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The Importance of Sleep for People With Chronic Pain: Current Insights and Evidence

During the webinar presented by Dr Karen McCloy, the issue of how sleep deprivation can severely affect people living with chronic pain was discussed, and she emphasised the importance of sleep, not only for people with chronic pain, but many other medical conditions.
The following Research Paper explores the current thinking around the impact of sleep deprivation
 2022 Jul; 6(7): e10658.
Published online 2022 Jun 17. doi: 10.1002/jbm4.10658
PMCID: PMC9289983
PMID: 35866153
Katie Whalecorresponding author¬†1 ,¬†2¬†and¬†Rachael Gooberman‚ÄźHill¬†1 ,¬†2

ABSTRACT

We are currently in the midst of a sleep crisis. Our current work and lifestyle environments are normalizing poor sleep with substantial negative impact on our health. Research on sleep has linked sleep deprivation to poorer mental health, obesity, cancer, diabetes, heart disease, and a myriad of other health conditions. Sleep deprivation is an even greater issues for people with musculoskeletal conditions and chronic pain. Between 67% and 88% of individuals with chronic pain experience sleep disruption and insomnia, and at least 50% of people with insomnia report chronic pain. The link between sleep and pain is well documented. Experimental, cohort, and longitudinal studies have all demonstrated that restricted sleep is linked to greater pain. Poor sleep therefore not only affects general health but has a direct impact on inflammation, pain response, and experience. Improving sleep in people living with musculoskeletal conditions and with chronic pain has the potential to deliver great benefit to many. This article describes the evidence base that can underpin such work, including research about the link between pain and sleep as well as theories and approaches to intervention that may help.

© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Keywords:¬†PRACTICE/POLICY‚ÄźRELATED ISSUES, DISEASES AND DISORDERS OF/RELATED TO BONE, EPIDEMIOLOGY, ORTHOPAEDICS

Introduction

Good quality sleep is essential to health and wellbeing across the whole life course. Sleep deprivation is associated with mental health difficulties,( ) obesity,( , ) cancer,( , ) type 2 diabetes,( ) heart disease,( ) and many other health conditions. Conversely, good quality sleep supports physical recovery, memory consolidation, learning, and positive mood.( ) Poor sleep is common among people living with painful musculoskeletal conditions and can have a serious negative impact on their lives and pain management. Addressing sleep and providing ways to support and improve sleep can provide benefit to many. We suggest that there is a clear need to develop, evaluate, and implement care for sleep among people living with musculoskeletal pain. This article describes the evidence base that can underpin such work, including research about the link between pain and sleep as well as theories and approaches to intervention that may help.

Prevalence of Sleep Issues and Chronic Pain

Sleep deprivation and interrupted sleep are substantial issues for people who experience chronic pain (pain lasting longer than 3‚ÄČmonths). A recent systematic review on the prevalence of sleep disturbance for those with non‚Äźcancer pain indicates that between 72% and 75% of this population experience sleep disturbance,(¬†)¬†with other research putting the figure at 88%.(¬†,¬†)¬†Musculoskeletal conditions are frequently associated with sleep issues with prevalence of up to 65% in rheumatoid arthritis, 70% in osteoarthritis, and 95% in fibromyalgia.(¬†)¬†Individuals who experience both chronic pain and sleep problems are likely to have greater pain severity, longer duration of pain, greater disability, and be less physically active than those without sleep disturbance.(¬†)¬†In addition, people who have both pain and sleep difficulties are more likely to experience depression, catastrophizing, anxiety, and suicide ideation.(¬†)

Link Between Sleep and Pain

There is a robust evidence base for the link between sleep and pain. Experimental, cohort, and longitudinal studies have all demonstrated that restricted sleep is linked to greater pain. Experimental studies have examined the short‚Äźterm impact of sleep restriction on pain, commonly using pain threshold tests such as cold pressure. These studies have consistently shown that sleep deprivation in healthy subjects, in particular slow wave sleep restriction (deep restorative sleep), is associated with increased pain stimulus responses.(¬†,¬†)¬†However, these approaches have limited generalizability for people with chronic pain because they do not mirror their experience. People living with chronic pain commonly experience waking several times each night as well as long‚Äźterm reduced sleep quality. Some studies have sought to address this by using ‚Äúforced awakening‚ÄĚ techniques, which forcibly awaken participants multiple times per night. Smith and colleagues(¬†)¬†conducted a study in which otherwise healthy women were awakened at eight intervals during the night over an 8‚Äźhour sleep period. This restricted their total sleep time to 280‚ÄČminutes (just over 4.5‚ÄČhours). Compared with a group who had restricted sleep (same total sleep time but uninterrupted) and a control group who slept for 8‚ÄČhours, forced awakening was associated with greater next‚Äźday spontaneous pain reports and reduced conditioned pain modulation (reduction in the body’s ability to process pain resulting in greater pain experiences).

Prospective longitudinal studies focusing on the effect of sleep on future pain have reported similar findings. Studies in people who experience headaches and migraines have shown that elevated insomnia symptoms increase the risk of exacerbating existing headache, and in developing new headache symptoms at long‚Äźterm follow‚Äźup ranging from 1 to 12‚ÄČyears.(¬†,¬†)¬†Sleep quality has also been examined in relation to postsurgical pain: preoperative sleep quality affects postoperative pain,(¬†,¬†,¬†)¬†including joint arthroplasty.(¬†) This is of particular interest in chronic pain research as joint replacements are predominantly carried out to relieve the symptoms of chronic pain for conditions such as osteoarthritis.

Temporal Relationship Between Sleep and Pain

A subject of recent research has been the temporal relationship between sleep and pain and the day‚Äźto‚Äźday predictive associations. The bi-directionality of the relationship is widely accepted,(¬†,¬†)¬†with poor sleep leading to worse pain and pain negatively impacting sleep; however, the strength and direction of the association is less clear. There is growing body of evidence that suggests a temporal precedence for sleep over pain, such that sleep impairment is a stronger predictor of pain than pain is a predictor of sleep impairment.(¬†,¬†)¬†A study including adolescents with a range of chronic pain conditions found that total sleep time and wake after sleep onset (waking during the night) were associated with next‚Äźday pain reports; however, pain levels did not predict sleep quality or efficiency.(¬†)

Sleep problems have been identified as a risk factor for development of musculoskeletal pain. A Swedish prospective population study identified that problems with initiating sleep, maintaining sleep, early awakening, and nonrestorative sleep predicted the onset on chronic widespread pain over 5 and 18‚ÄČyears in individuals with no pain at baseline, irrespective of mental health status. In addition, sleep problems and fatigue independently predicted chronic widespread pain at 5‚ÄČyears.(¬†)¬†Research has suggested the underlying mechanism for this association is increased systemic inflammation.(¬†)¬†New research examining this relationship has found that this association is mediated by high or low affect (mood/emotional state).(¬†) Low positive affect and sleep disturbance were associated with increased inflammation levels, and high positive affect identified as a protective factor.

Relevance for Research and Treatment of Chronic Pain

Musculoskeletal chronic pain conditions come with different pain profiles, and sleep experience may vary according to condition. Understanding the nature of the relationship between sleep and pain in a variety of conditions may provide key information for design of treatment approaches.

As well as defining pain by reference to condition or diagnosis, considering pain type without reference to associated condition provides key information that may be relevant to sleep. Nociceptive and inflammatory pain is associated with damage to tissue, such as osteoarthritic joint damage.(¬†)¬†Nociceptive pain (pain caused by damage to body tissue) is commonly treated with traditional analgesics and anti‚Äźinflammatory medication.(¬†)¬†Neuropathic pain is associated with changes to the nerves themselves and affects the way pain signals are sent back to the brain.(¬†)¬†Medicines that may provide benefit for people with nociceptive pain may do little to alleviate neuropathic pain symptoms. Of the 20% of the population who live with chronic pain in the UK, approximately 8%‚Äď9% experience chronic neuropathic pain,(¬†)¬†highlighting a large population who may not benefit from conventional pharmacological pain management.

In 2017, a new category of pain experience was introduced by the International Association for the Study of Pain (IASP): ‚Äúnociplastic‚ÄĚ pain.(¬†)¬†Nociplastic pain is defined as ‚Äúpain arising from the altered function of pain‚Äźrelated sensory pathways in the periphery or central nervous system, causing increased sensitivity.‚ÄĚ(¬†)¬†This type of pain can occur in isolation or alongside chronic pain conditions that are primarily nociceptive or neuropathic. Nociplastic pain in common in fibromyalgia and is thought in part to be due to changes in how pain is processed by the nervous system, such as in central sensitization (increased pain response/pain hypersensitivity to external stimuli).(¬†)

Non-pharmacological treatment approaches focused on pain management are the first line recommendation for nociplastic pain, and these include sleep hygiene (healthy sleep habits). Along with patients who experience neuropathic pain, sleep interventions may offer a positive treatment approach for nociplastic pain.

Intervention Approaches

Interventions to improve sleep for people with pain include pharmacological and a range of other approaches. Although pharmacotherapy treatments may offer short‚Äźterm solutions to problems such as sleep latency (taking a long time to fall asleep), they may have unwelcome side effects and are not recommended for long‚Äźterm use.(¬†)¬†Behavioral and psychological interventions have gained traction in recent years as ways to improve sleep without side effects and to provide long‚Äźterm support.

Our recent systematic review of non-pharmacological sleep interventions for chronic pain identified a large range of existing sleep interventions including relaxation, mindfulness, physical therapies, and exercise.(¬†)¬†Cognitive behavioral therapy (CBT) approaches provided the largest evidence base, and these included CBT for insomnia (CBT‚Äźi), CBT for pain (CBT‚ÄźP), and combined approaches (CBT‚ÄźiP). CBT‚Äźi can be delivered on an individual or group basis and consists of a course of sessions focusing on psychoeducation and sleep hygiene information, sleep restriction, relaxation, stimulus control, and cognitive therapy.

Evidence about the effectiveness of CBT for improving sleep indicates that CBT can provide equal benefit or be superior to pharmacotherapy.(¬†)¬†Systematic reviews of CBT interventions demonstrate significant improvements in sleep quality in the short and medium term for CBT‚Äźi(¬†)¬†and for global measures of sleep.(¬†)¬†Condition specific reviews including patients with lower back pain, fibromyalgia, and osteoarthritis show similar results with CBT therapies improving short‚Äźterm sleep outcomes.(¬†,¬†,¬†,¬†)

CBT may be particularly suitable for people with chronic pain because such approaches can address pain and sleep in tandem. Some individuals who live with chronic pain may engage in ‚Äúpain catastrophizing.‚ÄĚ Individuals who experience pain catastrophizing experience greater pain related fear (fear of physical movement and activity resulting in pain), this can lead to pain avoidant behaviors and pain hypervigilance.(¬†)¬†Engaging in the fear‚Äźavoidance cycle of pain means it can be very difficult for these individuals to focus on anything other than their pain or break this cycle 66‚Äď67. Pain catastrophizing has an additional negative impact on pain related sleep issues as pain rumination contributes to sleep disturbance.(¬†,¬†)¬†CBT‚ÄźP and CBT‚ÄźiP have been shown to improve pain coping, reduce catastrophizing, and increase pain acceptance.(¬†)

Until recently, behavioral and psychological therapies were usually delivered in person either on a one‚Äźto‚Äźone or group basis. Increasingly, therapies are delivered remotely using video appointments, websites, or digital apps. Websites and apps may deliver automated CBT, and studies that have evaluated such approaches have found them to be an effective and acceptable means of delivery.(¬†,¬†)¬†With growth in the online wellness industry, the range of smartphone apps providing digital access to relaxation and mindfulness methods has increased substantially in recent years. Unlike the evidence base for automated CBT, evidence relating to relaxation and mindfulness is less developed; however, a studies of a commercial relaxation app found that most users reported improved sleep, including falling asleep and staying asleep, and overall sleep quality.(¬†,¬†) However, findings were limited to a sample who were primarily female and who had high levels of education. Socio-economic factors are an important consideration when designing and assessing the impact of digital sleep interventions; although digitally enabled interventions may provide an accessible route for many, those without digital access may be excluded. Availability of devices, digital literacy, internet access in rural and urban areas, and the range of language availability need to be considered.(¬†)

Support for Change: The Role of Behavior Change Theories

Individuals’ beliefs about their health conditions or experiences can have considerable impact on engagement in interventions‚ÄĒsuch as CBT‚ÄĒthat require behavior change. From health psychology, the common sense model of health representation, first proposed by Leventhal, Meyer, and Nerenz, focuses on the relationship between illness‚Äźrepresentation (individual beliefs and expectations about an illness), coping, and health outcomes.(¬†)¬†This model suggests that perceived causes of a condition and the curability or controllability form part of an individual’s illness perception. This perception then impacts how someone responds to treatment recommendation. Although musculoskeletal conditions may be associated with different types of sleep difficulties, it is also likely that perceived causes of a condition, curability, and controllability weigh heavily in beliefs about sleep. Furthermore, in current society, although sleep is increasingly the subject of wellness intervention, poor sleep (particularly short duration of sleep) is frequently normalized or accepted as part of life.(¬†)¬†People who live with painful musculoskeletal conditions may see poor sleep as an inevitable consequence of living with pain(¬†)¬†and as out of their personal control.(¬†)¬†Addressing these deeply held views about sleep and condition may be an important element of methods to improve sleep.

Individuals with chronic pain may experience disturbed sleep for many months or years, which means that engagement with sleep interventions need to be long‚Äźterm. Despite an absence of evaluations of the longer‚Äźterm effectiveness of sleep interventions for people with chronic pain, health psychology offers guidance about how behavior change can be sustained. For instance, theories of motivation‚ÄĒsuch as self‚Äźdetermination theory(¬†,¬†)‚ÄĒposit that intrinsic motivation is key to long‚Äźterm change. Intrinsic motivation is internal personal motivation, which can be developed and supported through support for individuals’ feelings of autonomy, competence, and relatedness. In other words, people are more likely to be motivated to change if they believe that they are in control of the change, feel able to achieve the change, and sense that they are supported by and connected to other people. Beliefs about sleep and pain may undermine feelings of autonomy and self‚Äźefficacy. Reductions in these feelings may impact on motivation that would bolster and facilitate engagement in active treatments or behavioral change. Bringing focus on health beliefs and motivation together highlight the importance of education about sleep and pain alongside or within interventions that promote autonomous motivation and competence.

Conclusions

Promoting good quality sleep is important for people with pain related to musculoskeletal conditions. A range of sleep problems can be addressed through existing interventional approaches that are underpinned by established theories. Identifying which approach to use when and with whom depends on a full understanding of individual health beliefs that relate to sleep as well as identification of barriers to behavior change. Progress in our understanding of the complex relationship between sleep and pain provides a promising basis for interventions that may improve sleep, help with pain, and augment health‚Äźrelated quality of life. Future research to develop and evaluate tailored sleep interventions should identify whether support for sleep should be embedded into self‚Äźmanagement and healthcare provision.

Author Contributions

Katie Whale:¬†Conceptualization; formal analysis; writing ‚Äď original draft; writing ‚Äď review and editing.¬†Rachael Gooberman‚ÄźHill:¬†Conceptualization; writing ‚Äď review and editing.

Peer Review

The peer review history for this article is available at https://publons.com/publon/10.1002/jbm4.10658.

Acknowledgments

This study was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.

Authors’ roles: KW was responsible for the conception of this review, review and analysis of existing literature, manuscript preparation, and approval of the final submitted version. RGH was responsible for the conception of this review, manuscript preparation, and approval of the final submitted version.

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53.¬†Deci EL, Ryan RM.¬†Self‚Äźdetermination theory: a macro-theory of human motivation, development, and health.¬†Can Psychol. 2008;49(3):182‚Äź185.¬†[]
54.¬†Deci EL, Ryan RM.¬†The “what” and “why” of goal pursuits: human needs and the self‚Äźdetermination of behavior.¬†Psychol Inq. 2000;11(4):227‚Äź268.¬†[]

Articles from JBMR Plus are provided here courtesy of Wiley-Blackwell

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Transcranial Magnetic Stimulation for Chronic Neuropathic Pain

Transcranial Magnetic Stimulation for Chronic Neuropathic Pain a research trial conducted by the  University of California and San Francisco (UCFS)

Summary

for people ages 18-80 (full criteria)
at San Francisco, California
study started estimated completion 
by Julian C Motzkin, MD/PhDPrasad Shirvalkar, MD/PHD

Description

SUMMARY

OFFICIAL TITLE

A Pilot Trial of Longitudinal Repetitive Transcranial Magnetic Stimulation (rTMS) for Chronic Neuropathic Pain

DETAILS

Eligibility YOU CAN JOIN IF…

Open to people ages 18-80

  • Meets Criteria for Chronic¬†Neuropathic Pain¬†(NP):
    1. “Pain caused by a lesion or disease of the somatosensory nervous system
    2. Intractable pain longer than 6 months after pain onset
    3. Baseline VAS score 30-94-mm
    4. Currently prescribed pain medication for NP, history of prior medication trials without adequate pain control, or refused treatments for individual reasons
    5. Continuous pain in face and/or extremities
  • Age 18-80
  • Any gender and all ethnoracial categories
  • Stable on chronic pain medications for 4 weeks prior to the study and agreeable to continue throughout the study. These medications include: Tricyclic antidepressants (e.g., nortriptyline, amitriptyline), SNRIs (e.g., duloxetine, venlafaxine), gabapentinoids (e.g., gabapentin, pregabalin), antiepileptics (e.g., valproic acid, carbamazepine, lamotrigine), and daily anti-inflammatories (e.g., meloxicam), among others (as determined by study physician at the time of screening). Note: Medications that are known to increase cortical excitability (e.g., buproprion, maprotiline, tricyclic antidepressants, classical antipsychotics) or to have an inhibitory effect on brain excitability (e.g., antiepileptics, benzodiazepines, and atypical antipsychotics), or any other medications with relative hazard for use in TMS will be allowed upon review of medications and/or motor threshold determination by TMS specialist.
  • Participants may continue to take as-needed pain medications and record daily usage throughout the experiment
  • Capacity to provide informed consent
  • Ability to tolerate study procedures
  • Successfully complete the screening forms without contraindications

¬†YOU CAN’T JOIN IF…

  • Neurologic: Dementia, Severe¬†neurocognitive disorder¬†(MoCA < 22), Severe aphasia,¬†Seizure disorder, certain structural brain lesions (e.g., intracranial mass lesions, hydrocephalus, sequelae of meningitis), or complete paralysis at target site
  • Psychiatric: DSM Axis I disorder, Suicidal thoughts, prior psychosurgery, prior ECT
  • Procedural: prior rTMS within 1 year of consent, enrollment in other clinical trial in the past 6 months
  • TMS contraindications: implanted device; presence of metal in the head, including eyes and ears (excluding dental implants); certain tics; medications or systemic illness that predispose seizure risk
  • Participants with an unstable physical, systemic, or metabolic disorder (e.g., unstable¬†hypertension,¬†cardiac disease)
  • Females who are pregnant or nursing
  • Inability to complete the research study

Location

  • UCSF Medical Center¬†accepting new patients
    San FranciscoCalifornia94158United States

Lead Scientists

  • Julian C Motzkin, MD/PhD
    Fellow, Neurology, School of Medicine. Authored (or co-authored) 16 research publications
  • Prasad Shirvalkar, MD/PHD
    Associate Professor, Anesthesia, School of Medicine. Authored (or co-authored) 33 research publications. Research interests: Pain Management · Neuromodulation · Deep Brain Stimulation · Headache · Neuropathic Pain · Spinal Cord Stimulation · Post Stroke Pain · Phantom Limb Pain

Details

Status
accepting new patients
Start Date
Completion Date
 (estimated)
Sponsor
University of California, San Francisco
ID
NCT05593237
Study Type
Interventional
Participants
Expecting 20 study participants
Last Updated

 

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High concentration topical capsaicin for chronic neuropathic pain

We are constantly looking for treatments which may have an application to relieve neuropathic pain.

In 2002 an Australian Doctor Hugh Spencer published his story about utilising capsaicin to cure his own trigeminal neuralgia.¬† His process required making a mouth guard from an imprint of the patient’s teeth, adding a cloth brushed with capsaicin and rubbing alcohol, and adding to the outside of the guard to have contact to the gums. The process took time and effort and the treatment not very pleasant in the short term,¬† however his pain receded and eventually disappeared.

In the following years there has been research completed on the benefits of capsaicin.

CapsaicinChemical compound
Capsaicin is an active component of chili peppers, which are plants belonging to the genus Capsicum. It is a chemical irritant and neurotoxin for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact. Wikipedia

  • Formula: C18H27NO3
  • Scoville scale: 16,000,000 SHU
  • Heat: Above peak; (pure Capsaicin is toxic)

High concentration topical capsaicin for chronic neuropathic pain

Published by Dr Hanan Khalil May 2017

369 participants included patients with peripheral diabetic neuropathy reported. The study reported that 10% more participants had at least a 30% reduction with high-concentration capsaicin than with placebo at 8 and 12 weeks of treatment.

Four studies included 1,272 participants with post-herpetic pain and found improvement of pain intensity reduction of 30% or greater in favour of the intervention compared to the control group.

Adverse events were common but not significantly different between the control and intervention groups. Withdrawal rates did not differ between the two groups. The treatment was not associated with death. The included studies that reported on pain reduction in favour of the intervention also reported on improvement of sleep, fatigue, depression and quality of life of the participants.

Conclusion

The small number of trials included in this summary found that high concentration of capsaicin was effective in reducing neuropathic pain associated with diabetes, HIV and post-herpetic neuralgia. There was also additional improvement of sleep, fatigue, depression and quality of life amongst the participants using the high concentration of capsaicin.

Implication for practice

High concentration topical capsaicin can be used to relieve neuropathic pain. Further studies on the effects of its long-term use in patients with chronic neuropathic pain are warranted.

DR HANAN KHALIL is the Director of the Centre for Chronic Disease Management, a collaborating centre of the Joanna Briggs Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, and a reviewer for the consumer group of the Cochrane Collaboration. She is also Editor in Chief of the International Journal of Evidenced Based HealthCare.

The purpose of this evidence summary is to provide the best available evidence for the effectiveness of vitamin E for managing mild cognitive impairment and Alzheimer’s dementia.

For the Full Cochrane review, please refer to: Farina N, Llewellyn D, Isaac MG, Tabet N. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD002854. DOI: 10.1002/14651858.CD002854. pub4.1 

References

  1. Derry S, Rice ASC, Cole P, Tan T, Moore RA. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD007393. DOI: 10.1002/14651858.CD007393.pub4
  2. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N.¬†Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 2014;155(4): 654‚Äď62. [DOI: 10.1016/j.pain.2013.11.013]
  3. Pergolizzi J, Ahlbeck K, Aldington D, Alon E, Coluzzi F, Dahan A, Huygen F, Kocot-Kńôpska M, Mangas AC, Mavrocordatos P, Morlion B.¬†The development of chronic pain: physiological CHANGE necessitates a multidisciplinary approach to treatment. Current medical research and opinion. 2013 Sep 1;29(9):1127‚Äď35.
  4. Khalil H.¬†Painful diabetic neuropathy management. International Journal of Evidence-Based Healthcare. 2013 Mar 1;11(1):77‚Äď9.
  5. Anand P, Bley K.¬†Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. British Journal of Anaesthetics 2011;107(4):490‚Äď502. [DOI: 10.1093/bja/ aer260]

Other Research

Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses

Capsaicin 8% Dermal Patch: A Review in Peripheral Neuropathic Pain

The association does not recommend a particular treatment for trigeminal neuralgia.  Please always consult your medical practitioner to discuss products and options appropriate for your specific care.

 

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Trigeminal Neuralgia Pain and Erenumab

There has been some talk on social media trigeminal neuralgia sites, that a possible drug developed for severe migraine, could be used  for trigeminal neuralgia pain.

There have been a number of studies out of Israel which has shown some positive results.  The drug mentioned is ERENUMAB  (aimovig). This drug has not been approved for managing migraine on the PBS but can be purchased on a private prescription at quite a monthly cost.

The below information was taken from Headache Australia Org

Cost & access in Australia

Aimovig is available in Australia for the preventive treatment of migraine in adults. It is a prescription medication so you will need to see your neurologist to access it. If you are not seeing a neurologist at the moment, you can find one in our doctor directory.

Unfortunately Aimovig is not available under the Pharmaceutical Benefits Scheme (PBS). After several failed attempts, Novartis withdrew their application in November of 2019.

The cost for 140 mg of Aimovig (two x 70 mg pens) is $695. You can order this online and it will be shipped to a pharmacy of your choice for pickup. At this stage, Novartis is not offering any free trials or discount programs.

At a glance

Brand name Aimovig
Active ingredient Erenumab
Manufacturer Novartis Australia
Dosage 70 mg or 140 mg per month
Administration Subcutaneous injection (self-administered)
Availability Prescription-only
Cost per 140 mg dose $695
PBS Status? Private prescription only (PBS application withdrawn in November 2019)

This treatment has been approved in 71 different countries including USA

https://www.fda.gov/news-events/press-announcements/fda-approves-novel-preventive-treatment-migraine

https://www.pharmaceutical-technology.com/data-insights/erenumab-amgen-trigeminal-neuralgia-tic-douloureux-likelihood-of-approval/

Efficacy of Erenumab in the Treatment of Trigeminal Neuralgia: A Retrospective Case Series

Eliot Parascandolo et al. Neurol Clin Pract. 2021 Jun.

Abstract

Objective: Trigeminal neuralgia (TN) is a chronic, often refractory, pain condition, which adversely affects the lives of patients. Current treatments are only mildly effective. Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have been successfully studied in the treatment of migraines. CGRP plays a role in both TN and migraine. It is prudent to attempt CGRP monoclonal antibody therapy in TN. Erenumab, a human anti-CGRP monoclonal antibody medication, modulates CGRP, which is elevated in patients with TN. The primary objective of this study was to evaluate the efficacy of erenumab for patients with TN.

Methods:¬†Retrospective analysis was performed on data collected from 10 patients diagnosed with TN and treated with erenumab for 6 months. Pain was tracked using a numeric pain rating scale (NPRS) from 0 to 10. The effect of erenumab on NPRS after 6 months’ time was the primary end point. Secondary end points included side effects to therapy, improvement in headache frequency in those with comorbid migraine, evaluating mood following therapy, and global mood improvement using scale (worse, no change, improved).

Results: Nine of 10 patients (90.0%) reported improvement in pain severity and in global mood improvement. Three patients reported resolution of anxiety and/or depression. Side effects were minimal, with 3 patients reporting constipation, injection site reactions, or both.

Conclusions: Based on these results, erenumab appears to be an efficacious treatment option for patients with refractory TN. Patients experienced improvement in pain, reduced frequency of headache, and improvement in mood. Treatment was well tolerated with only mild side effects reported.

Classification of evidence: This study provides Class IV evidence that erenumab increases the probability of improved pain control in patients with medication-resistant TN.

Further research articles

1-Study TN and erenumab

2-Study re erenumab

We do not recommend a medical course of action for individuals.  Always discuss medical options with medical professionals.

 

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Vitamin D supplementation reduces risk of major cardiovascular events in older adults

This study evaluates whether Vitamin D supplementation reduces risk of major cardiovascular events in older adults.  Vitamin D has also been linked in studies to reduce inflammation and is so important to help live life well.

Why would this be important for people who live with trigeminal neuralgia?

Statics show that trigeminal neuralgia affects older females.  Females are often not aware of their risk factor around heart health and are more likely to be diagnosed with TN.

More than half a million women have cardiovascular disease

In 2017‚Äď18, an estimated 510,000 (4.8%) Australian women aged 18 and over had 1 or more heart, stroke and vascular diseases, based on self-reported data. About 206,000 women had coronary heart disease, and 37,000 had heart failure.

Cardiovascular disease in Australian women‚ÄĒ a snapshot of national statistics

Cardiovascular disease (CVD) is the leading cause of death worldwide, yet important differences exist between men and women. Men generally develop CVD at a younger age and have a higher risk of coronary heart disease (CHD) than women. Women, in contrast, are at a higher risk of stroke, which often occurs at older age.

The incidence of TN was estimated to be 5.5 (95% confidence interval 4.7‚Äď6.4) per 100,000 person-years. The incidence increased with age, from 0.1 in 0- to 19-year-olds to 23.1 per 100,000 person-years in 80+-year-olds. Females exhibited a higher incidence at 7.3 than males at 3.7 per 100,000 person-years.20 Jan 2023

Background
Within the vascular system, most of the cells that express the vitamin D receptor also express 1őĪ-hydroxylase and can convert 25-hydroxyvitamin D (25(OH)D) to calcitriol, the active form of vitamin D. Calcitriol has several
important biological functions including inflammation reduction, inhibition of
proliferation of vascular smooth muscle, and regulation of the renin-angiotensin-aldosterone system.
One meta-analysis of RCTs indicated that vitamin D supplementation was
ineffective in preventing cardiovascular events. However, this outcome was
contradicted by the Women’s Health Initiative Trial, which included women participants and a low dose of Vitamin D.
The D-Health Trial was launched to evaluate whether monthly vitamin D supplementation improves the health outcomes of older adults. Although a previous analysis using the D-Health cohort reported that vitamin D supplementation did not reduce mortality due to cardiovascular disease or all-cause mortality, their effect on the incidence of major cardiovascular events was not determined.

Read the full findings in the below research paper

Vitamin D supplementation reduces risk of major cardiovascular events in older adults

Further research Vitamin D and Inflammation

Vitamin D deficiency and C-reactive protein: a bidirectional Mendelian randomization study

A study from Ireland

Vitamin D status & associations with inflammation in older adults

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Acupuncture for the treatment of trigeminal neuralgia: A systematic review and meta-analysis

Can acupuncture for the treatment of trigeminal neuralgia help reduce pain?

A review of studies and data to evaluate if acupuncture is useful as part of trigeminal neuralgia pain management plan.

 

ABSTRACT
Background and purpose: Few systematic reviews have examined the effects of acupuncture on trigeminal neuralgia. This review aims to provide up-to-date evidence on the efficacy of acupuncture for managing pain in patients with trigeminal neuralgia.
Methods: Eleven databases were searched from inception until November 2022 for relevant articles Two researchers independently conducted study selection, data extraction, and evaluation. The present review solely targeted randomized controlled trials (RCTs). The Cochrane risk of bias assessment tool 2.0 was employed to
assess the risk of bias. Data were compiled using RevMan 5.4.1 software, and the quality of the evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)
approach.
Results: Thirty studies involving 2295 patients were included in this review. Compared with carbamazepine,
acupuncture led to improvements in pain scores (15 RCTs, mean difference (MD) – 1.40, 95% confidence interval
(CI)-1.82 to ‚ąí 0.98 [95% prediction interval, ‚ąí 3.137,0.343], p < 0.00001, low certainty of evidence (CoE)),
response rates (29 RCTs, risk ratio (RR) 1.20, 95% CI 1.15 to 1.25 [95% prediction interval, 1.067, 1.346], p <
0.00001, low CoE), frequency of pain attacks (2 RCTs, MD -2.53, 95% CI -4.11 to ‚ąí 0.96, P = 0.002, low CoE),
and adverse effects (13 RCTs, risk difference (RD) ‚ąí 0.15, 95% CI -0.19 to ‚ąí 0.11 [95% prediction interval,
‚ąí 0.193, ‚ąí 0.108], P < 0.00001, very low CoE).
Conclusion: Although the quality of evidence is low, compared with carbamazepine, acupuncture may improve
trigeminal neuralgia-related pain. Further rigorously designed studies are warranted to confirm the effects of acupuncture on patients with trigeminal neuralgia.

Research Document: Acupuncture for the treatment of trigeminal neuralgia: A systematic review and meta-analysis

What is acupuncture?

Acupuncture is an ancient medical practice, originating in China more than 2,000 years ago. It uses metal needles to stimulate points in the body, often with the addition of manual manipulation, heat or electrical stimulation. Some practitioners use lasers instead of needles to stimulate the acupuncture points.

While acupuncture does appear to help in the treatment of some conditions, the theory of acupuncture is not able to be explained by current medical science. It is considered a complementary therapy.

What is the difference between acupuncture and dry needling?

Like acupuncture, dry needling is a technique that involves puncturing the skin with fine needles to relieve pain. Dry needling targets trigger points in muscles to relieve pain and muscle tightness, while acupuncture stimulates nerves and aims to affect energy and organ systems.

Dry needling is most often performed by physiotherapists.

Is acupuncture effective?

Acupuncture may help relieve common types of pain including:

  • neck and shoulder pain
  • headaches and migraines
  • fibromyalgia

Is acupuncture safe?

When performed by a suitably trained practitioner, acupuncture is generally considered to be safe for most people, but any procedure that involves puncturing the skin with needles or manipulating the human body carries some risk.

Potential side effects of acupuncture can include:

  • bleeding or bruising at puncture sites
  • infection at puncture sites
  • contact dermatitis
  • nerve damage
  • transmission of blood-borne diseases, such as hepatitis C and HIV/AIDS
  • puncture of organs

Acupuncturists should use sterile, disposable needles to prevent the transmission of blood-borne diseases and reduce the likelihood of infection at the puncture site.

What happens during acupuncture treatment?

A typical acupuncture session begins with a discussion of your problem and a physical examination.

The acupuncturist may then stimulate certain points on the body, either by inserting the fine metal needles or using a laser.

The needles used in acupuncture are typically much finer than the needles used to take blood, and the process is usually painless. Once the needles are inserted, they will be left in place while you lie still, and hopefully relaxed. As many as 20 needles may be used in one session.

The needles may be turned or wobbled as part of the treatment. The needles will be removed at the end of the session.

Should I talk to my doctor?

Yes, if you are planning on using acupuncture, it is important to discuss this with your doctor.

It may be important to discuss any possible conditions or medicines that may increase your likelihood of a poor outcome from acupuncture, such as

  • bleeding problems or medicines that thin the blood
  • reduced immunity
  • some types of cancer
  • a metal allergy

If you have an automatic implantable cardioverter-defibrillator or pacemaker, you should avoid electrical stimulation.

If you have any blood-borne diseases, such as hepatitis C or HIV/AIDS, you may need to discuss the risk of transmission with your doctor and acupuncturist before undergoing the procedure.

You shouldn’t delay or stop any medical treatment in favour of acupuncture without first discussing this with your doctor.

Where can I find an acupuncturist?

It is important to check the registration of your acupuncturist with the Australian Health Practitioner Regulation Agency (AHPRA). You can search for registered Chinese medicine practitioners on the AHPRA website.

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Feasibility of Olive Oil for Reducing Facial Pain of Trigeminal Neuralgia

cannabis
STUDY Feasibility of Olive Oil for Reducing Facial Pain of trigeminal neuralgia.
Brief Summary:
This is a 16-week non-blinded, parallel, controlled trial to determine the feasibility and potential efficacy of an olive oil dietary intervention to alleviate facial pain caused by trigeminal neuralgia type 1 (TGN).
Detailed Description:

Trigeminal neuralgia (TGN) pain is debilitating and unpredictable. Alleviation of intensity or frequency to any degree will improve the quality of life of the individuals affected. Current medical treatments for TGN are often not effective. In some cases, the pain is a result of myelin degeneration. If diet can provide the basic building blocks for myelin regrowth, then the investigators may be able to reduce facial pain by supporting the myelin nerve sheath.

Animal studies have shown that a dietary intervention with olive oil favorably impacts myelin but no human study has been conducted to date. The investigators propose undertaking a feasibility study to determine if a comparable intervention may work in a similar way in humans. If olive oil impacts myelin repair, then pain will be decreased by this dietary intervention and quality of life will be improved. However, it is not known if individuals with TNG will be able to consume a diet relatively high in olive oil. Feasibility will include testing the logistics of distributing the olive oil intervention to the study subjects, incorporation of olive oil into the participants’ daily diets, and online/distance monitoring of compliance and reporting of pain intensity, pain frequency, and quality of life. This feasibility study will lay the groundwork for potential future studies examining the efficacy of olive oil on alleviating facial pain caused by TNG and may provide data for a power analysis for a future interventional trial.

https://clinicaltrials.gov/ct2/show/NCT05032573?id=NCT05032573+OR+NCT05217628&draw=2&rank=2&load=cart

Olive Oil Information 

Recognized for its’ abundant health benefits, olive oil is being chosen by many consumers as a preferred form of fat in diets and is being recommended by nutritionists and health professionals as one of the best alternative oils to traditional fats and oils. Olive oil has great diversity in how it can be used as an ingredient in recipes and as a food-enhancer.

Olive trees originated in Asia, but are more commonly know as an agricultural product in Mediterranean countries. Olive oil comes from the process of pitting, grinding, and pressing of the olive fruit.

In countries where olive is most highly consumed ‚Äď Italy, Greece, and Spain, the incidences of cardiovascular disease is low and this is attributed the health benefits olive oil provides. One tablespoon of olive oil contains 120 calories and 14 grams of fat. However, the fat in olive oil is primarily monounsaturated which, when consumed can help reduce blood cholesterol levels leading to improved cardiovascular function.

Other Health Benefits of Olive Oil:

  • Olive oil is beneficial as an antioxidant since it contains high levels of vitamin E.
  • When consumed, olive oil promotes digestion, stimulates metabolism, and lubricates mucous membranes (olive oil contains vegetable mucilage that helps protect the gastrointestinal tract).
  • Olive oil can aid in relieving constipation. Consuming 1 teaspoon of olive oil with lemon juice (preferably on an empty stomach) can promote proper bowel movements.
  • Olive oil for skin therapy. Olive oil can be added to dry skin acting like a moisturizer and can also be applied to nails to increase nail strength and to promote healthy cuticles.

How to Choose Olive Oil:

  • Explore how you can replace butter, margarine, and low quality vegetable oils in your cooking especially in preparing salads, saut√©ed dishes, and sauces.
  • Purchase olive oil that is labeled as‚Äúextra virgin‚ÄĚ, which insures that the oil has been cold pressed. Cold pressed olive oil has been produced with freshly harvested olives and has gone through less processing and has not been degraded with heating or chemicals.
  • A good quality olive oil will be golden yellow in color versus lower quality olive oils that are light green in color.
  • Note: olive oil will congeal (form as a solid) in the refrigerator, but remains a liquid at room temperature.

When used in moderation, olive oil is a nutritious fat that promotes a great deal of health benefits. Like wines, olive oils will have differences in flavor depending on the region and producer of the oils. Olive oils can also be infused with herbs, garlic, peppers and other flavorful ingredients to add extra excitement to your dishes.

 

 

 

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Trigeminal Neuralgia Electronic Diary Trial

Pain Diary

Noema Pharma announces completion of enrollment in the Trigeminal Neuralgia Electronic Diary (TNED) validation study

Study to validate the novel Patient-Reported Electronic Diary designed to more efficiently and accurately measure disease burden associated with trigeminal neuralgia

LIBRATN (NOE-101 Phase 2/3 study in Trigeminal Neuralgia) is on track to report top-line data in H1 2024

BASEL, Switzerland/ Boston, MA, September 6, 2022 ‚ÄstNoema Pharma, a clinical-stage biotech company targeting debilitating central nervous system (CNS) indications,today announces it has completed participant enrollment and data collection in the validation study of a novel Trigeminal Neuralgia Electronic Diary (TNED). The results will be presented at a scientific meeting and published in a specialized peer-reviewed journal.

The TNED validation study was conducted in two leading centers in the US and Europe, the result of a collaboration between University College London Hospitals UCLH/UCL in the UK, the Kaizen Brain Center in the US, the Trigeminal Neuralgia Association UK, and Noema Pharma. Thirty participants with a confirmed diagnosis of trigeminal neuralgia (TN) volunteered to complete the electronic diary. The diary,which was completed daily, includes a self-assessment of the different aspects of their condition; frequency and severity of intermittent attacks, also known as ‚Äúflare-ups‚ÄĚ, the duration of associated continuous pain when present, and the impact of these attacks on personal, social, and professional functioning. While the analysis of the validation data is ongoing, the electronic diary was generally found to be easy to use and enabled participants to accurately describe the burden of trigeminal neuralgia (TN).

‚ÄúThe TNED is a better alternative to the conventional paper-and-pencil method that is used to report the different aspects of facial pain,‚Ä̬†said Professor Joanna Zakrzewska Principal Investigator of the LIBRA trigeminal neuralgia study at UCLH/UCL. ‚ÄúIn addition to being patient friendly and easy to use, TNED¬†is the first electronic diary designed specifically for people who suffer from TN. It measures different aspects of the condition and will allow regular measurement of the different aspects of the condition. In addition to being an excellent research tool for TN clinical studies, TNED¬†can be used by patients with TN in clinical practice as a reliable tool to communicate symptom severity and frequency to their health care provider leading to improved quality of care as it enables assessment of the timing of flare ups and the efficacy of medication.‚ÄĚ

‚ÄúIt‚Äôs very exciting to have completed the recruitment of the TNED¬†validation study. This research tool is very well received by patients with TN, easy to use, and has the potential of becoming a routine activity with minimal burden on patients. We see great potential for the TNED¬†to become a state-of-the-art research tool to be used in all TN clinical trials, including Noema‚Äôs LIBRATN,‚Ä̬†said¬†George Garibaldi, President and Head of Research and Development at Noema Pharma.¬†‚ÄúTreatment options are scarce in TN with only one treatment that was approved over 50 years ago. We believe that patients suffering from TN deserve the benefit of the latest innovations and discoveries. Through the TNED, Noema is making a significant contribution to research in this field.”T

TN, also called ‚Äútic douloureux‚ÄĚ, is a chronic severe pain condition that affects the trigeminal nerve, which carries sensation from the face to the brain. TN is a form of neuropathic pain, associated with nerve injury or a nerve lesion. New cases of TN affect 4 to 5 of every 100,000 people in the United States each year.

Noema is investigating the effect of NOE-101 (basimglurant), a highly selective, potent, and cell-penetrant negative allosteric modulator of mGlu5 receptors for the management of pain associated with TN. It was effective in controlling pain in multiple animal models predictive of a therapeutic effect in neuropathic pain. The currently ongoing placebo-controlled clinical study named LIBRATN (NCT05217628) aims to recruit up to 200 participants in centers across Europe and the U.S. Top-line data from the study is expected in H1 2024. 

About Noema Pharma
Noema Pharma (www.noemapharma.com) is a clinical-stage Biotech company targeting debilitating central nervous system (CNS) indications characterized by imbalanced neuronal networks. The company is actively developing three mid-clinical-stage therapeutic product candidates in-licensed from Roche. Basimglurant, an mGluR5 inhibitor, is Phase 2b-ready for two indications: persistent seizures in Tuberous Sclerosis Complex and severe pain in Trigeminal Neuralgia. Gemlapodect, a PDE10A inhibitor, is currently enrolling a Phase 2a clinical trial in patients with Tourette Syndrome.

https://clinicaltrials.gov/ct2/show/record/NCT05217628?term=Noema+Pharma&draw=2&rank=2

The Company has completed validation studies and is pursuing the development of NOE-115 in Behavioral Metabolic Cluster disorders. It is also planning to develop NOE-109 an mGluR2/3 inhibitor, in undisclosed indications. Noema Pharma was founded in 2020 by the leading venture capital firm Sofinnova Partners. Investors include Polaris Partners, Gilde Healthcare, Invus and Biomed Partners.

Contacts 

Noema Pharma
Luigi Costa
Chief Executive Officer
info@noemapharma.com

Investors
LifeSci Advisors ‚Äď Guillaume van Renterghem
gvanrenterghem@lifesciadvisors.com
+41 (0) 76 735 01 31 

Media
LifeSci Advisors ‚Äď Bernhard Schmid
bschmid@lifesciadvisors.com
+41 (0) 44 447 12 21

 

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FPA – New Life for Cancer Drug

New life for cancer drug that reprograms pain pathway to fight chronic pain

Chronic pain associated with nerve injury and chronic bone pain from metastatic cancer are unmet medical needs. This sober sentence vastly understates the crushing and devastating impact of these forms of pain on victims’ lives, their families, and their social and professional lives.

‚ÄúI just can not sleep any more because turning in bed hurts, my spine hurts lying down, and sitting up to sleep hurts even more. During daytime, I have constant brain fog, interrupted by pain that within minutes gets worse (10-out-of-10) against a background of constant burning pain which gets worse toward the afternoon and evening. I hurt more when I go to the bathroom. The pain medication makes my brain fog worse, I feel like a zombie, I am badly constipated and itch all over.‚ÄĚ That is how a patient with bone cancer pain feels. Testimony from victims of chronic nerve injury pain, through peripheral nerve damage from diabetes or medications, or in the aftermath of shingles, indicates that their lives are equally turned upside down from the pain.

New treatments against pain are needed. What is the desired profile ? ‚ÄúNew drugs and other therapies against chronic pain need to be safe, i.e the fewer side effects the better, especially non-addictive and non-sedative, and effective. For example they should work against nerve injury pain and cancer pain, finally and practically, with minimal time to official drug approval. ‚ÄúSince chronic pain, like many chronic diseases, has an important root in genetic switches being reprogrammed in a ‚Äėbad‚Äô way, a disease-modifying treatment for chronic pain should reset the genetic switches, not just cover up the pain as with opioid and aspirin/tylenol-like painkillers,‚ÄĚ says Dr. Wolfgang Liedtke, who practiced pain medicine for the last 17 years at Duke University Medical Center in Durham, NC, USA, and directed the former Liedtke-Lab to elucidate basic pain mechanisms. Dr. Liedkte moved to an executive position at Regeneron Pharmaceuticals in Tarrytown NY, in April 2021.

Liedtke‚Äôs Duke team, jointly with colleagues from University of California Irvine, tackled the problem by starting with a collection of ‚Äújunkyard of cancer drugs‚ÄĚ, 1,057 compounds originating from two Compound Libraries of the National Cancer Institute. Liedtke picked cancer drugs because a sizeable number of them influence epigenetic regulation of genes, which stops rapidly dividing cancer cells from dividing, but can reset maladaptive genetic switches in non-dividing nerve cells. In order to identify useful candidate anti-pain drugs from this starting pool, Liedtke‚Äôs team devised a screening method that relied on brain nerve cells from genetically-engineered mice that were ‚Äúknockin‚ÄĚ for a convenient reporter gene system so that compounds that enhance expression of an anti-pain target gene would generate a bio-luminescent signal which can be readily measured, allowing 1,057 compounds to be tested.

The selected anti-pain target gene was Kcc2 which encodes a chloride extruding transporter molecule, KCC2. KCC2 churns out chloride from nerve cells, low chloride means strong function of inhibitory neurotransmission, also in pain pathways, thus silencing the pain signal, or not allowing it to break through. In essentially all forms of chronic pain studied in experimental animals and also human spinal cord models, KCC2 disappears from the primary pain gate in the dorsal spinal cord. Liedtke’s team identified 137 first-round winners, i.e Kcc2 gene expression-enhancers, which then were retested iteratively, with a yield of four final co-winners. Kenpaullone was selected for work-up because the compound had a strong record of protecting nerve cells in human ALS models, also hearing and brain neurons from damage. In mice, Kenpaullone functioned effectively against pain caused by nerve constriction injury and by cancer cells seeding in the femur. Pain relief was profound, long lasting and with protracted onset, indicative of Kenpaullone impacting gene regulation.

Says Liedtke ‚ÄúAt this stage, we knew we had met the basic requirement of our screen of shelved cancer drugs, namely identified¬†Kcc2¬†gene expression-enhancers, and demonstrated that they are analgesics in valid preclinical pain models.‚ÄĚ Thus encouraged, Liedtke‚Äôs team addressed whether Kenpaullone affected spinal cord processing of pain, with affirmative findings, then whether the pain-relaying nerve cells in the dorsal spinal cord can lower their elevated chloride, caused by nerve injury, by Kenpaullone treatment ‚Äď again with resoundingly affirmative results. This was great news and prompted the investigators to query how exactly Kenpaullone works in nerve cells so that the¬†Kcc2¬†gene is expressed stronger.

They discovered the underlying signaling mechanism, a key element of it completely new. Kenpaullone inhibits the kinase GSK3-beta which adds phosphate tags to other proteins which in turn switches their function powerfully. They found that the kinase target of GSK3beta is delta-catenin, delta-cat, which when phosphorylated is tagged for the cellular garbage bin. That means that chronic pain, via activation of GSK3-beta leads to loss of delta-cat in pain relaying neurons. What is the original function of delta-cat in relation to pain relay, and in relation to gene expression of Kcc2 ?  Liedtke’s team found that non-phosphorylated delta-cat transfers into the cell’s nucleus and binds to the Kcc2 gene’s DNA in its promoter region, where it switches back on the switched-off Kcc2 gene. To prove the relevance of this pathway for pain, they devised a gene-therapeutic approach so that phosphorylation-resistant delta-cat becomes the payload of an AAV9 gene-therapy viral vector, which infects spinal cord dorsal horn neurons. Injection of this gene therapy vector into the cerebrospinal fluid of mice was similarly analgesic as Kenpaullone.

These findings suggest that Kenpaullone and similarly-acting kinase-inhibitory compounds, also delta-cat gene therapy can become new tools in our toolbox against chronic ‚Äúrefractory‚ÄĚ pain, also caused by nerve injury, also caused by cancer bone pain, likely against other forms of chronic pain where¬†Kcc2¬†is not expressed well (trigeminal pain), and possibly other neurologic and psychiatric disorders where this mechanism appears to contribute to disease.

Amidst Duke co-authors, 1st author Dr. Michele Yeo successfully elucidated basic regulation of the Kcc2 gene together with Liedtke for more than a decade and ran the 1,057 compound screen, co-first author Dr. Yong Chen provided skillful animal experimentation, and co-senior author Dr. Ru-Rong Ji (Director of Translational Pain Research) and his team covered dedicated assessment of spinal cord relay mechanisms. Collaboration with Dr Jorge Busciglio’s laboratory at UC Irvine was key to validate human relevance of Kenpaullone.

Summary Figure
Upper right¬†‚ÄúJunkyard of cancer‚ÄĚ drugs were screened, akin to sieving through sand, looking for gold nuggets. Kenpaullone was identified as a ‚Äúwinner‚ÄĚ, capable of switching on the Kcc2 gene, which previous research predicted to be beneficial for chronic pain.
Upper left Nerve injury pain and bone cancer pain are serious and pressing unmet medical needs. Preclinical models were used totest Kenpaullone which proved to be highly effective in both.
Middle panels, left-hand Nerve injury by constriction or cancer cells populating a bone activates GSK3ß, an enzyme that tags other proteins with phosphate. In nerve cells dedicated to pain relay in the spinal cord, GSK3ß tags d-catenin
(d-CAT), which routs d-CAT to the cellular garbage bin. Without d- CAT in the cells‚Äô nucleus, the Kcc2 gene remains switched off. This in turn makes the pain relay neurons run full of chloride which makes them electrically more jittery, with chronic ‚Äúrefractory‚ÄĚ pain a result.
Right-hand panel Treatment with Kenpaullone inhibits GSK3b’s phosphate-tagging capability, so that d-CAT becomes untagged, which clears the way to the nerve cells’ nucleus. There it binds to the DNA region of the Kcc2 gene critical for switch-on or switch-off, the promoter. By binding there, d- CAT reverts the switch-off to switch-on and the Kcc2 gene is running again, making KCC2 protein. KCC2 in turn pumps chloride ions out of the pain-relay nerve cells, making them electrically more stable. This leads to circuit repair and pain relief, based on resetting of the genetic switches. Instead of Kenpaullone, d-CAT can serve as payload of a gene therapy approach that directs expression of d-CAT and hence KCC2 to pain relay nerve cells in the spinal cord.

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Australian Organisations Raising Awareness about Trigeminal Neuralgia

Our organisation has been a registered Charity since 2003 and next year will be our 20th Anniversary.  We work tirelessly to ensure all sufferers receive support and our new website has certainly raised our profile in the digital space

In 2018 another organisation was established in Victoria founded by Skye and Peta called FightingTN

These two ladies have created an amazing community where local business support their fund raising by offering a % of profits.

All funds raised by FightingTN are directed to the brain org who utilise the funds for research.

You can buy product on their website, see upcoming events, create and register your own fundraising event too.

https://www.fightingtn.com.au/host-a-fundraiser

Every year FightingTN hosts an awareness day event for Light up in Teal

https://www.fightingtn.com.au/2022ftnevent

We are all working for the same outcome  Рa cure for Trigeminal Neuralgia.

 

 

 

 

 

 

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