Treating benign prostatic hyperplasia with botulinum neurotoxin

Botulinum toxin (BoNT) has been increasingly used in the interventional treatment of several disorders; the use of this agent has extended to a plethora of conditions including focal dystonia, spasticity, inappropriate contraction in most gastrointestinal sphincters, eye movement disorders, hyperhidrosis, genitourinary disorders and aesthetically undesirable hyperfunctional facial lines. In addition, BoNT is being investigated for the control of pain, and for the management of tension or migraine headaches and myofascial pain syndrome. Benign prostatic hyperplasia (BPH) is a common condition in ageing men; the goal of therapy is to reduce the lower urinary tract symptoms (LUTS) associated with BPH and to improve the quality of life. However, medical treatment, including drugs that relax smooth muscle within the prostate and drugs that shrink the gland are not totally effective or without complications. The standard surgical treatment for BPH is progressively changing to minimally invasive therapies, but none of them has provided clear results. The use of BoNT-A to inhibit the autonomic efferent effects on prostate growth and contraction, and inhibit the abnormal afferent effects on prostate sensation, might be an alternative treatment for BPH. BoNT injections have several advantages over drugs and surgical therapies in the management of intractable or chronic disease; systemic pharmacologic effects are rare, permanent destruction of tissue does not occur, and graded degrees of relaxation may be achieved by varying the dose injected. In this paper, clinical experience over the last years with BoNT in BPH impaired patients will be illustrated.     

Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development

Botulinum neurotoxins (BoNTs) show increasing therapeutic applications ranging from treatment of locally paralyzed muscles to cosmetic benefits. At first, in the 1970s, BoNT was used for the treatment of strabismus, however, nowadays, BoNT has multiple medical applications including the treatment of muscle hyperactivity such as strabismus, dystonia, movement disorders, hemifacial spasm, essential tremor, tics, cervical dystonia, cerebral palsy, as well as secretory disorders (hyperhidrosis, sialorrhea) and pain syndromes such as chronic migraine. This review summarizes current knowledge related to engineering of botulinum toxins, with particular emphasis on their potential therapeutic applications for pain management and for retargeting to non-neuronal tissues. Advances in molecular biology have resulted in generating modified BoNTs with the potential to act in a variety of disorders, however, in addition to the modifications of well characterized toxinotypes, the diversity of the wild type BoNT toxinotypes or subtypes, provides the basis for innovative BoNT-based therapeutics and research tools. This expanding BoNT superfamily forms the foundation for new toxins candidates in a wider range of therapeutic options.     

Botulinum Toxin for Neuropathic Pain: A Review of the Literature

Botulinum neurotoxin (BoNT), derived from Clostridium botulinum, has been used therapeutically for focal dystonia, spasticity, and chronic migraine. Its spectrum as a potential treatment for neuropathic pain has grown. Recent opinions on the mechanism behind the antinociceptive effects of BoNT suggest that it inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. There is some evidence showing the axonal transport of BoNT, but it remains controversial. The aim of this review is to summarize the experimental and clinical evidence of the antinociceptive effects, mechanisms, and therapeutic applications of BoNT for neuropathic pain conditions, including postherpetic neuralgia, complex regional pain syndrome, and trigeminal neuralgia. The PubMed and OvidSP databases were searched from 1966 to May 2015. We assessed levels of evidence according to the American Academy of Neurology guidelines. Recent studies have suggested that BoNT injection is an effective treatment for postherpetic neuralgia and is likely efficient for trigeminal neuralgia and post-traumatic neuralgia. BoNT could also be effective as a treatment for diabetic neuropathy. It has not been proven to be an effective treatment for occipital neuralgia or complex regional pain syndrome.     

Treatment of Depression with Botulinum Toxin

Injection of botulinum toxin (BoNT) into the glabellar region of the face is a novel therapeutic approach in the treatment of depression. This treatment method has several advantages, including few side effects and a long-lasting, depot-like effect. Here we review the clinical and experimental evidence for the antidepressant effect of BoNT injections as well as the theoretical background and possible mechanisms of action. Moreover, we provide practical instructions for the safe and effective application of BoNT in the treatment of depression. Finally, we describe the current status of the clinical development of BoNT as an antidepressant and give an outlook on its potential future role in the management of mental disorders.     

Botulinum Toxin in the Treatment of Headache

Botulinum toxin type A has been used in the treatment of chronic migraine for over a decade and has become established as a well-tolerated option for the preventive therapy of chronic migraine. Ongoing research is gradually shedding light on its mechanism of action in migraine prevention. Given that its mechanism of action is quite different from that of the new monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) or its receptor, it is unlikely to be displaced to any major extent by them. Both will likely remain as important tools for patients with chronic migraine and the clinicians assisting them. New types of botulinum toxin selective for sensory pain neurons may well be discovered or produced by recombinant DNA techniques in the coming decade, and this may greatly enhance its therapeutic usefulness. This review summarizes the evolution of botulinum toxin use in headache management over the past several decades and its role in the preventive treatment of chronic migraine and other headache disorders.     

Opioids and the treatment of chronic pain: controversies, current status, and future directions

Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic noncancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainty about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice.     

Underutilisation of opioids in elderly patients with chronic pain: approaches to correcting the problem

The impact of poorly managed chronic pain on the quality of life of elderly patients and the problems related to its management are widely acknowledged. Underutilisation of opioids is a major component of poor pain management in this group of patients, despite good evidence for the effectiveness of opioids and published guidelines directing their usage. Reasons for this underutilisation are, among others, poor assessment of pain in this age group; fear of polypharmacy and opiophobia; and avoidance of opioids because of concerns about tolerance, physical dependence, addiction and adverse effects. This review suggests approaches to overcome these barriers to opioid usage, such as regular pain assessments, education to overcome opiophobia, rational prescribing, utilisation of less conventional opioids and non-oral routes of administration, avoidance of inappropriate opioids, opioid rotation, and education about managing or preventing adverse effects, the reasons why opioid therapy may be unsuccessful, and the effects of psychological factors on the pain experience. This more rational and knowledge-based approach to the use of opioids in the management of chronic pain in the elderly population should correct the current problems with underprescribing in this age group.     

Biological activity of plant extracts: novel analgesic drugs

The plant-derived secondary metabolites have, over the years, greatly contributed to our current understanding of the important mechanisms related to the process of pain transmission and treatment. Furthermore, they have permitted us to characterise receptor types and identify endogenous ligands involved in the mechanism of nociception. In this review, we discuss the recent advances that have occurred regarding plant-derived substances in the process of development of new analgesic drugs. Plants, such as Papaver somniferum, Cannabis sativa and those of the Capsicum and Salix species, have greatly accounted for the development of clinically relevant drugs which are useful for the management of pain disorders. The recent advances in our understanding of the mechanisms of action of the above plant-derived substances, together with use of molecular biology techniques, have greatly accelerated attempts to identify promising targets for the discovery of new, safe and efficient analgesic drugs. Despite the great progress which has occurred in the elucidation of pain transmission and despite decades of use, leaving aside its known undesirable sides effects, morphine continues to be one of the most used drugs in clinical practice for the treatment of pain disorders. Thus, safer and more efficacious analgesic drugs are urgently needed. A search through the literature reveals that many potentially active antinociceptive plant-derived compounds have been identified. However, studies aiming to investigate their cellular and molecular mechanisms of action and well-controlled clinical trials to prove their efficacy in humans are still lacking. Nevertheless, natural or synthetic substances that bind to vanilloid or cannabinoid receptors, or even those that are capable of modulating the endogenous ligands which bind to these receptors, are expected to soon appear to assist in the treatment of several pain disorders, including those of neuropathic or neurogenic origin.     

Botulinum Toxin Type A as a Therapeutic Agent against Headache and Related Disorders

Botulinum neurotoxin A (BoNT/A) is a toxin produced by the naturally-occurring Clostridium botulinum that causes botulism. The potential of BoNT/A as a useful medical intervention was discovered by scientists developing a vaccine to protect against botulism. They found that, when injected into a muscle, BoNT/A causes a flaccid paralysis. Following this discovery, BoNT/A has been used for many years in the treatment of conditions of pathological muscle hyperactivity, like dystonias and spasticities. In parallel, the toxin has become a “glamour” drug due to its power to ward off facial wrinkles, particularly frontal, due to the activity of the mimic muscles. After the discovery that the drug also appeared to have a preventive effect on headache, scientists spent many efforts to study the potentially-therapeutic action of BoNT/A against pain. BoNT/A is effective at reducing pain in a number of disease states, including cervical dystonia, neuropathic pain, lower back pain, spasticity, myofascial pain and bladder pain. In 2010, regulatory approval for the treatment of chronic migraine with BoNT/A was given, notwithstanding the fact that the mechanism of action is still not completely elucidated. In the present review, we summarize experimental evidence that may help to clarify the mechanisms of action of BoNT/A in relation to the alleviation of headache pain, with particular emphasis on preclinical studies, both in animals and humans. Moreover, we summarize the latest clinical trials that show evidence on headache conditions that may obtain benefits from therapy with BoNT/A.     

Antidepressants in chronic pain: a review of efficacy

Antidepressant drugs have gained widespread clinical usage alone or as adjuncts in the treatment of chronic pain disorders. Of 17 controlled studies of antidepressants in chronic pain, 13 demonstrated significant pain relief with antidepressants compared to placebo. These studies were too different from one another to allow any general conclusions concerning efficacy, however. Five studies of either migraine or chronic tension headache all demonstrated superior efficacy of antidepressants versus placebo, while those of back and arthritic pain yielded mixed results. Of 3 studies of pain of several etiologies, 2 failed to demonstrate efficacy of antidepressants over placebo. These studies do not provide answers to many clinical questions on the use of antidepressants for chronic pain, such as drug of choice or appropriate dosage. Rather, they suggest that these agents may be beneficial in some patients with chronic pain.     

Tramadol as an analgesic for mild to moderate cancer pain

In most cancer patients, pain is successfully treated with pharmacological measures such as opioid analgesics alone or opioid analgesics combined with adjuvant analgesics (co-analgesics). Opioids for mild-to-moderate pain (formerly called weak opioids) are usually recommended in the treatment of cancer pain of moderate intensity. There is a debate whether the second step of the WHO analgesic ladder, which, in Poland, is composed of opioids such as tramadol, codeine, dihydrocodeine (DHC), is still needed for cancer pain treatment. One of the most interesting and useful drugs in this group is tramadol. Its unique mechanism of action, analgesic efficacy and profile of adverse effects are responsible for its successful use in patients with different types of acute and chronic pain, including neuropathic pain. The aim of this article is to summarize the data regarding pharmacodynamics, pharmacokinetics, possible drug interactions, adverse effects, dosing guidelines, equipotency with other opioid analgesics and clinical studies comparing efficacy, adverse reactions and safety of tramadol to other opioids in cancer pain treatment.     

Multidimensional Effectiveness of Botulinum Toxin in Neuropathic Pain: A Systematic Review of Randomized Clinical Trials

Although botulinum toxin (BoNT) has been suggested as a treatment to counter neuropathic pain, no previous systematic reviews investigated the multidimensional effects of BoNT on pain relief and Health-Related Quality of Life (HR-QoL). The aim of this systematic review is to summarize the current evidence on the effectiveness of BoNT treatment for neuropathic pain, and to characterize its multidimensional effectiveness in order to guide physicians in clinical practice. Five databases were systematically searched up to 4 April 2022, to identify randomized controlled trials satisfying the following criteria: adults suffering from neuropathic pain, BoNT administration, any comparator, multidimensional assessment of pain as primary outcome, HR-QoL, physical function, anxiety and depression, and sleep quality as secondary outcomes. Twelve studies were included. The multidimensional pain scales used were short-form McGill Pain Questionnaire, Neuropathic pain scale, Neuropathic Pain Symptom Inventory, International SCI Pain Basic Data Set, West Haven-Yale Multidimensional Pain Inventory, Brief Pain Inventory, and Douleur Neuropathique 4. These scales highlighted the positive effects of BoNT administration. According to the Jadad scale, all the RCTs included were high-quality studies. BoNT administration might be effectively introduced in the comprehensive management of neuropathic pain. Further research should focus on optimal and cost-effective therapeutic protocols.     

Responsible prescribing of opioids for the management of chronic pain

The management of patients with chronic pain is a common clinical challenge. Indeed, chronic pain is often inadequately controlled in patients with cancer and in those with non-cancer chronic pain. Because of the complex nature of chronic pain, successful long-term treatment is more difficult than for acute pain. Most often acute pain is nociceptive, whereas chronic pain can be nociceptive (i.e., in response to noxious stimuli), neuropathic (i.e., initiated by a primary lesion or dysfunction in the nervous system) or mixed in origin. Opioids are the current standard of care for the treatment of moderate or severe nociceptive pain. Opioids mediate their actions by binding and activating receptors both in the peripheral nervous system and those that are found in inhibitory pain circuits that descend from the midbrain to the spinal cord dorsal horn. Opioid agonists exert a number of physiological responses including analgesia, which increases with increasing doses. The use of opioids to manage pain in patients with cancer is well accepted. The WHO step-wise algorithm for analgesic therapy based on pain severity reserves the use of opioid therapy for moderate and severe pain. The WHO algorithm has proven to be highly effective for the management of cancer pain. However, the use of opioids to treat patients with chronic non-cancer pain is controversial because of concerns about efficacy and safety, and the possibility of addiction or abuse. The results of clinical surveys and retrospective case series involving patients with non-cancer chronic pain have been inconsistent in regard to resolving these controversial issues. The oral route of drug administration is most appropriate for patients receiving opioids; although rectal, transdermal and parenteral routes of administration are used in specific situations. For continuous chronic pain, opioids should be administered around-the-clock and several long-acting formulations are available that require administration only once or twice daily. Opioid doses should be titrated according to agent-specific schedules to maximise pain relief and maintain tolerability. Adverse effects include constipation, nausea and vomiting, sedation, cognitive impairment and respiratory depression. Tolerance to the analgesic and adverse effects as well as physical dependence, which causes withdrawal symptoms upon discontinuance, may occur with opioid use. Estimates of addiction rates among patients with chronic non-cancer pain range from 3.2 to 18.9%. Successful pain treatment and symptom management is an attainable goal for the majority of patients with chronic pain. Further controlled clinical trials are needed to define the role of opioid therapy in chronic non-cancer pain, and to establish criteria for patient selection and specific treatment algorithms.     

Use of botulinum toxin A in adult neurological disorders: efficacy, tolerability and safety

The protein botulinum neurotoxin A (BoNT/A) is one of seven distinct neurotoxins produced by Clostridium botulinum. BoNT/A blocks cholinergic synapses with an extremely high specificity and potency. Appropriately purified and diluted, BoNT/A serves as a reliable and well tolerated drug that is applied by local injection.The efficacy of BoNT/A is evident in the symptomatic therapy of disorders in which muscular hyperactivity plays a prominent role, such as focal dystonias and hemifacial spasm; in these disorders, BoNT/A is considered first-line therapy. BoNT/A is also beneficial in the treatment of both adults and children with spasticity of various causes. The pain that frequently accompanies these conditions is effectively reduced by BoNT/A. A genuine analgesic effect for BoNT/A unrelated to skeletal muscle spasmolysis has been suggested on the basis of in vitro and in vivo (animal) data. However, studies in humans designed to detect such an effect were negative, as were controlled studies of BoNT/A in patients with primary headache disorders.BoNT/A also acts on cholinergic synapses of the autonomic nervous system, and injection of BoNT/A into salivary glands significantly decreases the production of saliva. This may be beneficial for patients with Parkinson's disease, in whom the excessive production of saliva may be problematic.Overall, BoNT/A has been confirmed as an efficacious, predictable and well tolerated drug in an ever-increasing number of neurological disorders.     

Botulinum toxin in the treatment of OAB, BPH, and IC

Botulinum neurotoxins (BoNTs) are well known for their ability to potently and selectively disrupt and modulate neurotransmission. BoNT is currently undergoing regulatory evaluation for urological disorders in the United States and the European Union and is not FDA approved for urologic use. Overactive bladder (OAB) and benign prostatic hyperplasia (BPH) are common urologic conditions characterized by urinary frequency, urgency, nocturia, urge incontinence and, in the case of BPH, decreased urine flow that are currently being evaluated in clinical trials with BoNT-A. Interstitial cystitis (IC) is a chronic condition in which patients describe urinary frequency, urgency and associated bladder/pelvic pain. In the two former conditions, BoNT-A is currently being evaluated in Phase II or Phase III clinical trials as a therapeutic agent. Evidence for BoNT in the treatment of IC is limited to small case series. The purpose of this article is to provide up to date clinical evidence regarding the use of BoNT to treat these three urologic problems. For the sake of clarity, BoNT-A describes the use of Botox^® unless otherwise specified. In addition, when describing OAB, two sub-populations exist: those with OAB of neurogenic origin (NDO) and those with OAB of unknown (idiopathic) origin (IDO).     

Chronic orofacial pain animal models - progress and challenges

ABSTRACT

Introduction: Chronic orofacial pain is one of the most common pain conditions experienced by adults. Animal models are often selected as the most useful scientific methodology to explore the pathophysiology of the disorders that cause this disabling pain to facilitate the development of new treatments. The creation of new models or the improvement of existing ones is essential for finding new ways to approach the complex neurobiology of this type of pain.

Areas covered: The authors describe and discuss a variety of animal models used in chronic orofacial pain (COFP). Furthermore, they examine in detail the mechanisms of action involved in orofacial neuropathic pain and orofacial inflammatory pain.

Expert opinion: The use of animal models has several advantages in chronic orofacial pain drug discovery. Choosing an animal model that most closely represents the human disease helps to increase the chances of finding effective new therapies and is key to the successful translation of preclinical research to clinical practice. Models using genetically modified animals seem promising but have not yet been fully developed for use in chronic orofacial pain research. Although animal models have provided significant advances in the pharmacological treatment of orofacial pain, several barriers still need to be overcome for better treatment options.     

Botulinum Toxin Type A for the Treatment of Neuropathic Pain in Neuro-Rehabilitation

Pain is a natural protective mechanism and has a warning function signaling imminent or actual tissue damage. Neuropathic pain (NP) results from a dysfunction and derangement in the transmission and signal processing along the nervous system and it is a recognized disease in itself. The prevalence of NP is estimated to be between 6.9% and 10% in the general population. This condition can complicate the recovery from stroke, multiple sclerosis, spinal cord lesions, and several neuropathies promoting persistent disability and poor quality of life. Subjects suffering from NP describe it as burning, itching, lancing, and numbness, but hyperalgesia and allodynia represent the most bothersome symptoms. The management of NP is a clinical challenge and several non-pharmacological and pharmacological interventions have been proposed with variable benefits. Botulinum toxin (BTX) as an adjunct to other interventions can be a useful therapeutic tool for the treatment of disabled people. Although BTX-A is predominantly used to reduce spasticity in a neuro-rehabilitation setting, it has been used in several painful conditions including disorders characterized by NP. The underlying pharmacological mechanisms that operate in reducing pain are still unclear and include blocking nociceptor transduction, the reduction of neurogenic inflammation by inhibiting neural substances and neurotransmitters, and the prevention of peripheral and central sensitization. Some neurological disorders requiring rehabilitative intervention can show neuropathic pain resistant to common analgesic treatment. This paper addresses the effect of BTX-A in treating NP that complicates frequent disorders of the central and peripheral nervous system such as spinal cord injury, post-stroke shoulder pain, and painful diabetic neuropathy, which are commonly managed in a rehabilitation setting. Furthermore, BTX-A has an effect in relief pain that may characterize less common neurological disorders including post-traumatic neuralgia, phantom limb, and complex regional pain syndrome with focal dystonia. The use of BTX-A could represent a novel therapeutic strategy in caring for neuropathic pain whenever common pharmacological tools have been ineffective. However, large and well-designed clinical trials are needed to recommend BTX-A use in the relief of neuropathic pain.     

The role of antipsychotics in the management of fibromyalgia

Fibromyalgia is a syndrome characterized by chronic generalized pain associated with different somatic symptoms, such as sleep disturbances, fatigue, stiffness, balance problems, hypersensitivity to physical and psychological environmental stimuli, depression and anxiety. It has been estimated to affect roughly the 2-4% of the general population in most countries studied, and it has been shown to be much more prevalent in women than in men. Although its pathophysiology is not yet fully understood, it is known that both genetic and environmental factors are involved in its development. Fibromyalgia shares a high degree of co-morbidity with other conditions, including chronic headache, temporomandibular disorder, irritable bowel syndrome, major depression, anxiety disorders and chronic fatigue syndrome. Therefore, this is a syndrome difficult to treat for which multimodal treatments including physical exercise, psychological therapies and pharmacological treatment are recommended. Although different kinds of drugs have been studied for the treatment of fibromyalgia, the most widely used drugs that have the higher degree of evidence for efficacy include the α(2)δ ligands pregabalin and gabapentin, and the tricyclic antidepressants (TCAs) and serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). However, there is a need to look for newer additional therapeutic pharmacological options for the treatment of this complex and disabling disease. First- and second-generation antipsychotics have shown analgesic properties both in an experimental setting and in humans, although most of the available evidence for the treatment of human pain concerns older antipsychotics and involves clinical trials performed several decades ago. In addition, several second-generation antipsychotics, risperidone, olanzapine and quetiapine, have shown efficacy in the treatment of some anxiety disorders. Some second-generation antipsychotics, mainly quetiapine, aripiprazole and amisulpride, have demonstrated antidepressant activity, with quetiapine approved for the treatment of bipolar depression and refractory major depression, and aripiprazole approved as an adjunctive treatment for major depressive disorder. Finally, several old and new antipsychotics, including promethazine, levopromazine, olanzapine, quetiapine and ziprasidone, have been shown to improve sleep parameters in healthy subjects. Each of these properties suggests that antipsychotics could represent a new potential alternative for the treatment of fibromyalgia syndrome. To date, most of the published studies on the use of antipsychotics in the treatment of fibromyalgia syndrome have been uncontrolled, either case reports or case series, dealing with olanzapine, quetiapine, ziprasidone, levopromazine and amisulpride. The studies on olanzapine and quetiapine have suggested therapeutic efficacy although, in the case of olanzapine, hampered by tolerability problems. A double-blind controlled trial, published in 1980, showed that chlorpromazine increased slow-wave sleep and improved pain and mood disturbances. More recently, four double-blind controlled studies have explored the efficacy of quetiapine, either alone or as an add-on treatment, in fibromyalgia management. None of these trials has yet been published, although two of them have been presented as congress communications, both of them suggesting that quetiapine could be a potential alternative treatment for fibromyalgia. In summary, the current available evidence suggests that at least some antipsychotics, specifically quetiapine, could be useful for the treatment of fibromyalgia and that further studies on the efficacy of these compounds are worth pursuing.