Sunday, 17 December 2017

Chronic Pain Drugs And Obesity - Seriously! Is That A Reason To Ban The Drugs?

Today's post from pulsetoday.co.uk (see link below) was sent in by Nigel, who's comment pretty much sums it up:- "It would seem that being in pain is OK...being fat is not. One would think that the clue is in the title 'chronic'." It's pretty typical of the sort of article that is swamping the medical internet at the moment. By jumping on the anti-opioid and strong painkiller bandwagon, people will find any reason they can to label those drugs as 'bad' at all costs. In this case, the claim is made that opioids and other drugs used to control chronic nerve pain, lead to obesity and general health deterioration - as if obesity is worse than the chronic pain that people need these drugs for (nobody is suggesting that obesity isn't a problem here)! Meanwhile, drink yourself into an early grave - nobody cares as long as opioids are banned! That all said, nobody disputes the fact that the side effects of strong analgesics should never be under-estimated; that's why your doctor should be monitoring you every step of the way, in order to avoid side effects before they happen and when necessary, switch medications to avoid addiction but that is not banning them!! This article advises using opioids and others for a short period of time - okay...and what then!! Why do these people think that neuropathy patients end up on the strongest pain killers! It's not through some perverse desire to become addicted, or 'enjoy' potential side effects - it's because they've already tried everything else available and find that nothing else works to dampen their nerve pain. There is no alternative for many people, so what's happening in America and eventually in the rest of the world, means that taking these drugs away because of some hysterically political media campaign, leaves chronic pain patients suffering like never before.  The problems with opioids and other strong drugs are social and require a multi-disciplinary but caring approach - banning them just drives people onto the black market and heroine and the like - is that the result they want? I'm sorry but suggesting that strong analgesics should be banned because they make people fat, is plain nonsense and they spent your taxes on this sort of non-research!


Prescribe chronic pain medications for shorter periods of time, researchers advise
11 December 2017 By Melissa Jacobs

Commonly used analgesic drugs significantly impair cardio-metabolic health and obesity and should be used for shorter periods of time, a Newcastle University study has found.

The research, published in PLOS ONE found that gabapentinoids and opiates doubled the risk of obesity and were associated with increased rates of hypertension and poor sleep.

Scientists assessed the cardio-metabolic (CM) health and sleep patterns of more than 133,000 participants from the UK Biobank.

Body Mass Index, waist circumference and blood pressure were compared between those taking painkillers for chronic, non-cancer pain and cardio-metabolic drugs, compared to those prescribed cardio-metabolic treatment only.

After controlling for the factors which impact upon CM health, the odds of being obese, having a ‘very high risk’ waist measurement and hypertension were significantly increased in those on analgesic medication.

Patients on opiates and cardio-metabolic drugs had the worst CM profile, and were 95% more likely to be obese, 82% more likely to have a 'very high risk’ waist circumference and 63% more likely to have hypertension, as compared to those on cardio-metabolic drugs only.

Those taking neuropathic pain medications and CM drugs also reported a worse CM profile than those taking CM drugs only.

The proportion of patients sleeping less than six hours or more than nine hours a night was higher in the analgesic groups, with those taking combination prescriptions of both neuropathic pain medication and opiates showing the worst sleep.

Dr Sophie Cassidy, lead author and research associate at Newcastle University’s institute of cellular medicine, noted the large increase in opioid and non-opioid prescriptions for pain in last two decades. She said: ‘This is the largest study looking at the links between commonly prescribed painkillers and cardio-metabolic health.

‘We already know that opiates are dependency-forming but this study also found patients taking opiates have the worst health.

‘These results add further weight to calls for these chronic pain medications to be prescribed for shorter periods.’

Study co-author, Dr Kirstie Anderson, honorary senior lecturer at Newcastle University and consultant neurologist at Newcastle Hospitals NHS Foundation Trust, added: ‘There has been recent concern about opioids and a large number of side-effects, including worsening overnight breathing and therefore disturbed sleep.

‘Our study is the largest of its kind to look at this group of drugs and show an association between obesity and poor sleep.

‘Further studies are needed to understand how the drugs may affect metabolism over time.’

This comes as the government is consulting on its plan to reclassify the gabapentinoids as controlled Class C drugs, following a spike in the number of related deaths and series of studies warning about the adverse effects of the medication.

http://www.pulsetoday.co.uk/clinical/prescribing/prescribe-chronic-pain-medications-for-shorter-periods-of-time-researchers-advise/20035813.article

Saturday, 16 December 2017

The Future Of Pain Treatment

Today's post from link.springer.com (see link below) is an article neuropathy patients need but may not want to read. It's an up to date overview of the thinking behind current drug treatment and pain control and is written for and from the point of view of doctors and pharmaceutical companies looking for new and much more efficient methods of treatment for chronic pain. Where does that leave the patient? Well, pretty far behind I'm afraid. This is the science of pain, not how it feels for the sufferers. Nevertheless, it's vital information that we as patients need to know because then we can feel more involved in the process (even if that's not really practical). The problem here is that the article requires concentration (and possibly a medical dictionary) and a willingness to investigate what's being said. Quite rightly and understandably, the average nerve pain patient is already burdened with daily pain and may not have the energy to plough through articles like this to find out what's being done on their behalf. Give it a go though - you'll be surprised how much you learn about how your pain works and how they're trying new methods to tackle it.


Hopes for the Future of Pain Control
December 2017, Volume 6, Issue 2, pp 117–128 | 
 Kirsty Bannister
Mateusz Kucharczyk
Anthony H. DickensonEmail author


Kirsty Bannister
1
Mateusz Kucharczyk
1
Anthony H. Dickenson
1 Email author
1.Department of Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUK

Open Access Review

First Online: 23 May 2017
 
Abstract


Here we aim to present an accessible review of the pharmacological targets for pain management, and succinctly discuss the newest trends in pain therapy. A key task for current pain pharmacotherapy is the identification of receptors and channels orchestrating nociception. Notwithstanding peripheral alterations in the receptors and channels following pathophysiological events, the modulatory mechanisms in the central nervous system are also fundamental to the regulation of pain perception. Bridging preclinical and clinical studies of peripheral and central components of pain modulation, we present the different types of pain and relate these to pharmacological interventions. We firstly highlight the roles of several peripheral nociceptors, such as NGF, CGRP, sodium channels, and TRP-family channels that may become novel targets for therapies. In the central nervous system, the roles of calcium channels and gabapentinoids as well as NMDA receptors in generating excitability are covered including ideas on central sensitization. We then turn to central modulatory systems and discuss opioids and monoamines. We aim to explain the importance of central sensitization and the dialogue of the spinal circuits with the brain descending modulatory controls before discussing a mechanism-based effectiveness of antidepressants in pain therapy and their potential to modulate the descending controls. Emphasizing the roles of conditioned pain modulation and its animal’s equivalent, diffuse noxious inhibitory controls, we discuss these unique descending modulations as a potential tool for understanding mechanisms in patients suffering from pain. Mechanism-based therapy is the key to picking the correct treatments and recent clinical studies using sensory symptoms of patients as surrogates for underlying mechanisms can be used to subgroup patients and reveal actions of drugs that may be lost when studying heterogenous groups of patients. Key advances in the understanding of basic pain principles will impact our thinking about therapy targets. The complexity of pain syndromes will require tailored pharmacological drugs, often in combination or through drugs with more than one action, and often psychotherapy, to fully control pain.

Keywords

Analgesia Anti-depressants Central sensitization Descending controls Pain mechanisms Pregabalin

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Overview of Pain Processing


Organisms need to process incoming sensory information and then respond to the external world. Consequently, pain alters and overlaps with other CNS functions such as those concerned with mood and responses to the outside world. All organisms need to sense their environment and so our peripheral pain receptors evolved from sensors seen in primitive creatures. Organisms need to learn about sensory stimuli and so centrally, the ability of spinal neurones to become sensitized by repeated stimuli is believed to be a part of associative learning. Thus, the ancient origins of pain and its widespread effects on CNS processes are responsible for the challenges of controlling pain and the misery it brings.

The future of pain control will involve novel agents and a better use of existing therapies, including steps towards predicting patient responses based on improving our knowledge of pain and its modulation. We are off to a solid start in terms of success in dealing with the challenges since translation from basic science to patients, and vice versa, are becoming more prevalent and connected. Parallel rodent neuronal and human psychophysical studies can inform on peripheral and central mechanisms in experimental pain and so drug development will find an easier and more predictive transition from experimental drugs to phase I studies [49, 61]. Differentiation of the modulation of on-going and evoked pains in rodent models [33] has been achieved and this separation has a bearing on responses to analgesics in neuropathic patients [18]. In this account, we highlight how anti-NGF and anti-CGRP antibodies are reaching the patient, the effect of tapentadol and the rationale for selective sodium channel blockers, which are currently being tested in patients [71].

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Different Types of Pain

A key issue is defining the receptors and channels involved in pain transmission and modulation, both of which change following pathophysiological events, such as those that occur in patients with neuropathic and/or inflammatory pain. Low back pain and cancer pain can be a combination of the two, and are thus mixed pains. Indeed, there are about 40% of cancer patients with neuropathic pains and similar numbers with neuropathic elements to low back pain; the neuropathic components in pain states can be teased out by questionnaires and assessment of the sensory symptoms [13]. This is an important issue since treatments aimed at the peripheral pain mechanisms have to distinguish these two main types of pain. Pain from tissue damage (inflammatory pains) will respond to the NSAIDs and steroids, whereas neuropathic pain (resulting from a lesion or disease of sensory nerves) will respond to drugs that target the altered ion channels within the nerves. Thus, peripherally targeted treatments must reflect the type of pain mechanism.

We have managed to characterize many of the pain sensors in the body. Nociceptors have a polymodal nature so heat and cold sensors have been found as well as a large number of receptors that respond to chemical stimuli. A family of particular sodium channels, some selective to pain signaling, have been isolated [29]. The peripheral mechanisms of the broad types of pain are very different and so treatments are linked to the pain type. Examples would be the use of the NSAIDs and steroids for the aforementioned inflammatory pains, but the need for drugs acting on ion channels for neuropathic pains where the lesion or disease of a nerve leads to disordered electrical events. However, on arrival within the central nervous system, the signaling and controlling systems appear to use common mechanisms, so that opioids, ketamine, and agents acting on the monoamine systems have broader spectrums of activity. Furthermore, the underlying mechanisms of some manifestations of pain are more likely to be central than peripheral, and here both fibromyalgia and irritable bowel syndrome are best explained by problems with brain control systems [53, 55]. The periphery provides the basic information but each patient builds up their own pain experience based on context, memory, emotions, and social/other issues. The outcome is subject to the incoming pain messages being modified and altered by the CNS, both up and down. Thus, we should never be surprised by any disconnect between the extent of peripheral damage and the pain score.


Peripheral Events that Generate Nociceptive Pain

Many pains start in the periphery where pain sensors are likely to be continually activated when tissue is damaged. Chemicals are released including the prostanoids, bradykinin, CGRP, and ATP, as well as many chemokines. The problem is that, at present, only steroids and cyclooxygenase inhibitors are able to modulate these events with a ceiling on efficacy since they will only modulate some of the chemical mediators. Hopes for drugs that block the receptors for ATP are high, and here the P2X3 receptor is a key target [9]. NGF is a key target for inflammatory pains but there were problems with initial therapies and their side effects.

Anti-NGF Therapies

NGF is a key molecule for the sensitization of primary afferent nociceptors associated with tissue inflammation. It acts via neurotrophic tyrosine kinase receptor A (TrkA), as well as via p75 neurotrophin receptor (p75NTR) and levels of NGF increase in inflamed tissue. The molecule has a number of direct and indirect (through Mast cells and autonomic actions) effects to enhance pain signaling. Preclinical data revealed that neutralization of endogenous NGF prevents inflammatory hyperalgesia [35, 45, 56, 60]. NGF causes acute pain in humans but the NGF-TrkA complexes are also retrogradely transported by sensory fibers to the cell bodies, resulting in a number of genomic actions that increase the sensitivity of pain fibers. In addition to increased ion channel functions, it causes the release of substance P and CGRP at both peripheral and central levels, and therefore contributing to sensitization [60]. Hence, several studies illustrated the importance of NGF and/or CGRP sequestration strategies in the variety of pain states where tissue is damaged.

Among several agents developed to counteract the NGF-mediated sensitization, particular attention should be drawn to monoclonal antibodies like tanezumab, fulranumab, and fasinumab. Several clinical trials revealed a long-lasting (several weeks after a single injection) pronounced efficacy of tanezumab in the management of osteoarthritic, chronic low back, diabetic peripheral neuropathic, and cancer-induced bone pains [32, 39, 62].

The major obstacle linked to the use of anti-NGF antibodies that arose from clinical trials was their osteonecrotic activity, often leading to premature joint replacement. Recent trials have adjusted the dose of tanezumab used, and identified an interaction with other pharmacotherapies often used to manage inflammatory conditions. Tanezumab monotherapy does not elevate the risk of total joint replacements, however if coadministered with NSAIDs, the risk is notably manifested [59]. Also, there was a minimal incremental benefit of high doses of tanezumab high (10–20 mg) versus low (2–5 mg) doses, further restricting side effects [12, 24]. Finally, anti-NGF antibodies do not appear to have cardiovascular or gastrointestinal safety liabilities of NSAIDs, as well as undesirable effects of centrally acting analgesics such as opioids. 


Anti-CGRP Agents in Headache

CGRP is a peptide found in many C-fibers and released at both their central and peripheral terminals. The latter action is a key event in the production of migraine where the peptide is likely to have both pain generating and vascular actions in dura and scalp [27]. Antibodies to CGRP have been developed and been proven effective, and it is hoped that these agents will become alternatives to the triptans [46]. In general, monoclonal antibodies are target-specific, which limits off-target toxicities common to most small molecules. Their actions are prolonged, which leads to less frequent dosing of about once a month or less. Their long half-life may lead to these molecules being used for migraine prevention and CGRP attenuation has potential use in other inflammatory pain conditions.

Peripheral Events that Generate Neuropathic Pain


Ion Channels

Critical changes in ion channels, in particular sodium channels, arise after nerve injury, thought to produce abnormal peripheral transmission to the spinal cord and we have proof of concept since mutations in some of these peripheral sensors and channels cause human familial pain disorders [19]. The description of certain sodium channels, namely Nav 1.7 and 1.8, which are preferentially found in small fibers, lead to the possibility that their blockers could be novel analgesics with pain-selective actions, unlike present drugs such as lidocaine, which also blocks large fibers. Indeed, there are a number of gain-of-function of 1.7 mutations that lead to pain in the absence of injury and a loss of function mutation that renders the subjects analgesic [10, 20]. This proof of concept supports the idea that selective pain-related sodium channel blockers could become orally effective local anesthetic-like drugs [43] since their selective roles in pain would not require local administration and clinical studies with NaV1.7 blockers are on-going [71].

These drugs could have broad efficacy that includes inflammatory pains, where peripheral sensitization will also lead to altered action potential transmission. At present, we have drugs such as carbamazepine that work to subdue abnormal sodium channel function. Potassium channels provide another interesting target since these inhibitory channels are down-regulated after nerve injury, but at present we lack drugs that act to open them [66]. Further, new analgesics could include drugs that target our sensors for heat, cold, and irritants such as the TRP family of channels. These are already pain-control targets since capsaicin is an agonist at TRPV1. A low dose desensitizes the channel whilst a high dose activates—it is the human heat pain sensor—but then causes the fine pain fibers to pull back from the area of application, producing prolonged pain relief [48]. TRPM8 is our cold sensor, responding to menthol and this channel could be a useful target in patients with cold hypersensitivity such as those receiving cancer chemotherapy [25, 51]. TRPA1 is an irritant sensor and a gain-of-function mutation leads to a pain syndrome in humans, validating the channel as a target [37]. 


Botulinum Toxin

Botulinum toxin has been used to control pain in migraine and in patients with peripheral neuropathy. As a paralytic agent, the drug blocks transmitter release at the neuromuscular junction, but this action can be harnessed to control pain. In headache, the local administration to sensory nerve terminals is thought to block the release of CGRP as well as the insertion of certain pain sensors into the membrane of the nociceptors [52]. In neuropathy, the authors concluded that the toxin may be transported to the central terminals of the pain fibers where it could block central transmitter release [2].

Spinal Cord Mechanisms of Pain

Whatever the cause of pain in the body, the next key stage in communication between peripheral nerves and CNS neurones is the release of transmitter into the spinal cord. Calcium channels are required for transmitter release and so control neuronal activity of spinal neurones. Calcium channel levels and function are altered in different pain states. In particular, in both inflammatory and neuropathic pains, there are increases in their function, and in the latter the alpha-2 delta subunit is highly upregulated [15, 50]. This is the target for the drugs gabapentin and pregabalin, which appear to prevent the correct movement of the channels to the membrane [7], and so act to alter transmitter release through mechanisms brought into play by pathophysiological events. These drugs are active in certain physiopathological states (which may be generated peripherally by neuropathic mechanisms or intense stimuli), but also in disorders of central processing such as fibromyalgia, where they alter glutamate signaling in the brain [30]. Both preclinically and also in patients, the alpha-2 delta ligands appear to act preferentially on evoked hypersensitivities and not on-going pain, forming a basis for differentiation of patients who might respond to them [50].

Central Sensitization


In the spinal cord, activation of the N-methyl-d-aspartate (NMDA) receptor is produced by the repeated release of peptides and glutamate from peripheral nerves. These actions of glutamate at the NMDA receptor in persistent pain states, acting alongside other systems, produce hypersensitivity of spinal sensory neurones. Consequences of this are wind-up, long-term potentiation (LTP) and central sensitization. This leads to both an increase in the pain sensation and the receptive field size of the spinal neurones [21]. This spinal hypersensitivity is the most plausible explanation for allodynias since the deep dorsal horn neurones subject to wind-up receive both low and high threshold inputs. The NMDA receptor is a key target for controlling pain. Ketamine blocks the NMDA receptor complex at sub-anesthetic doses but with side effects, and there is a potential for drugs with better profiles through NMDA receptor sub-type selective agents. The other receptors for glutamate are unlikely to be viable targets since glutamate is the main CNS excitatory transmitter. Tissue and nerve trauma causes abnormal impulse propagation towards the spinal cord and marked changes in calcium channels causing them to release more transmitter, thereby favoring central spinal hypersensitivity. Here, the relation between the extent of peripheral activity and central consequences diverge and shift towards central hypersensitivity. It has been difficult to directly modulate central sensitization, but certain drugs can be useful: directly as with ketamine, and indirectly as with opioids and gabapentinoids [58, 67]. Central sensitization has been observed in many patient groups, ranging from neuropathy to osteoarthritis including fibromyalgia [54]. Given that the originating events in these very different pains can be clearly peripheral or more likely central, such as in fibromyalgia, it becomes clear that altered processing and sensitization can be observed at many CNS sites. 


Altered Pain Transmission in the Brain

Increased activity within spinal circuits produced by peripheral activity, whether arising from tissue or nerve damage, is the rationale for the use of regional blocks since in most cases, the spinal events are driven by peripheral inputs. Increased spinal neuronal activity will in turn trigger ascending activity to the brain. There are two parallel pathways; firstly, ascending activity to the thalamus and the cortex, the sensory components of pain, allow us to locate and describe the intensity of the pain. Equally important are the pathways to the midbrain and brainstem, where the activity contacts and disrupts the limbic brain, areas such as the amygdala, and generates the common comorbidities that follow pain such as depression, fear, sleep problems, and anxiety. The brain processes and signals, in a dynamic fashion, the sensory and affective components of pain as well as the salience and aversive aspects of pain through connections between various areas that include insula, prefrontal and cingulate cortices, as well as the somatosensory cortex [38]. The ascending pain messages from the cord that input these various brain regions also contact descending control pathways that run from the brainstem back to the spinal cord. These monoamine and opioid projections can be inhibitory or excitatory, so that cognitive and emotional events are able to switch pain on or off. 


Central Inhibitory Mechanisms

Blocking the generation of excitability is one approach, and this can be achieved by targeting the periphery or the spinal cord, but increasing inhibitions may also provide control of pain. Opioids work at spinal levels by pre- and post-synaptic mechanisms and the spinal application of morphine in animals rapidly lead to the human epidural route in patients. Systemic opioids both increase descending inhibitions and reduce descending facilitations by CNS actions. All of these mechanisms are altered as pain shifts from acute to chronic. Opioids can be useful in pain control, although this is less clear for chronic non-malignant pain where there are issues with side effects, abuse potential, and overdose risk from the opioid load and potential paradoxical hyperalgesia as the inhibited spinal neuronal systems compensate [64]. An advance has been tapentadol, which is a mu opioid with noradrenaline reuptake inhibition, a dual-action molecule, with key spinal actions [8]. The latter action targets and enhances descending inhibitions and so opioid side effects are reduced. All presently used opioids act at the mu opioid receptor but can differ in potency, pharmacokinetics, and route of administration. Recently, after many decades of attempts to produce drugs acting on the other opioid receptors, agonists at the NOP receptor have gone into patients [42].

A severe loss of spinal GABA-mediated inhibitions is reported within the spinal cord after peripheral nerve injury, which compound the gain of excitation. The widespread nature of the roles of GABA in the brain means that therapies aimed at restoring its normal inhibitions are not currently feasible. Altering the function of the chloride channel that GABA operates is being attempted [22]. 


Pathways from the Brain to the Spinal Cord that Alter Pain

Abnormal signaling from the spinal cord alters pain processing in the brain. Pathways from the brain can in turn alter spinal sensory processing [4]. These projections originate from the midbrain and brainstem in predominantly monoamine systems (noradrenaline and 5HT). The actions of anti-depressant drugs in pain therefore link to these systems. These pharmacological circuits also play major roles in the generation and control of emotions such as mood, fear, and anxiety as well as in thermoregulation and the sleep cycle. Pain inputs into these areas will alter descending controls and also form a basis for pain-induced co-morbidities. Early work in this field focused on descending inhibitions, which are now known to be predominantly noradrenergic acting through the alpha-2 adrenoceptor [31]. A recruitment of descending inhibitions underlies placebo analgesia and a failure of descending inhibitions has been reported in many patient groups with diverse types of pain [68]. However, pain could equally be increased by enhanced descending facilitations through the 5HT3 receptor [57, 65]. These excitatory influences from the brain will act to favor the development and maintenance of central sensitization in the spinal cord [14]. Part of the substrates for these bidirectional controls are ON and OFF cells found in brainstem nuclei [26]. There appear to be altered descending excitatory controls in patients with severe pain from osteoarthritis [28]. In animals, there is a loss of descending noradrenaline controls after nerve injury and correspondingly, animals with nerve injury that have activated their descending inhibitory noradrenergic systems are protected against the pain and recovery from surgical pain is enhanced when the same systems operate [17].

In general, painful inputs into the limbic brain and the resultant descending controls link emotional states and the levels of pain perceived, and could be one of the ways by which higher functions such as coping and catastrophizing can modulate sensory components of pain at the level of the first relays in the spinal cord. The levels of midbrain-generated modulation, both positive and negative, may be a key factor in individual variations in pain, the potential target for non-pharmacological therapies and contribute to some “dysfunctional” pain states such as fibromyalgia. Here, a “normal” peripheral input could be enhanced if the descending systems are abnormal and so enhance excitability of the spinal cord through central events [53, 63]. Diffuse pains may have their origins in disordered central pain modulation. Animal studies reveal that altered descending controls are important in the maintenance of persistent inflammatory and neuropathic pains [4]. 


Gauging Descending Inhibitions in Patients

The balance shifts towards descending facilitation in persistent pains and importantly the extent of loss of descending inhibitions in patients can be gauged. The finding that one pain could inhibit another through descending controls formed the basis for diffuse noxious inhibitory controls (DNIC) [41] and its human counterpart, conditioned pain modulation (CPM) [68], a descending inhibition that is lost in patients with brainstem lesions and spinal sections [11].

Recent studies reveal that DNIC use a descending noradrenaline and alpha-2 adrenoceptor-mediated pathway from the brain to the spinal cord [5]. Sham surgery produces no change in DNIC and no pain phenotype corresponding to reduced CPM being a risk factor for persistent pain after surgery [69]. After peripheral neuropathy, DNIC is lost, yet can be restored by drugs that enhance noradrenalin levels and also by blocking the 5HT3-mediated descending facilitations [5]. In patients, reduced CPM is seen in many pain states, including neuropathy, osteoarthritis, headache, CRPS, fibromyalgia, and others [1, 40, 70]. CPM can be quantified by one pain versus another, often heat versus cold but as with DNIC, the modality of the conditioning stimulus only has to be noxious and the wide dynamic range of the neurones in animals subject to DNIC means that the conditioned response can be noxious or innocuous [36]. Importantly, CPM can be restored in patients with peripheral neuropathic pain by the MOR-NRI drug tapentadol and a reduced CPM is predictive of efficacy of the SNRI duloxetine, suggestive of a loss of key noradrenaline signaling in patients akin to that seen with DNIC in animals [44, 70]. Both DNIC and CPM are dynamic—CPM can be present early in a pain condition but lost later such as with CRPS and alters over the course of headaches [47]. 


On-Going and Evoked Pains

CPM allows for the quantification of descending inhibitions and so is a key step towards precision medicine. An overwhelming question is whether it is the spontaneous or the stimulus-evoked component of pain that is the greater problem for patients who are simply asked to rate their pain on a VAS score. Differentiating the two pain events, for example neuropathic spontaneous pain and inflammatory tonic pain from evoked, particularly mechanical hypersensitivity, is an on-going research goal both pre-clinically and clinically. Despite its terminology, spontaneous pain not only refers to the intrinsic firing of neurons active in pain-signaling pathways, but may rather—in the case of neuropathy for example—refer to deafferentation-induced spontaneous discharge in CNS neurons. The sensitization of such pain signaling neurons may then be responsible for on-going chronic pain. Stimulus-evoked hypersensitivity meanwhile refers to an enhanced neuronal, and therefore pain, response to an innocuous or noxious insult at the periphery.

The presence of spontaneous pain is a common complaint amongst chronic pain patients, for example those with a neuropathy [3]. An increased sensitivity to evoked stimuli is also present in such patients. Importantly, hyperalgesia can be pharmacologically treated in the absence of the relief of on-going pain [23] and so it is likely that the underlying mechanisms governing on-going versus evoked pain are distinct and thus should be treated clinically as separate components of the pain state. It is well accepted that translating mechanisms in animal models can guide potential treatments in the patient domain. While detecting and mechanistically evaluating spontaneous pain pre-clinically was viewed as a complicated task, an insightful study by Frank Porreca and colleagues used conditioned place preference (CPP) to not only detect tonic pain in neuropathic rats but also to determine the efficacy of specific analgesic relief [34]. Their study provided evidence for a tonic pain state in animals that had undergone spinal nerve ligation (SNL) surgery, while the presence of a spinal cord lesion similarly coincides with the expression of spontaneous pain, with CPP this time revealing that clonidine or motor cortex stimulation was able to unmask a tonic aversive state [16]. Further studies reveal that certain brain areas such as the anterior cingulate cortex may contribute more to the longing aversive state rather than modulating evoked responses and importantly such studies impact the assessment of analgesic therapeutic potential on these different responses [33].

Targeting Pain Mechanisms in Patients


Whilst awaiting new agents, our understanding of mechanisms for pain and its treatments allows for a rationale for all approaches to pain control. These could range from regional blocks to restoration of normal central modulation with drugs to cognitive behavioral approaches. Indeed, even the descending controls, embedded deep in the brain, are altered by peripheral inputs and so could be altered by peripheral and spinal interventions.

But who will respond to each particular treatment? NNTs for many pain drugs are quite high but trials have been based on etiology and so presume homogeneity, whereas the patients may have differing mechanisms and sensory profiles. Mechanism-based therapy is a laudable concept but unlikely to be helpful since how could mechanisms be identified in most patients? A brilliant variant on this would be to use the sensory phenotype of the patient as a surrogate reflection of underlying pain mechanisms. Using the sodium channel blocker oxcarbazepine, it was revealed that those patients with “irritable nociceptors”, i.e., having evoked hypersensitivity rather than on-going pain, responded to the drug, an effect that was lost in the whole group analysis [18]. Subtypes of patients with neuropathic pain, fibromyalgia and post-surgical pain can be formally distinguished. Analysis of patients with neuropathic pain has revealed three clusters of patients: Cluster 1—those with sensory loss; Cluster 2—those with thermal hyperalgesia; Cluster 3—those with mechanical hyperalgesia. In the near future, we will know if these subtypes have differential responses to different drugs if stratified trials can be conducted, but there are already hints of differential sensitivities to treatments. Cluster 1 patients responded to oral opioids and not well to Na channel block, whereas Cluster 2 patients did respond to this drug and also to BoTox. Cluster 3 had greater efficacy of pregabalin and topical or IV lidocaine [6]. There is also the use of CPM, as discussed previously, to inform on impaired descending inhibitions and so predict responders to SNRIs and sensitivity to tapentadol. Other studies, at present limited to neuropathic pain, reveal heterogeneous responses to drugs in different subgroups of patients [13], and this needs to be extended to nociceptive pain patients and those with fibromyalgia.

There is considerable hope for the future. However, the use of both CPM and/or quantitative sensory testing are not appropriate for routine clinical practice, so if there is a relation between particular sensory profiles of patients and particular pharmacological agents, simple tests could be developed. Patients should be able to distinguish on-going from evoked pains during the taking of a history and could be asked if their pains were predominantly thermal or mechanically evoked, so delineating the clusters described above [6]. Maybe patients could be asked if one pain could inhibit their pain—bite your thumb? This could represent a simple test of CPM.

We have a lot further to go but the union of informed and thoughtful preclinical science and clinical medicine will lead us onwards.

Notes

Acknowledgements


This work was funded by the Wellcome Trust Pain Consortium and Bonepain (European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No. 642720). No funding was received for the publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Disclosures


Kirsty Bannister and Mateusz Kucharczyk have nothing to disclose. Anthony H. Dickenson has been a speaker for Allergan, Grunenthal, and Teva.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Open Access


This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

For references go to original article at the link below:-


https://link.springer.com/article/10.1007/s40122-017-0073-6

Friday, 15 December 2017

Should Nerve Damage Patients Buy Into The Gluten-Free Hype?

Today's post from minnesotamonthly.com (see link below) asks the question: should we as neuropathy patients, buy into the current craze for gluten free diets? It's known that gluten can affect our nerves and maybe even damage them - good heavens, via celiac disease, it could already be the cause of the neuropathy we have now but how much basis of truth is there in the hype? This article doesn't really answer the question, preferring to concentrate on the 'fashionable'/'fad' aspect of gluten-free eating but neuropathy patients have been advised for years to at least try a gluten free diet, to try to reduce the possibility of celiac disease that can cause nerve damage. It is of course, easier said than done! Eliminating gluten from our diet can be a tortuous prospect but there are enough neuropathy witnesses who swear by the improvement they've felt since eliminating gluten. Read the article:- it won't give you the answer you're looking for but it will increase your understanding of the whole issue. From then on, further research and talks with your doctor will help in decision making.


The Gluten-Free Craze: Should You Join In?
By Rachel Fergus Published: December 2017

A look at the gluten-free trend popping up in new restaurants across the Twin Cities

 It seems like there is a new food fad every few decades: TV dinners, space-age snacks, and the recent cupcake craze that has resulted in an explosion of television shows and bakeries devoted to the cake-for-one dessert. But among all these culinary trends, the popularity of gluten-free (GF) foods has perhaps felt most omnipresent—accommodating a diet taken by many whose celiac disease or wheat allergy makes gluten, a protein found in wheat grains, damaging to their small intestine.


There’s GF everything now: bread, pizza, cookies, pasta, donuts, bagels, even much-loved cupcakes. The GF industry made $3.5 billion in global sales in 2016 alone, according to the U.S. Library of Medicine.


A quick search of GF options in the Twin Cities makes it clear it’s highly accessible here, too. If you walk into a restaurant that opened this year, chances are there will be GF meals or substitutions on the menu. In fact, only one out of the 42 new restaurants that I contacted, Cardigan Donuts, doesn’t have anything GF because, well, it’s a donut shop that specializes in wheat-filled donuts.


Offering GF food is clearly on trend here, but there is a big difference between offering GF food and offering celiac-friendly food. Although numerous restaurants offer GF meals, a lot of the food might still have flecks of gluten in it. That means options for celiac-friendly foods in restaurants seems to be about the same as it was before the trend. Why? 


A 2016 Mayo Clinic study looked into the continued increase of GF options in the U.S. The study explains that, between 2009 and 2010, 5 percent of the people who chose to avoid gluten had celiac disease; 51 percent who avoided gluten had celiac but were undiagnosed; and 44 percent were people without CD.


By 2013–2014, 16 percent of those who ate GF were diagnosed with CD; 12 percent had undiagnosed CD; and 72 percent of those eating GF did not have CD. According to the same study carried out by Mayo, there was no significant change in the prevalence of CD between 2009 and 2014. In other words, eating foods without wheat has become popular among those who are able to eat and digest gluten. This population is, in fact, largely responsible for driving the demand for GF foods.


So, people who don’t have celiac or other gluten-related illnesses are all about eating foods that don’t include gluten. Why? Maria Luci, the communications coordinator at national nonprofit Beyond Celiac, says that there are a few myths that have fueled the movement.
First, there is the myth that cutting gluten from a diet will result in weight loss, an idea that research has already proven false, as reported in studies conducted by Harvard University, the National Library of Medicine, and other credible sources.


This myth, Luci explains, has been indirectly spurred by books such as Wheat Belly and Grain Brain, two best-sellers warning that wheat, carbohydrates, and sugar aggravate a slew of health problems, including ADHD, anxiety, chronic headaches, and Alzheimer’s.
Luci also points to celebrities going GF for health reasons or to lose weight. Kim and Kourtney Kardashian, Gwyneth Paltrow, Victoria Beckham, Russell Crowe, and Lady Gaga are some of the well-known names who have given up gluten without CD.


Slashing wheat and other gluten-filled foods from a diet is trendy, but one peer-reviewed study published in the British Medical Journal this year suggests it may not be healthy. The study concluded:

“Long term dietary intake of gluten was not associated with risk of coronary heart disease. However, the avoidance of gluten may result in reduced consumption of beneficial whole grains, which may affect cardiovascular risk. The promotion of gluten-free diets among people without celiac disease should not be encouraged.” One big health issue related to going GF comes from what you replace the gluten with. Walking through the aisles at the grocery store, it’s not uncommon to see packages with “gluten free” written in huge letters. But in order to make the product still taste good, many GF foods are high in trans-fat, artificial sweeteners, and other inorganic stuff. So, while many go GF in attempts to be healthier and lose weight, their health may worsen because of the foods they’re eating as gluten substitutes.


Despite the studies that show gluten is an important part of most diets, businesses that specialize in GF foods continue to grow and thrive in Minnesota. Still, that’s not necessarily a bad thing.


You can eat gluten-free food without substituting anything for it, after all. A gluten-free bakery, for example, sells items that should be eaten in moderation whether they contain gluten or not. You’d be hard-pressed to name anything truly nutritious in a donut, and if replacing wheat-filled donuts with gluten-free donuts puts your health at risk, you should probably reconsider your diet.


Sift, a gluten-free bakery founded in 2013, is one such business caught up in the recent findings. Founder Molly Miller began baking GF foods to manage her Crohn’s symptoms, a digestive disorder that she was diagnosed with as a young teenager. Cooking for herself quickly turned into a business, and she now provides GF baked goods to Peace Coffee, Quixonic Coffee, T-Rex Cookie Café, and other Twin Cities coffee shops and eateries. Miller’s GF treats are so popular that Sift is opening its own store on 45th and Bloomington in Minneapolis.


I asked Miller about the increase in the demand for GF foods and why she thinks that cutting wheat from diets is so popular right now. “People are really starting to make the connection between how what they eat can influence how they feel,” she says, “and removing gluten from a person’s diet is just one way to influence that.”


Miller says that while many of her customers have celiac and other gluten sensitivities, a large portion of her clientele consists of people who choose GF snacks because they seem healthier than something with gluten in it. "I don't claim to be an expert in this area,” she explains. “I just know there are many connections between food and health."


While many experts are saying that going GF is not a great idea for most people, it is important to remember two things: First, experts have changed their minds before. For example, Americans have been told to avoid carbs, eggs, and fat in the past, all things that are now allowed, and even encouraged (in moderation) by experts today.


The second thing to remember is that everyone’s body is different. Just because one doesn’t have CD does not mean that his or her body can process gluten as it should, and some gluten sensitivities may not currently have a label.


So, when your friend says that she isn’t eating gluten anymore, don’t force a cupcake down her throat and tell her that it’s good for her. She could be experiencing real health problems.


That said, here are some tips:

 
1. Remember that some people are GF because they have to be for their health. If you choose to go GF, don’t advertise your choice and praise the “diet.” For you it might be a choice, but for others it’s a medical necessity.
2. Unless you have celiac or other gluten sensitivities, gluten isn’t inherently bad. In fact, it adds important protein to a diet.
3. Before going GF, talk to a doctor. If you think that you have celiac or a different GI disease, it will be easiest to test and find if you have been eating gluten.
4. If you decide to go GF for any reason, it’s important to realize that there is gluten in a lot of food, not just the obvious breads and pastas. Canned soup, sauces, and fried foods might have gluten in them. Make sure you read labels and ask servers if dishes have gluten in them.
5. Even some beauty products have gluten in them. If you have any questions about whether you should be using these topical products, check Beyond Celiac’s website for a discussion on whether people with gluten sensitivities can/should use these products.
6. Even if a restaurant says that a dish is GF, it’s not a bad idea to tell the server that you can’t have gluten. This helps to ensure there is no cross-contamination when preparing your food.
7. Most importantly, remember that gluten can actually play an important role in most diets.
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http://www.minnesotamonthly.com/Blogs/Taste-Blog/The-Gluten-Free-Craze-Should-You-Join/

Thursday, 14 December 2017

Basic Neuropathy (Vid)

Today's post from livestrong.org (see link below) is another general post about neuropathy as a condition that affects up to 20,000,000 people in the US alone. As regular readers will know, every now and then this blog publishes such a post, for people both new to the disease and those who know people affected by nerve damage. You can talk about research into neuropathy at a molecular level, or the effects of complex medications and supplements till the cows come home but unless you have a basic knowledge of what neuropathy involves, none of that will make any sense. That's why it's important to publish new and sensible articles that cover the basics of the problem,  in terms that everybody will understand. This is just such a post and is worth reading for everybody living with or near this frustrating and painful affliction.


Neuropathy
December 2017 

 






Neuropathy causes tingling or numbness, especially in the hands and feet. It affects about one to two percent of Americans and is caused by damage to a single or multiple nerves. There are different types, but peripheral neuropathy is the most common in those with cancer.

Peripheral neuropathy may develop at any phase of the cancer journey, even some time after treatment is finished. Knowing what some of the causes are and being able to describe your symptoms to your health care team can help you manage neuropathy. Symptoms are often ignored by both patients and health care professionals. If you have symptoms of neuropathy, it is important to discuss this with your health care team as soon as possible.

Symptoms of Neuropathy

Peripheral neuropathy can affect the nerves that tell you the position of your hands or feet that let you sense hot or cold or that senses pain. You can experience a tingling or numbness in certain areas of the body, commonly the hands and feet. These sensations can range from mild to painful and are almost always greatest at night.

Common signs and symptoms include:

Numbness or tingling, especially of the hands or feet.
Pain or cramping, especially of the hands, feet or calf muscles.
Sensitivity to touch or temperature.
Loss of reflexes.
Muscle wasting in the hands and feet.
Weakness, especially in the feet or hands.
Clumsiness.
Loss of balance, particularly in the dark.
Dizziness, especially when getting up from a bed or a chair.
Sexual dysfunction.

It’s not easy to deal with neuropathy. If you notice symptoms, talk to your health care team immediately.

Factors that Increase Risk of Neuropathy

Neuropathy may occur from cancer or the treatment received. Cancer types with higher risk of neuropathy include: lung, breast, ovarian, myeloma, lymphoma and Hodgkin's disease and testicular.

Life factors that may increase the chances of developing neuropathy: 

Advanced age.
A family history of neuropathy (such as with familial diabetes).
Malnourishment.
Excessive use of alcohol.
Having a preexisting medical condition such as diabetes or thyroid dysfunction.
Some medications (including chemotherapy medications) also increase risk.
Medications that may increase the risk of neuropathy:
Platinum compounds.
Taxanes.
Vinca alkaloids.
Thalidomide.
Velcade.
Cytosine arabinoside.
Misonidazole.
Interferon.

Discuss all of these risks with your health care team.

Treatments for Neuropathy

The peripheral nerves have a great ability to heal. Even though it may take months, recovery can occur. However, in some situations, symptoms of neuropathy may lessen but not completely go away. For example, nerve injury caused by radiation often does not recover well. Neuropathy caused by chemotherapy is also difficult to cure, and recovery may take 18 months to five years or longer. During recovery of platinum-induced neuropathy, patients may suffer increased symptoms.

Treatments for peripheral neuropathy depend on the cause. For instance:

If it is related to nutritional deficiencies, supplements may help.
If the neuropathy is related to a medical condition, such as diabetes or thyroid dysfunction, treating the condition can sometimes reverse the neuropathic symptoms.
For neuropathy related to chemotherapy, most treatments are supportive and designed to improve symptoms and function.
If problems develop during treatment and you continue to receive chemotherapy, the neuropathy can get worse.
Clinical trials research shows promise in some treatments with medications that help peripheral nerves to heal and prevent the neuropathy associated with chemotherapy from occurring or being as severe.
Recovery may be helped by:
Good nutrition including foods rich in thiamine, protein and antioxidants.
Controlling and correcting contributing conditions such as diabetes or hypothyroidism.
Appropriate pain medications.
Physical and occupational therapy. 

How Neuropathy Affects Your Life

Pain from neuropathy can greatly affect your daily activities and quality of life. Symptoms of neuropathy can range from mild to severe. Each survivor's experience will be different. However, with appropriate treatment, the effects of neuropathy can be limited.

If you have neuropathy, you may have: 

Difficulty standing for long periods or walking without assistance.
Problems with balance and an increased risk of falling.
Difficulty with activities like buttoning and tying laces or ties.
Sensitivity to heat or cold.
Numbness or lack of pain sensation.
Pain.

Survivors with temperature sensitivity should avoid extreme temperatures, and use protective clothing as needed. If there is numbness or an inability to feel pain, it is important to pay careful attention to the skin on the hands and feet because there could be an undetected wound or a break in the skin.

Find a Neuropathy Support Group

If there is pain, day-to-day activities such as putting on shoes or using covers over the feet at night can be difficult. Keep in mind that there are treatments that can lessen the pain. Talk with your health care team about potential treatments as soon as possible.

If neuropathy affects your ability to feel the foot pedals of a car, you should not drive unless your car is adapted for hand controls. Slowed reaction time in moving your foot from the accelerator to the brake pedal may cause an accident. If you lose the ability to drive, you may feel you are losing your independence. However, consider the increased risk to your safety and to the safety of others.

Ask your health care team to provide suggestions and special equipment to make daily tasks safe and easier to manage. The suggestions may include night lights, grab bars and other home safety measures to help reduce the risk of falling. Physical and occupational therapists can assist survivors with physical exercises that can help them maintain physical abilities.

For some, neuropathy can lead to physical and mental stress. Watch for signs of depression, and seek immediate help from your health care team. Together, you can deal with peripheral neuropathy.

https://www.livestrong.org/we-can-help/finishing-treatment/neuropathy

Wednesday, 13 December 2017

Catastrophizing: Do Neuropathy Patients Do That?

Today's post from relief.news (see link below) talks about a word that neuropathy patients may come across during their research but also, even in their doctor's consulting room and that is 'catastrophizing'. Now I would hazard a guess that most nerve pain patients are pretty stoical about their pain - they have no choice- there's only so much complaining their family and friends can take and remember, neuropathic pain just doesn't give up! It may be less at some times than others but it doesn't go away and is a typical chronic pain condition. How we respond to that pain is the key here and has given doctors and clinical psychologists a perfect weapon to beat us around the head with. Moan too much and it's called catastrophizing and (we're told) can lead to the pain worsening. This begs the question: does pain cause catastrophizing or does catastrophizing cause the pain. Personally, I believe we're entitled to a good moan now and then - nerve pain is really the pits and we shouldn't be made to feel guilty that we're self-harming by exaggerating our pain. I would guess that the vast majority of neuropathy patients don't exaggerate their pain but it may seem that way and if they do, it's because the world around them has gone glassy-eyed and isn't listening anymore but that's more a social tactic than a psychosomatic reaction. That's not to say that catastrophizing isn't a real thing - it is but my beef is with the word itself - it has too many negative connotations and stigmatises patients before they start. The next time that a doctor or some other well-meaning person suggests that you may be catastrophizing, ask them what they mean by that precisely and then you'll see if you're being labelled or not.





Pain 101: The Latest Thinking About Pain Catastrophizing and Why It Matters for Chronic Pain


By Shana Burrowes December 2017

Editor’s Note: The second North American Pain School (NAPS) took place June 25-29, 2017, in Montebello, Quebec, Canada. This educational initiative brought together leading experts in pain research and management to provide 30 trainees–part of the up-and-coming generation of pain researchers–with scientific education, professional development and networking experiences. Six of the trainees were also selected to provide first-hand reporting from the event, including summaries of talks presented at the meeting. Here, Shana Burrowes, a graduate student and epidemiologist at the University of Maryland, summarizes a talk delivered by Jennifer Haythornthwaite, a pain psychologist at Johns Hopkins University. Haythornthwaite’s talk focused on the role of catastrophizing in chronic pain.

People who suffer from chronic pain know that very often the pain is not the worst part. Instead, the effect of pain on functioning—the challenge of just making it through the day—is much more burdensome.

How people cope with their pain and poor functioning was the focus of a talk at the North American Pain School by Jennifer Haythornthwaite, a pain psychologist at Johns Hopkins University in Baltimore. The take-home message of her presentation, entitled “Thinking Inside and Outside the Box About Psychosocial Factors,” was for researchers and physicians alike to approach pain differently. They need to recognize that pain is very much a psychological and social experience with complicated origins that are still not well understood. From this perspective, Haythornthwaite focused on pain catastrophizing, an important emotional component of pain that plays a significant role in the pain experience.

What is pain catastrophizing?

Individuals differ in how they perceive pain, and in how they react to any painful experience. Some can work through the pain and make it through the day, while others think about their pain constantly, worry about when it will end and how much worse it will get. This negative emotional response to pain is called pain catastrophizing, a subject of much of Haythornthwaite’s research.

Pain researchers measure pain catastrophizing using a scale that captures three main components: rumination, magnification and helplessness. Patients with chronic pain who ruminate may say, “I worry about whether the pain will end.” Patients who magnify their pain may remark, “I keep thinking about how much it hurts,” while those who feel helpless about their pain might state, “It’s awful and I feel that it overwhelms me.”

Patients who score high on the catastrophizing scale have poorer clinical outcomes in the short and long term, reporting less improvement in pain and physical functioning.

The role of catastrophizing in the response to pain treatment

Studies show that patients who catastrophize a lot respond poorly to pain treatment. For instance, a 2014 study published in the Journal of Pain Research assessed catastrophizing in patients with pain from nerve injury (neuropathic pain) who received drugs for their condition. For the 62 subjects who took part in the study, treatment was deemed successful if there was at least a 30% improvement in pain at three or six months of follow up.

Results showed that higher levels of catastrophizing were associated with a poorer response to treatment, a higher likelihood of discontinuing treatment, and poorer quality of life.

Research in other pain populations has shown that catastrophizing persists over time even when there has been successful treatment and predicts whether treatment will be successful or not. For example, in a study published in 2009 in the journal Pain Research and Management, of 43 osteoarthritis patients who underwent total knee replacement surgery and were followed for a year, catastrophizing scores remained unchanged even after the surgery helped to relieve their pain. In addition, those with higher pain catastrophizing and depression reported more pain.

Along similar lines, in a study published in 2004 in the Journal of Pain that looked at 46 patients with acute dental pain, results indicated that patients catastrophized to the same degree even when no longer experiencing pain. This study also examined how sensitive the patients were to experimentally applied heat—a common way to assess pain in laboratory studies. The more that patients catastrophized, the more sensitive they were to heat even after their dental pain had been relieved.

Such studies suggest to researchers that in some respects catastrophizing may be a stable trait that not only predicts how well patients will cope with future pain but how they will respond to treatment. However, physicians could potentially intervene to reduce levels of catastrophizing before administering treatment, in order to increase the likelihood that therapies will relieve pain.

Studying pain catastrophizing in the lab

To better understand pain catastrophizing, researchers like Haythornthwaite study not only pain patients but also healthy individuals who are subjected to pain in laboratory studies. In such studies, one area of research she has pursued examines the role of situational catastrophizing and whether the findings from those investigations can further the understanding of pain catastrophizing in patients. Situational catastrophizing is catastrophizing that is measured either during or after being exposed to a painful stimulus in the lab.

For example, one of Haythornthwaite’s studies published in 2010 in the Journal of Pain measured situational catastrophizing and pain intensity at three different time points in 38 healthy individuals who received a cream containing capsaicin (the ingredient in chili peppers that makes them hot). Results showed that changes in catastrophizing during the course of the study predicted how much pain participants reported in response to the cream: those who had the biggest initial increase in catastrophizing had the biggest subsequent increase in pain.

These findings are important because it hasn’t always been clear if pain makes people catastrophize or if catastrophizing leads to pain. This study showed that changes in catastrophizing came before changes in pain, at least in this sample of healthy people.

Learning more from patients


What else have researchers learned from patients about the role of catastrophizing in pain? In a 2003 clinical trial of patients with post-herpetic neuralgia (PHN), a condition where patients suffer pain due to nerve damage after an outbreak of shingles (which is caused by reactivation of the virus that causes chicken pox), catastrophizing predicted whether pain would persist in those individuals in the future. In another study published in 2011, catastrophizing was also found to predict the development of chronic pain after surgery.

While catastrophizing has been shown to predict future pain to a moderate degree, how much catastrophizing a person engages in has varied depending upon which patient population is under study. This may be due to the severity of illness, how long a person has suffered from pain, or the setting in which the patient was treated.

Searching for an explanation

What explains the link between catastrophizing and pain? While this is still not well understood, there are three main factors that pain researchers have focused on in this regard: poor coping, the biological stress response and poor endogenous pain modulation.

Poor coping refers to the difficulties that people who are high catastrophizers have in using certain strategies to deal with their pain. For example, in a 2010 study from Haythornthwaite and colleagues in which subjects played video games to distract them from their pain, high catastrophizers took longer to report that their pain was reduced by playing the games.

The biological stress response refers to the body’s production of hormones when under stress. In one study published in 2010, researchers found that catastrophizing was associated with how much cortisol, a stress response hormone, was produced in the saliva in response to experimental pain testing in the laboratory. This was true both of patients with jaw pain and in healthy individuals used as a control group.

Finally, endogenous pain modulation is the ability of a person to naturally inhibit pain. A 2009 study found that high pain catastrophizers had poor endogenous pain modulation. This led them to report more pain in response to pressure and cold temperature, two types of experimental pain often tested in the laboratory, compared to those who did not catastrophize as much.

What’s next?

Many questions still linger about pain catastrophizing. For instance, while there has been some research indicating a genetic component underlying this phenomenon, how environmental factors such as early exposure to pain, poverty, and education affect the development of catastrophizing remains unclear.

Still, there are several consistent findings that reveal the importance of catastrophizing in chronic pain. Catastrophizing is a relatively stable trait whose magnitude differs from patient to patient, and also depends on the type of pain from which patients suffer as well as the setting in which they are evaluated. It also consistently predicts future pain, as well as whether treatments for pain will be successful. This current knowledge provides a framework for future studies so researchers can learn more about the importance of catastrophizing in chronic pain.

http://relief.news/pain-101-latest-thinking-pain-catastrophizing-matters-chronic-pain/

Tuesday, 12 December 2017

Return Of The Puffer Fish To Treat Nerve Pain (Vid)

Today's short post from abc30.com (see link below) hails the return of the Japanese Puffer fish to the headlines. The Puffer fish and its poison have appeared over the last few years here on the blog as a potential nerve medication but until now, it's been somewhat theoretical (just like other animal toxins) - promising in theory but a long way from the chemists' shelves. Now an American company, Chromocell, has been granted fast track status by the FDA, to develop a working drug based on the puffer fish venom. It will bypass the brain so will not be addictive or psychoactive but will target the nerves relaying pain signals and as such may be a godsend for neuropathy patients. Nice to see progress in the 'alternative' science world.


New Treatment for Neuropathy: Medicine's Next Big Thing?
By Margot Kim Saturday, December 09, 2017

Thirty percent of all Americans will be affected by peripheral neuropathy, a condition that impacts nerves leading to the arms and legs. In many cases, doctors prescribe medicines to help manage the pain, burning and tingling.




Now, researchers are testing a new non-addictive treatment inspired from a surprising source.

Joseph Malkevitch has been a math enthusiast for most of his adult life. Ironically, for years Joseph has been battling a medical condition that is highly unpredictable.

Malkevitch explained, "I noticed it in the form of tingling in my feet and toes and initially it went away and so I just tossed it aside as a glitch."

Joseph's doctors diagnosed him with peripheral neuropathy; damage to the nerves in the peripheral system which lead from the brain to the extremities. But they could not determine a cause. Medical experts say that's not uncommon.

David M Simpson, MD, FAAN, Professor of Neurology; Director, Clinical Neurophysiology Laboratories; Director, Neuromuscular Division; Director, Neuro-AIDS Program, Icahn School of Medicine at Mount Sinai said, "In upwards of 30 percent of patients with peripheral neuropathy one can't identify a cause."

Now, researchers are testing a drug to treat neuropathy pain. Right now it's known only as CC8464. Inspired by the toxin found in Japanese pufferfish, the drug copies how the fish toxins disrupt signals to the body.



"How it works in the body is by targeting those peripheral nerve fibers and not penetrating the brain," said Heikki Mansikka, MD, PhD, VP Clinical Development at Chromocell. (Read Full Interview)

Researchers say since the drug candidate bypasses the brain and works directly on the peripheral nerves, it may not be addictive. While Joseph chooses to manage his neuropathy without medication, he knows others with this condition may be searching for serious pain relief.

The potential new drug is being developed by the New Jersey-based company, Chromocell. The FDA granted the drug "fast-track" status based on need. It is currently in phase one clinical trials.

http://abc30.com/health/new-treatment-for-neuropathy-medicines-next-big-thing/2763554/

Monday, 11 December 2017

The Problem With Idiopathic Neuropathy Is That It's A Non-Diagnosis

Today's important post from neuropathyjournal.org (see link below) lays bare the innate ridiculousness of the diagnosis, 'idiopathic neuropathy' It basically means they don't know what the cause of your nerve pain is and worse still, thanks to their diagnostic processes, can't pin a label on any one of the more than one hundred sorts of neuropathy so they call it 'idiopathic'. So what do you do if you're presented with the diagnosis of idiopathic neuropathy? First you should accept the fact that many doctors won't accept and that is that idiopathic neuropathy is not a diagnosis at all - it's an admission of testing failure, thanks to the limitations of modern testing for nerve damage and its symptoms. They are telling you that you have neuropathy (which you undoubtedly already knew) but why and how is unknown. So you're not really any further down the road but are nevertheless put onto a course of standard medications that are not exactly reliable and have side-effects of their own. It's a bit of a Catch 22 situation but that's the way it is until testing methods are refined to reveal accurate results. This article fills in the gaps for you and tells you much of what you need to know about the vagueness of the diagnosis:- idiopathic neuropathy. Hopefully better times and patient power lie ahead.

The Problem with a Diagnosis of Idiopathic Neuropathy
By LtCol Eugene B Richardson, USA (Retired) BA, MDiv, EdM, MS14 Comments

Idiopathic Neuropathy according to medical experts writing in the Journal of the Peripheral Nervous System should be considered as a disease entity in and of itself. It is recommended that this condition be diagnosed as Chronic Idiopathic Axonal Polyneuropathy or (CIAP) as a major health problem. (See reference 1.)

I would ask, what does the word ‘idiopathic’ add to this diagnosis? Why not Chronic Axonal Polyneuropathy or (CAP)?

With the greatest of respect for the writers of the article, following forty-four years of living with neuropathy , a diagnosis of idiopathic neuropathy is a ‘failed diagnosis’ given the diagnostic tools and information medicine has available in 2016.

Read on to understand your patient mission: Help influence better awareness, clinical thinking and knowledge about Peripheral Neuropathy and the available tests in the health care system by learning, sharing documents, information, sources, and asking good “I” questions of your doctor. Become a partner in your own health care and a facilitator of change. In the process you may even get the help you need for your neuropathy.

We patients understand that there are no tests to diagnose Peripheral Neuropathy per se, as this must be done based on the patients symptoms and medical history. The available tests can only either rule out a cause for the symptoms or confirm that damage has been done to the large or small fiber nerves.

However, failure to find either a cause or damage does not rule out a neuropathy. The symptoms of Peripheral Neuropathy are often present without the damage to the axon (nerve) or myelin (nerve covering) as that may occur later in the course of the disease. (For example regarding GBS, see “Journal of the Peripheral Nervous System”, Research Report, Volume 19 no. 3, September 2014 page 239, paragraph 3 as but one example of what research states in this regard, beyond my own experience of decades of symptoms before damage was measurable.)

It is this focus in searching for a cause that sets the patient and doctor up for a diagnosis of idiopathic. As noted below, medical science does not know the cause for many diseases, yet they do not over use the term idiopathic in their diagnosis of the patient.

Understanding the results and meaning of the tests now available, combined with the complete patient medical history, often point to a more precise diagnosis, possible treatment options or at a minimum an idea that might help the patient.

I always loved Mims Cushing’s’ definition of idiopathic. In her book “You Can Cope with Peripheral Neuropathy” she defines it as being “idiot” for ‘idio’ and “pathetic” for ‘pathic’. In fact this bit of harsh humor hits the nail right on the head.

Idiopathic to doctors of course means of “unknown cause” and is a legitimate word when seeking the cause of some disease, but it is rarely used in MS or cancer and other ‘recognized or accepted’ diseases when the cause is not known! Why? Does research not focus on the cause of all disease to find answers that we still do not have?

The other issue is that for lawyers’ idiopathic means “no objective proof of a problem” providing the foundation for legal denial of help for the patient. Talk about frustrated patients! In both situations, this leaves the neuropathy patient without help that may be possible with a more precise diagnosis.

Based on the complete information available in patient history and testing doctors can provide a helpful diagnose beyond that of Idiopathic Peripheral Neuropathy.

Examples to name a few, without including the word “idiopathic” which adds nothing but uncertainty, would include the following. You can add acute (two months) or chronic (beyond two months) or progressive (remits and relapses with increasingly worse symptoms) to any of these focused findings.

While not exhaustive, this list will highlight the point being made: 


Peripheral Neuropathy / Polyneuropathy
Axonal Neuropathy / Polyneuropathy
Sensory Neuropathy / Polyneuropathy
Multifocal Motor Neuropathy (MMN)
Multifocal Demyelinating Sensorimotor Neuropathy (Lewis Summer Syndromes)
Neuropathy with IgM Monoclonal Gammopathy
Anti-Mag or Gangliosides Antibodies
Sensory/Motor Neuropathy / Polyneuropathy
Immune Mediated Neuropathy / Polyneuropathy
Large Fiber Neuropathy / Polyneuropathy
Small Fiber Neuropathy (SFN)
Autonomic Neuropathy
Autoimmune Sensory Neuronitis
Guillain Barré Syndrome (GBS)
Distal Symmetric Polyneuropathy
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Sjogren’s Syndrome

Types when there is a suspected cause:

The type of neuropathy often points to either a cause or a possible treatment. Example: Progressive Polyneuropathy was my diagnosis that came closest after a history of symptoms for decades. The neuropathy had progressed for over four decades when this typing was made. The type along with the medical history with other testing ruling out other causes, screamed out to do the spinal tap to check for an immune mediated neuropathy, but the diagnosis remained as idiopathic.

One University Neurologist who was determined to prove it was due to spinal surgery a few years before never consider the spinal tap. He never looked at the history of over four decades prior to any spinal surgery. In fact the spinal surgery was necessary due to the use of steroids for the neuropathy that had weakened the spine and caused cataracts! A spinal tap and possible use of a trial of IVIg did not occur to this doctor in 2001, and the opportunity to stop the damage did not occur until four years later because they held onto the word ‘idiopathic” and/or ignored the medical history and facts. Respectfully challenge the doctor, it is your body and your illness! 


Diabetic Neuropathy or Glucose Intolerance
Diabetic Amyotrophy
Vitamin E, B1, B6, B12 Deficiency
Vitamin B6 toxicity
Bariatric Surgery and Malabsorption with nutritional deficiency
Celiac Neuropathy
Chemotherapy/Radiation induced neuropathy
Neuropathy in alcoholic abuse
Hereditary or genetic neuropathy
Neuropathy in Agent Orange exposure***
Entrapment Neuropathy (Carpel Tunnel Syndrome)
Toxic neuropathy
Drug induced neuropathy
Neuropathy with IgA, IgM Monoclonal Gammopathy
Hepatitis C Infection
Vasculitic neuropathy
Neuropathy in AIDS
Neuropathy in Lyme Disease
Diphtheric (bacterial infections) neuropathy
Sarcoid or Parasitic Infection (Chagas’ Disease) neuropathy
Leprosy
Neuropathy in cancer or Lymphoproliferative disorders
Paraneoplastic neuropathy
Neuropathy in myeloma or POEMS
Neuropathy in amyloidosis
Ulcerative Colitis
Crohn’s Disease
Shingles or Cytomegalovirus infections

(***Supported by the findings of the Institute of Medicine in 2010 and confirmed by the Veterans Affairs Administration law in 2012 as presumptive to Agent Orange exposure. For guidance in submitting a claim to the VA go to this link on Guidelines for Veterans or send an E Mail to gene@neuropathysupportnetwork.org for more guidance.)

The late Mary Ann Donovan, a neuropathy patient and co-founder of the now unfortunately defunct Neuropathy Association, gave me hope years ago during darker times. I had been literally tortured by ignorant ‘experts’ at a great University! Mary Ann answered my call for help. This is by the way what eventually inspired the production of the DVD, our websites at the NSN, and lead to our patient focused approach!

Patients saved my life or what was left of it because they shared what I needed to know. Patients may spread lots of misinformation that may or may not be actual fact, but then so do doctors even with their training. When doctors gave me the IVIg infusion to fast resulting in symptoms of congestive heart failure from fluid overload, a patient provided the insight of slowing the infusion and giving Lasix pre and post infusion. It worked! Thank heavens for the growing number of doctors who now know and are helping neuropathy patients sort it all out. But it takes patients and doctors working as partners to find solutions!

A Few Comments on “Tapes” Which Can Hinder a Correct Helpful Diagnosis:

Now doctors are human and are subject to the same errors all of us make in communication. One of these we shall call ‘tapes’ or one could see them as ‘voices from the past’. You will know you are using a ‘tape’ when you hear yourself saying something like, “All ____ look the same.” ‘Tapes’ is a technical description often found in communication used in the Transactional Analysis School of Psychotherapy. I long for the day when unhelpful ‘tapes’ or unhelpful assumptions about Peripheral Neuropathy are a thing of the past.

This will occur when doctors cease using the ‘tapes’ about neuropathy that are preventing them from thinking.

C J Holliday who leads the Piedmont Triad Peripheral Neuropathy Support Group in North Carolina spoke of unhelpful tapes as in, if your drink alcohol ‘you must be an alcohol” or it must ‘be due to diabetes’ if you are a diabetic without completing a complete evaluation of the patient. Or as one doctor noted recently to a patient, “If you do not have diabetes you do not have neuropathy”. Really?

Another tape I know of that caused an otherwise brilliant University Neurologist to fail in diagnose and treatment, was the one who said, “Agent Orange does not cause neuropathy, for I was involved in the research.” Later I learned that there actually was very little real research and this unchallenged tape resulted in delayed diagnosis and treatment for four more years. The facts were staring the expert in the face and this assumption or tape prevented a brilliant doctor from diagnosis and treatment.

Diagnosis is a Challenge Even for the Best:


Dr. Donofrio acknowledges the complexity of the over 100 causes of neuropathy and how important it is to do a complete workup of the neuropathy patient. His summary work up in chapter 1 of his book is right on target. I only wish more doctors would read it if they are going to diagnose and work clinically with neuropathy patients.

Here is the quote from the Dr. Donofrio book on page 4:

“SEARCH FOR CLUES TO DIAGNOSIS:

“When first evaluating a patient with a polyneuropathy, it is good practice to ask specific questions about previous diseases, viral illnesses, lifestyle, and work and occupational exposure that may render a clue to the diagnosis. Initial questions should be asked about diabetes, alcohol abuse, vitamin deficiencies, and dietary habits. Other questions should address the use of over the counter drugs, zinc consumption, gastric bypass surgery, and medications prescribed in the past (especially those used long term). If no clues arise after those questions, one should enquire about HIV infection, a family history of neuropathy, foot deformities in the family, amyloidosis, history of thyroid disease, chronic renal and liver disease, malignancy, previous treatment with chemotherapeutic agents ,connective tissue disorders, recreational use of substances, and exposure to heavy metals, industrial agents, herbicides and pesticides.”

Diagnosis is an art and a science. The statement by Dr. Donofrio does not relate to testing, but to communicating with the patient. Fortunately more doctors are returning to the day in which they spoke too and listen to the patient.

As one brilliant diagnostician at Harvard University, Jerome Groopman in his book How Doctors Think? said, “Often the most important thing a patient shares, is shared at the last moment when they are walking out the door.”

When left with a diagnosis of Idiopathic neuropathy, the patient is left without affirmation that is important in the strange world of neuropathy symptoms, robbing patients of self-esteem.

To name something that is real to the patient, is to provide an emotional/cognitive handle on the strange world of the neuropathy patient and their families.

From the experience of some neuropathy patients, a diagnosis of idiopathic too often results in a not too subtle suggestion that the patient has a mental illness (since all tests are normal and there is no cause it must be mental) and the statement is used as a club against the patient to send them on their way. Many neuropathy patients have been here including me.

To further frustrate the patient, if an employer finds about such a diagnosis, this can cost the employee their career. Been there and done that in my military and civilian career with supervisors who wanted to play doctor. Since the cause is unknown, it must be failure to handle stress both supervisors concluded.

Medicare in 2016 still leads the way in supporting the dismissal of neuropathy by not paying for some blood tests that a doctor orders under the neuropathy profile!

There are many diseases for which we do not understand or fully understand the cause or involves other disease processes.

As Dr. Thomas Brannagan of Columbia University states, the simple reason is that too many health care professionals do not have the clinical training for the proper diagnosis and treatment of the neuropathies.

The challenging question is, “Why not train them?”

I recently went on several health care websites and with very few exceptions, every major disease is listed, but there are too many who do not even list Peripheral Neuropathy and I struggled to have these sites to consider listing it when there are more patients with Neuropathy than MS. They always list MS. Why? (See the Journal of the Peripheral Nervous System Vol.17, Supplement 2, at Page 44 top left hand column.)

So why is idiopathic neuropathy even necessary when a more helpful diagnosis is possible when a trained physician knows how to use and interpret a skillful hands on examination, EMG, the Nerve Conduct Study, the spinal tap, the nerve/muscle biopsy, the blood work, a skin biopsy, a genetic test, radiology workup, or testing evoked potentials for autonomic function and actually thinking about the subjective information provided in the patients’ medical history?

Dr. Norman Latov of Weil Medical College at Cornell University, shared in 2006 that for “one quarter to one-third of patients, no cause can be found and the neuropathy is called “idiopathic.” He notes that these are usually “axonal and may be sensory or sensorimotor” and “classified according to the clinical presentation”, with “therapy primarily symptomatic.”

Patient Challenge:

I strongly recommend that patients never rest on a diagnosis of “idiopathic” neuropathy.

I remember the neurologist who was not clinically trained who wanted in a desperate way to make me a diabetic while resting on idiopathic. He delayed treatment another four years until I gave him the article on a trial of IVIg that worked for me. He was not aware of the usefulness of the spinal tap for such a neuropathy in 2004. Then in 2005 for the first time my doctor, Dr. Waden Emery III, Neurologist in Lighthouse Point, Florida asked, “Why did they not do a spinal tap?”

You may want to provide the doctor with a copy of the document recently published in Neurology Today, March 15, 2012, volume 12(6); pp 30, 32-33 by Mark Moran. Read the entire article at: How to Diagnose Peripheral Neuropathy? No Simple Answers

Unfortunately, this great article does fail to mention the diagnostic value of the spinal tap, a procedure that would have resulted in my earlier treatment years before my disability was serious. If you want a copy of this document, send an e-mail to gene@neuropathysupportnetwork.org

If you want a good description of the symptoms and causes of Peripheral Neuropathy, read Dr. Norman Latov’s book “Peripheral Neuropathy: When the Numbness, Weakness, and Pain Won’t Stop” or read The Top 20 Symptoms of Peripheral Neuropathy. Give this information to the doctor if needed.

Will the Doctor be defensive or get angry?

Perhaps, it may take a bit of skill using “I” messages such as “I wonder if it would be helpful to _____?” rather than ‘you’ messages to the doctor. ‘You’ messages are usually rejected and making the person defensive while ‘I’ messages sets the person free while stimulating thinking! This is true even if the thinking occurs after your appointment is over.

I remember when the military Men of the Chapel went fishing to catch sea bass off of Baltimore one year and we brought the large catch of fish to shore and gave it to the Priest who was feeding the poor of the city. In his office was a sign that read, “I give you fish and you sell fish. I am angry. So I refused to give you fish because you sell them. You are angry. Better you angry”.

Your mission: Help influence better awareness, critical clinical thinking and increased knowledge about Peripheral Neuropathy and the available tests in the health care system by learning, sharing documents, information, sources, and asking good “I” questions of your doctor. Become a partner in your own health care and a facilitator of change. In this decade with so many good resources to learn regarding neuropathy, patients have little excuse to remain in the dark! In the process you may even get the help you need for your neuropathy. In my life, such an approach with patient help saved what I had left of my life after being severely disabled from ‘idiopathic’ neuropathy.

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REFERENCES:


Reference 1: Journal of the Peripheral Nervous System, Vol. 17, suppl. 2, Page 43-49 “Idiopathic Neuropathy: New Paradigms, New Promise”, 2010 and other issues of this scientific journal of the Peripheral Nerve Society.

Reference 2: “Peripheral Neuropathy: When the Numbness, Weakness, and Pain Won’t Stop” , by Norman Latov, MD PhD, AAN Press 2007.

Reference 3: “How to Diagnose Peripheral Neuropathy? No Simple Answers: Experts Offer Some Guiding Principles”, in Neurology Today, March 15, 2012, volume 12(6); pp 30, 32-33 by Mark Moran. (Send E Mail togene@neuropathysupportnetwork.org)

Reference 4: Textbook of Peripheral Neuropathy, Peter D Donofrio, MD, Editor, Professor of Neuropathy, Chief of Neuromuscular Section, Vanderbilt University Medical Center, Nashville, TN Published by DEMOS Medical, 2012

Reference 5: “You Can Cope with Peripheral Neuropathy: 365 Tips for Living a Full Life” by Marguerite (Mims) Cushing (Neuropathy Patient) and Dr. Norman Latov, MD, PhD, published 2009.

Reference 6: “Sick and Tired” Part I and 2, Season Five TV show, The Golden Girls.

https://neuropathyjournal.org/the-problem-with-a-diagnosis-of-idiopathic-neuropathy/