hyperactivity or sensitization of nociceptor by lowering the pH) and (ii) indirect way – by preventing the release of neurotransmitters other than acetylcholine (such as substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin, serotonin, ATP, bradykinin (BKN) etc.) involved in sensitization and stimulation of muscle nociceptors, which lead to inhibition/enhancement of ascending/descending signals (such as chronic cases).Botulinum Toxin in Pain Management Essay

Types of pain
Pain is generally evoked by potential noxious stimuli such as heat, chemical, or mechanical exposure. The pain during a disease is different from normal pain. Two types of nociceptive pain are usually distinguished based on point of origin: a pain emanating from the skin and deeper tissues (e.g. joints and muscles) is referred to as somatic pain, while pain emanating from the internal organs is referred to as visceral pain. Somatic pain is usually well localized, whereas visceral pain is harder to pinpoint.

Different types of pain have been classified according to their pathogenesis. The simple but very important distinction is acute and chronic pain. An acute pain is caused by injury to a specific part of the body, restricted to the injury site and is abolished after healing. Chronic pain is the condition when pain itself becomes a disease. Chronic pain persists for longer than 6 months and can arise even in the absence of any pathological trigger. A more scientific distinction would have three types of pain: (i) acute physiological nociceptive pain, which protects tissues from further damage eliciting withdrawal reflexes, (ii) pathophysiological nociceptive pain occurs when the tissue is inflamed or injured. It may appear as a spontaneous pain, hyperalgesia, or allodynia. (iii) Neuropathic pain results from injury or damage to neurons. Neuropathic pain often feels abnormal and may be combined with hyperalgesia and allodynia. Cause of neuropathic pains includes nerve or plexus damage, metabolic disease, or herpes zoster. Pain can be neuropathic or inflammatory, although neuropathy may involve inflammatory components and neuropathic components may contribute to inflammatory pain. Other types of pain include pain during surgery, cancer pain, pain during degenerative disease, or pain in the house of psychiatric disease.Botulinum Toxin in Pain Management Essay

How nociceptors are activated and transmit signals?
Nociceptors respond to various stimuli which are generated by a variety of substances. These substances activate various channels (see below; Box 1). Globulins, protein kinases, arachidonic acid, histamine, nerve growth factor, SP, CGRP, potassium, serotonin, lactic acid, and acetylcholine are the substances generated or released in response to the stimulus. Nociceptors have ion channels for stimulus transduction, generate the action potential, and carry specific receptors. Let us discuss how these substances are involved in activation of nociceptors.

Botulinum toxin type A (BoNT/A) is among the most potent biological toxins in nature, and, together with serotypes B, E, and F, a cause of natural botulism in humans, which is characterized by flaccid paralysis of skeletal muscles and dysautonomia [1]. Based on early 19th century observations that a yet unknown toxin from contaminated food induced the symptoms of botulism, the idea emerged that a low dose of the agent could be used for overactive nerve disorder treatment. In the 20th century, different BoNT serotypes have been characterized and isolated, and Burgen et al. discovered that BoNT/A inhibits acetylcholine release from neuromuscular junctions (NMJs) in skeletal muscles [2]. These discoveries eventually lead to the development of its therapeutic use in the 1970s, when minuscule quantities of the toxin were first employed to correct the eye misalignment in strabism [3]. Today, botulinum toxin is the most commonly used therapeutic protein for the treatment of autonomic disorders, spasticity and hyperkinetic movement disorders, as well as in cosmesis for treating wrinkles [4]. BoNT/A is approved in upper limb spasticity, blepharospasm, hemifacial spasm, cervical dystonia, primary hyperhidrosis, and neurogenic detrusor overactivity [4,5].Botulinum Toxin in Pain Management Essay
BoNT/A effects on pain were reported in cervical dystonia in 1986 [6]. Initially, the analgesic effect in neuromuscular disorders and musculoskeletal pain was attributed to the muscle relaxant effect, until the antihyperalgesic effect in non-muscular pain models was unequivocally demonstrated in human patients and animal models [7]. A serendipitous discovery that BoNT/A injection into glabellar lines resulted in migraine resolution led to extensive investigation in headache, which demonstrated that BoNT/A treatment was beneficial in chronic, but not in episodic migraine [8,9]. Efficacy in chronic migraine was shown in two large industry-sponsored randomized controlled clinical trials (RCT), after which onabotulinumtoxin A (Botox®) eventually gained regulatory approval in 2011 [10]. So far, chronic migraine remains the only approved pain indication, even though several systematic reviews of clinical trials provide evidence for BoNT/A efficacy in different pain conditions [11]. Nevertheless, we have to add that, while the results are promising, the quality level of evidence is not yet high enough to provide explicit guidelines for pain physicians. Shortcomings of the available clinical research data include low number of participants, and thelack of standardized dosing and delivery protocols, as well.
In the present review, we summarize the available data on the mechanisms of action of BoNT/A on pain, considering both peripheral and central mechanisms along the nociceptive pathways. We also include an overview on the clinical evidence for chronic migraine and neuropathic pain syndromes. There is ample preclinical evidence that peripheral and central sensitization is effectively and safely alleviated by BoNT/A, but more clinical research is needed to determine the role of BoNT/A in chronic pain management.
2. Basic Pharmacology of BoNT/A: Mechanisms of Outstandingly High BoNT/A Potency and Long-Lasting Duration of Action
To describe how the effect of BoNT/A persists for months after its single use, it is important to understand the structure and function of the different toxin protein subunits, which mediate its high affinity recognition of neuronal targets and its intracellular enzymatic activity targeting the synaptosomal-associated protein 25 (SNAP-25), a part of heterotrimeric soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complex (Section 2.1, Section 2.2 and Section 2.3). Apparently, the most important factor regulating the longevity of toxin action is the ability of BoNT/A protease to avoid cellular degradation mechanisms and survive in the cell cytoplasm for a long period (Section 2.4). In Table 1 we summed up the general factors affecting the BoNT/A potency and selectivity in relation to its pharmacological properties, as well as possible improvement of its use. Botulinum Toxin in Pain Management Essay

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