Botulinum Toxin & Pain Management Controversy Essay
Botulinum toxin is one of the most potent molecule known to mankind. A neurotoxin, with high affinity for cholinergic synapse, is effectively capable of inhibiting the release of acetylcholine. On the other hand, botulinum toxin is therapeutically used for several musculoskeletal disorders. Although most of the therapeutic effect of botulinum toxin is due to temporary skeletal muscle relaxation (mainly due to inhibition of the acetylcholine release), other effects on the nervous system are also investigated.Botulinum Toxin & Pain Management Controversy Essay One of the therapeutically investigated areas of the botulinum neurotoxin (BoNT) is the treatment of pain. At present, it is used for several chronic pain diseases, such as myofascial syndrome, headaches, arthritis, and neuropathic pain. Although the effect of botulinum toxin in pain is mainly due to its effect on cholinergic transmission in the somatic and autonomic nervous systems, research suggests that botulinum toxin can also provide benefits related to effects on cholinergic control of cholinergic nociceptive and antinociceptive systems. Furthermore, evidence suggests that botulinum toxin can also affect central nervous system (CNS). In summary, botulinum toxin holds great potential for pain treatments. It may be also useful for the pain treatments where other methods are ineffective with no side effect(s). Further studies will establish the exact analgesic mechanisms, efficacy, and complication of botulinum toxin in chronic pain disorders, and to some extent acute pain disorders.Botulinum Toxin & Pain Management Controversy Essay
Introduction
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 & Pain Management Controversy 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 & Pain Management Controversy 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).
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.Botulinum Toxin & Pain Management Controversy Essay
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.
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 & Pain Management Controversy Essay
INTRODUCTION
Thoracotomy involves high-intensity noxious stimuli due to extensive tissue damage and inflammation [1]. Difficult access to lung means that one or more ribs are subjected to resection and retraction with damage to intercostal muscles, nerves and costovertebral joints. Although the modern thoracic surgery relies extensively on ports for the thoracoscopic approach, these can still produce tissue damage and nerve damage. Pain from tissue injury is exacerbated by the dynamic motion of breathing after surgery and the presence of intercostal drains irritating the pleura. Bearing in mind that patients undergoing thoracotomy often have serious underlying pathology with limited pulmonary reserves, inadequate pain control can have serious consequences. Limited inspiration due to pain impairs the mechanics of ventilation resulting in pulmonary shunting and hypoxia [1]. Additionally, the inability to take a deep breath also causes ineffective coughing and retention of secretions. This leads to mucus retention, plugging, atelectasis and pneumonia [2]. Aside from respiratory complications, there is an increased risk of nosocomial infections, delayed recovery and discharge. Furthermore, there is emerging evidence that severe acute pain is associated with increased risk of PTPS [3]. The burden of PTPS is increasingly being recognised. In one study, 70% of patients required three or more treatment modalities, 50% were referred to three different specialties and none reported to be symptom free [4]. However, the advances of pain management in recent years have seen the introduction of newer agents that are aimed at novel targets along the nociceptive pathway. There has been relative success seen in other chronic pain conditions resulting in its introduction to thoracic surgery [5].Botulinum Toxin & Pain Management Controversy Essay
2. ACUTE PAIN
Despite years of advances in pain management, the mainstay of postoperative pain therapy in many settings is still opioids [6]. However, their use is limited by side effects. Nausea, constipation and sedation are common side effects that contribute to poor post-operative recovery. More importantly, opioid-induced respiratory depression exacerbates the problems of pulmonary complications following thoracotomy surgery. Hence, systemic opioids are best used as part of a multimodal analgesic strategy that includes regional local anaesthetic and non-opioid analgesia.
There are numerous multimodal analgesic techniques and regimens used in practice. Typically, regional analgesia is instituted pre or intraoperatively and continued postoperatively either as an infusion or patient controlled analgesia system delivered through a catheter placed in situ – in the thoracic epidural or paravertebral space [7]. Regular paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs), if not contraindicated, are initiated immediately after surgery. Patient controlled opioid administration can be used to supplement regional analgesia. For simplicity, a fixed epidural or paravertebral local anaesthetic infusion can be complemented by a patient controlled intravenous infusion of opioids that is limited by demand dose only for safety. This allows for a smooth transition to oral analgesia when demand dose requirements are reduced [7].Botulinum Toxin & Pain Management Controversy Essay
While the combination of local anaesthetic and opioid analgesia is generally effective, it is far from perfect. Issues of poor ipsilateral shoulder pain cover [8], variable success rates of regional techniques and side effects of systemic opioids have prompted the search for adjuncts to be included in the armamentarium. Numerous trials have been conducted for ketamine, gabapentinoids, dexmedetomidine, clonidine and magnesium. Results of these studies have generally been positive. A best evidence topic reviewing five clinical trials with 243 patients undergoing thoracic surgery found that adding ketamine to patient controlled morphine significantly reduced pain scores and opioid requirements on day 3-4 postoperatively with no hallucinations or psychological side effects [9]. Another best evidence topic looking at gabapentin found that multi-doses perioperatively was safe and beneficial in reducing acute pain [10]. However, the caveat for these studies is that they are often small and generally underpowered. More clinical trials are required for a meta-analysis in order to properly assess their efficacy and side effect profile in post-thoracotomy patients. Hence, the use of these agents is not as widespread and often limited to rescue analgesia when conventional strategies have failed.
3. CHRONIC PAIN/POST-THORACOTOMY PAIN SYNDROME (PTPS)
Patients are at risk of developing pain that persists beyond the initial recovery following thoracotomy. The International Association for the Study of Pain (IASP) defines it as ‘pain that recurs or persists along a thoracotomy scar at least 2 months following surgical procedure’ [1]. The reported incidence is between 20-60% [7], with most cases experiencing mild pain at 3 months, which eventually wears off [11]. However, for the minority with persistent pain, the effects can result in severe physical and functional impairment.
The underlying mechanism and transition to developing PTPS are not well understood. Factors related to patients, surgical approach, perioperative timing and psychosocial elements have been studied without any conclusive findings. This may be partly due to studies being heterogeneous and underpowered [12]. However, the role of intercostal nerve injury appears to be the most consistent factor in contributing to PTPS. This is further strengthened by the association of prolonged intercostal chest drain duration [13], again with the putative mechanism of intercostal nerve injury being the cause [14]. However, this is counteracted by the fact that video-assisted thoracoscopic procedures have not been shown to reduce the incidence of PTPS compared to thoracotomies, despite the former causing less trauma to nerves [1].Botulinum Toxin & Pain Management Controversy Essay
Neuropathic pain is defined as pain that results from injury or dysfunction to the somatosensory system [15]. The current understanding of neuropathic pain is an extension of Melzack and Wall’s ‘gate theory’, which involves spatial (peripheral and central pathways), chemical (inflammatory mediators and ion channels) and neuronal interactions (sensitisation, wind up and disinhibition) [16]. In thoracotomy, inflammation at nociceptive sites leads to electrical conduction along pain fibres to the spinal cord and higher cortical areas. Chronic pain develops when there is spontaneous firing of neurotransmission despite tissue healing and cessation of nociceptive input [17]. Damaged intercostal nerves become foci of ectopic discharges. Chemical mediators such as calcitonin gene related peptide and substance P are released during inflammation together with by-products such as prostaglandin, histamine and cytokines, which reduce the firing thresholds for ectopic discharges. Furthermore, there is upregulation of sodium, calcium and potassium channels at the site of injured nerves and dorsal root ganglion, which increases excitation in an established spontaneous conduction pathway [18]. At the spinal level, there is a complex interplay of excitatory neurotransmitters and intracellular signalling cascades which lead to ‘wind up’ – a phenomenon where C fibres are repetitively activated causing increased frequency and magnitude of dorsal root ganglion firing [19]. Finally, disinhibition occurs at both peripheral and central conduction points due to increased chloride ion conduction at nerve terminals [20], downregulation of opioid μ-receptors and apoptosis of inhibitory interneurons [16].
This model of understanding is helpful in that it provides a blueprint for targeting therapy, but it also partially explains why neuropathic pain is not straightforward to treat given its multi-level complexity. Not only is complete afferent impulse blockade difficult to achieve, but also ‘humoral blockade’ involving a myriad of inflammatory markers is challenging [1]. Nonetheless, this has engendered the emergence of adjunct therapies that target calcium channels, N-methyl-D-aspartate (NMDA) receptors and sodium receptors in the neuropathic pain pathway. While demonstrating relative benefit in other chronic pain conditions, these novel therapies have started to be employed in managing PTPS.