Convergences in PP
Convergences in Pelvi-Perineal Pain is a society that aims to promote knowledge about chronic perineal pain. Over the 2-day programme of this society’s 2018 Congress in Brussels, there were many insightful talks by some of the top researchers and clinicians in this field, an overview of these are discussed in this article.
Chronic overlapping pain conditions
In this article by Christin Veasley, Co-Founder & Director of Chronic Pain Research Alliance, the emergence, symptoms, mechanisms and unmet needs of chronic overlapping pain conditions is discussed. Christin hopes to increase the awareness of the issues around chronic pain conditions in America.
Exploring the genome for novel pain targets
There exists significant unmet need for treatments that are targeted to the many underlying mechanisms that cause pain to arise. The genetic study of pain has already revealed some promising targets and it is hoped that research will translate into the development of targeted drugs and the advent of precision medicine in pain. This article summarises current approaches to the genetic study of pain and highlights Grünenthal’s ongoing research in this area.
Intractable and refractory pain
The lack of a clear and consistent definition for chronic neuropathic intractable or refractory pain is one of the main barriers to effective management of these conditions. In this article we have looked into the current thinking of what constitutes ‘refractory’ or ‘intractable’ pain, and the implications that the subtle differences between these words have on the management of these patients.
The neurobiology of the placebo effect – Webinar 1
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Prof. Ulrike Bingel
We are delighted to invite you to an interactive webinar on the neurobiology of the placebo effect session with the internationally renowned Prof. Ulrike Bingel.
Placebo Effect and Pain - Part 1
Understanding the placebo effect in clinical trials for painkillers
PainSolve Editorial Team
The placebo response: a hot topic for pain researchers?
The role of the placebo effect has become a focus in pain research due to its potential to reduce separation between the drug and control arms, and so influence the outcome in randomised controlled trials (RCTs).1 In clinical trials of analgesics, failure to demonstrate benefit over placebo has been a common finding over the past years.2 Many potentially effective analgesic compounds have been discarded in early drug development due to a lack of statistically significant reductions in pain reports in RCTs.2 For example, in the past 10 years it has been estimated that over 90% of candidate drugs in development for neuropathic and cancer pain have been discontinued after failing to show superiority compared with placebo.3
Placebo responses and symptom relief: from expectation to measurable biological effects
Although medical understanding of placebo responses is still far from complete, it is known that for certain conditions, especially those with subjective symptoms, patients receiving placebos may report similar health benefits to participants taking effective drugs.4 Placebos have measurable effects on many symptoms, including pain, depression, fatigue, and other perceptions of bodily dysfunction.4 Several interlinked neuropsychological and neurophysiologic mechanisms driving symptom improvements in response to placebo are recognised:5
- Priming and expectation: the patient believes that a particular intervention will provide benefit/relief. This expectation for the positive outcome seems to play a key role in placebo-related benefit, along with other factors such as optimism and social conditioning, and may produce a medium-sized benefit.
- Effects on brain activity: Functional imaging studies have confirmed that the placebo response of pain relief can be measured as neural activity documented in cortical areas directly associated with pain inhibition.
- Altered biochemical activity: Studies demonstrate that some placebo mechanisms operate by altering the activity of both cholecystokinin (CCK) and endogenous opioids. Other pain regulating pathways, for example involving dopamine and cannabinoid signalling, may also be involved in placebo responses.
The growing body of evidence demonstrating objective physiologic responses to placebo (in terms of measurable alterations in brain and biochemical activity) indicates that improvement in symptoms is a genuine effect, rather than simply spontaneous remission, normal symptom fluctuation, or regression to the mean.6
Are patients’ rising expectations for new pain medicines influencing trial outcomes?
A retrospective analysis of data from 84 published RCTs of drugs for the treatment of chronic neuropathic pain found that the placebo response (in terms of a reduction in pain) has grown over time: from an average of about 18% in the 1990s to an average of 30% by 2013.1 In contrast, the drug response remained stable, leading to a diminished treatment advantage. The authors attributed the increased placebo response to differences in the execution of trials within the US over this period – in particular, the growth in study size (from on average 50 patients per study in 1990, to over 700 per study in 2013), study duration (from on average 4 weeks per study in 1990 to 12 weeks in 2013) and the introduction of contract research organisations, whose clinical trialists may have provided more one-to-one support to patients than they would have received through routine care in primary/secondary care. These changes in trial format may enhance participants’ expectations of the treatment’s effectiveness.7 Similarly, exposure to direct-to-consumer advertising for medicines in the US may increase people’s expectations of the benefits of drugs, and has been proposed as a possible reason why the trend of a rising placebo response was observed in US neuropathic pain trials.3
- Tuttle AH, et al. Pain 2015; 156: 2616–26
- Frisaldi e, et al. Pain Ther 2017; 6: 107–110
- Marchant J. Nature 2015 News, Strong placebo response thwarts painkiller trials. Available at: https://www.nature.com/news/strong-placebo-response-thwarts-painkiller-trials-1.18511 (accessed 18 April 2018)
- Blease CR, et al. BMJ 2017; 356: j463
- Bhardwaj P, Yadav RK. Int J Clin Exp Physiology 2017; 4: 123–128
- Kaptchuk TJ, Miller FG. N Engl J Med 2015; 373: 8–9
- Scutti S. CNN 2016 Health, The real -- and growing -- effects of fake pills. Available at: https://edition.cnn.com/2016/10/27/health/placebo-effect-back-pain/index.html (accessed 18 April 2018)
Psychological Therapy in Pain
Pain is not all in a patient’s head, but can psychotherapy help?
PainSolve Editorial Team
The psychology of pain
Chronic pain is a highly intractable issue that is encountered by clinicians across hundreds of medical conditions.1 Pain can have multiple consequences for affected individuals, including increasing the likelihood for depression, inability to work, disruption to personal relationships, and suicidal thoughts.2 Chronic pain is also frequently accompanied by comorbid psychological disorders, together resulting in significant disability (as measured by impairment of daily activities).2 Since the 1960s, there has been progress in advancing understanding of pain, from seeing pain as a purely physical sensation to recognition that pain can often be a biopsychosocial phenomenon with far-ranging effects on biological, psychological and emotional processes.3,4 This view is reflected in the International Association for the Study of Pain (IASP) definition of pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’.5
Whilst the mechanisms behind the development of chronic pain are incompletely understood, one important contributor that has been identified is perceived stress and stress response systems.1 Supporting patients in better understanding their cognitive and emotional modulation of pain, and promoting self-management techniques through psychological treatments could be an overlooked, but key, part of the puzzle to solving pain.1
Psychological therapies as a tool to manage chronic pain
Psychological interventions are a recommended feature of a modern pain treatment service, where they can be effectively combined with medical treatment as part of the multidisciplinary management of chronic pain.6 Psychological therapies for pain are presumed to confer a low risk for adverse effects to the recipient.7 Rather than focusing on resolution of pain itself, psychotherapy for chronic pain primarily aims to improve physical, emotional, social, and occupational functioning.7
“There is no treatment for patients with chronic pain that makes a bigger difference than our empathy and our time.”1
Psychological therapies for chronic pain fall into four key categories (see table below):7
|Therapeutic modality||Description of treatment||Pain disorders with demonstrated efficacy|
|Operant-behavioural therapy||Treatment focuses on modifying behavioural responses though reinforcement and punishment contingencies, and extinction of associations between the threat value of pain and physical behaviour.||Complex regional pain syndromes, lower back pain, mixed chronic pain, whiplash-associated disorders.|
|Cognitive-behavioural therapy (CBT)||A biopsychosocial intervention focused on developing personal coping strategies. CBT protocols may involve psychoeducation about pain, behaviour, and mood, strategies for relaxation, effective communication, and cognitive restructuring for distorted and maladaptive thoughts about pain.||Cancer, chronic lower back pain, chronic headaches, chronic migraines, chronic orofacial pain, complex regional pain syndromes, fibromyalgia, HIV/AIDS, Irritable bowel syndrome, mixed chronic pain, non-specific heart pain, multiple sclerosis, nonspecific musculoskeletal pain, osteoarthritis, rheumatoid arthritis, spinal cord injury, systemic lupus erythematosus, whiplash-associated disorders.|
|Mindfulness-based therapy||A psychotherapy method that promotes a non-judgmental approach to pain and uncoupling of physical and psychological aspects of pain. Meditations and daily mindfulness practice are utilised to increase awareness of the body, breath and proprioceptive signals, and development of mindful activities.||Arthritis, cancer, chronic lower back pain, chronic headache, chronic migraine, complex regional pain syndromes, fibromyalgia, irritable bowel syndrome, rheumatoid arthritis, chronic neck pain.|
|Acceptance and commitment therapy||Treatment based on increasing psychological flexibility through acceptance of mental events and pain, and ceasing of maladaptive attempts to eliminate and control pain through avoidance and other problematic behaviours.||Musculoskeletal pain (full body, lower back, lower limb, neck, upper limb), whiplash-associated disorders.|
Beginning in the late 1970s and early 1980s, approaches to chronic pain based on CBT have become the dominant psychological approach within pain management.8,9 Among the various forms of psychotherapy applied for chronic pain, the evidence base for effectiveness is strongest for CBT.6 In adults, CBT has been evidenced to support marked improvements in quality of life, disability, psychological distress (principally depression) and, to a lesser extent, pain.6 The impact of CBT on pain is stronger in the paediatric population, where it has been described as ‘one of the most successful treatments for paediatric chronic pain’.6
Future directions to improve access to psychotherapy
Given the magnitude of the problem and the modest benefits from traditional medical, pharmacological, and surgical treatments, there is a growing realisation of the importance of considering psychosocial factors when addressing chronic pain and pain-related disability.4 An ideal pain management regimen will be comprehensive, integrative, and interdisciplinary, so including psychological interventions as part of a multimodal approach can provide a safe and effective means to help patients feel more in command of their pain control and enable them to live as normal a life as possible despite pain.10
Treatment accessibility may be a limitation for psychological intervention; for example, the availability of psychotherapists with appropriate expertise and experience in supporting patients with chronic pain management is limited in certain healthcare systems.7,9 Similarly, even when specialist support is available, patients in poverty or those living in remote geographical locations may struggle to access these.7 Technology allowing remote access, such as online video therapy sessions or virtual reality clinics, may help to improve access to these psychological therapies in pain management.7,11,12 Delivery of psychological interventions by healthcare professionals other than psychologists (for example nurses or physical therapists), or within collaborative care models in primary care (where a patient’s healthcare needs are supported in an integrated approach involving coordination with social and mental health teams) are gaining interest as innovative approaches to address access barriers.9
- Crofford LJ. Trans Am Clin Climatol Assoc 2015; 126: 167–183
- Goldberg DS, McGee SJ. BMC Public Health 2011; 11: 770
- Lumley MA, et al. J Clin Psychol 2011; 67: 942–968
- Jensen MP & Turk DC. Am Psychol 2014; 69: 105–118
- International Association for the Study of Pain (1994) IASP Taxonomy, Pain terms, Pain. Available at: https://www.iasp-pain.org/Taxonomy#Pain (accessed April 2018)
- Eccleston C, et al. Br J Anaesth 2013; 111: 59–63
- Sturgeon JA, et al. Psychol Res Behav Manag 2014; 7: 115–124
- Barker E & McCracken LM. Br J Pain 2014; 8: 98–106
- Ehde DM, et al. Am Psychol 2014; 69: 153–166
- Roditi D & Robinson ME. Psychol Res Behav Manag 2011; 4: 41–49
- Fisher E, et al. Cochrane Database Syst Rev. 2015; 3: CD011118
- Hoch DB, et al. PLoS ONE 7: e33843
The placebo effect and pain - Part 2
Future directions to minimise ‘false negatives’ in pain trials
PainSolve Editorial Team
Given that there is a measurable placebo response in pain and that the impact of this effect may be increasing over time, there is considerable interest in adapting pain clinical trial methodologies and designs to reduce the likelihood of ‘false negative’ trial outcomes due to large pain reductions in the placebo group.1 Several strategies have been proposed for this (see table 1 below):
Table 1: Potential approaches to take account of the placebo response in pain trials
|Using a placebo lead-in phase (where all participants are on placebo)||Allowing investigators to engage the placebo response prior to randomisation to active drug and placebo control conditions, and to then identify and remove participants who exhibit strong placebo response2|
|Informing patients in trials about placebo effects||Providing information leaflets about the potential for disease-specific symptom improvement when taking a placebo, thus reducing therapeutic misconceptions among participants3|
|Assessing patients’ expectations for treatment||Using a scale for the measurement of patients’ expectations about the therapy they are receiving, and then using the results of this assessment as a co-variable when interpreting trial endpoints4|
|Using functional imaging as an objective assessment of pharmacological responders||When applied to early proof of concept studies this approach can reduce the reliance on subjective measures of pain response by distinguishing between neural activity arising from pharmacological analgesia versus placebo response6|
|Analysis of published trial data to identify potential factors influencing the magnitude of placebo response||This approach has been applied in neuropathic pain5 and fibromyalgia7, and has identified patient demographic and baseline characteristics associated with elevated placebo response in these conditions|
|Identifying genetic signatures associated with variations in placebo responses||Although this approach is at an early stage, research is underway to identify the ‘placebome’: a group of genome-related mediators that affect an individual's response to placebo treatment, thus allowing researchers to minimise the effect of the placebo response in clinical trials8|
For researchers, excluding trial participants who are identified as being high placebo-responders may reduce the generalisability of the trial’s findings to real-world practice (where they would not be excluded from treatment) and increase the number of patients who need to be enrolled in a study.1 Thus, ensuring that variations in placebo response level between patients are identified and assessed as a co-variable (similar to other variables such as age, sex, BMI) may be a preferable approach. Management options for chronic pain are still suboptimal for many conditions, so understanding and addressing the challenge of the placebo response in clinical trials will be essential when developing more effective treatment options for patients and their healthcare providers.
- Gilron I. Expert Rev Clin Pharmacol 2016; 9: 1399–1402
- Harden RN, et al. Pain Medicine 2016; 17: 2305–2310
- Blease CR, et al. BMJ 2017; 356: j463
- Frisaldi e, et al. Pain Ther 2017; 6: 107–110
- Arakawa A, et al. Clin Drug Investig 2015; 35: 67–81
- Wanigasekera V, et al. Br J Anaesth 2018; 120: 299–307
- Chen X, et al, Clin Rheumatol 2017; 36: 1623–1630
- Scutti S. CNN 2016 Health, The real -- and growing -- effects of fake pills. Available at: https://edition.cnn.com/2016/10/27/health/placebo-effect-back-pain/index.html (accessed 18 April 2018)
TRP ion channels and analgesia – targeting cellular environmental sensors
PainSolve Editorial Team
Understanding nociception: the role of ion channels in detecting physical stimuli
Since the cloning of the capsaicin receptor, now known as TRPV1 (Transient Receptor Potential Vanilloid 1) in 1997, much progress has been made in understanding the role of this and related TRP ion channels as cellular sensors involved in nociception (Kaneko 2014). Currently, 28 TRP ion channels have been identified (Huang 2017), which are divided into six subfamilies on the basis of sequence homology (Kaneko 2014). Eight members from three subfamilies have been reported to be involved in nociception (table 1) (Gonzalez-Ramirez 2017).
|TRP ion channel subfamily||Members involved in nociception||Associated pain modalities|
|TRPV (Vanilloid)||TRPV1||Inflammatory pain, neuropathic pain, visceral pain|
|TRPV3||Nociceptive pain, inflammatory pain|
|TRPV4||Mechanically-evoked pain, inflammatory pain, neuropathic pain, visceral pain, headache|
|TRPM (Melastatin)||TRPM2||Inflammatory pain|
|TRPM8||Cold hypersensitivity, neuropathic pain|
|TRPA (Ankyrin)||TRPA1||Cold hypersensitivity, nociceptive pain, inflammatory pain, mechanical hyperalgesia, inherited episodic pain syndrome|
–: None to date.
All the TRP channels known to participate in nociception are ligand-gated cationic channels. These channels are expressed by excitable membranes, such as those in primary sensory neurons (PSNs). When activated, TRP channels become permeable to all major cations (Na+, K+, Ca2+) in the extra- and intracellular fluids. This depolarises the membrane and increases the probability of action potential generation, which induces excitation in postsynaptic neurons. Nociceptive neurons send signals from the periphery, through the afferent fibers, to the visceral, trigeminal, and somatic regions, and also connect the spinal cord to the brain, thus serving as mediators in painful stimulus transmission between the central and peripheral nervous systems (Gonzalez-Ramirez 2017). Selective and specific blockade of nociception-related TRP channels should reduce PSN excitation, thereby, providing significant pain relief (Sousa-Valente 2014).
Insights from early TRP channel modulators
TRPV1 is the most well-characterized TRP channel and can be activated by temperature (~42°C), pH, and a variety of endogenous and exogenous compounds (Gonzalez-Ramirez 2017). Many compounds have been developed to modulate TRPV1 activity (Carnevale 2016). However, early trials of TRPV1 antagonists revealed that they can cause hyperthermia and accidental burns in susceptible patients (by elevating the threshold for detection of noxious heat) (Gonzalez-Ramirez 2017). Consequently, several TRPV1 antagonists such as AMG-517 and AZD1386 were discontinued.
Investigational TRP channel modulators and future directions
Burn prevention measures such as prestudy counseling and provision of temperature-testing devices were employed in a phase I trial of mavatrep, a novel TRPV1 antagonist (Manitpisitkul 2016). An efficacy signal was observed in participants with osteoarthritis (OA) pain (Manitpisitkul 2018). Preliminary results from a phase II study of NEO6860, another TRPV1 antagonist, demonstrated that NEO6860 has an analgesic effect without affecting core body temperature or noxious heat perception in patients with severe OA pain (Neomed 2017).
|Type of molecule||Agent (company)||Indication||Trial phase (ClinicalTrials.gov Identifier)||Status|
|TRPV1 antagonist||Mavatrep/JNJ-39439335 (Janssen)||Chronic pain||Phase I (NCT00933582)||Completed|
|TRPV1 antagonist||NEO6860 (Neomed Institute)||OA pain, Neuropathic pain, Visceral pain||Phase II (NCT02712957)||Completed|
|TRPV1 agonist||Qutenza/capsaicin (Acorda; Grunenthal)||Peripheral neuropathic pain||Approved by FDA and EMA in 2009|
|TRPV1 agonist||Resiniferatoxin (Sorrento Therapeutics)||Neurogenic inflammatory pain||Phase I (NCT00804154)||Recruiting|
|TRPV3 inhibitor||GRC-15300 (Glenmark Pharmaceuticals; Sanofi)||Neuropathic pain||Phase II (NCT01463397)||Completed; development terminated in 2014|
|TRPA1 antagonist||GRC-17536 (Glenmark Pharmaceuticals)||Neuropathic pain||Phase II (NCT01726413)||Completed|
Nonsteroidal anti-inflammatory drugs (NSAIDs) have the potential for serous cardiovascular and gastrointestinal side effects and opioids are associated with respiratory depression. It is anticipated that TRP channel modulators will provide an alternative treatment option to NSAIDs and opioids (Dai 2016).
Grünenthal, the KU Leuven’s Centre for Drug Design and Discovery (CD3) and the Laboratory of Ion Channel Research (LICR) recently announced that they have entered into a research collaboration to develop an innovative non-opioid pain treatment (KU Leuven 2018).
- Carnevale V, Rohacs T. Pharmaceuticals (Basel). 2016; 9: pii: E52
- Dai Y. Semin Immunopathol. 2016; 38: 277-91
- González-Ramírez R, et al. Chapter 8. TRP channels and pain. In: Emir TLR, editor. Neurobiology of TRP Channels. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2017
- Huang S, Szallasi A. Pharmaceuticals (Basel). 2017; 10: pii: E64
- Kaneko Y, Szallasi A. Br J Pharmacol. 2014; 171: 2474–507
- KU Leuven. Grünenthal and KU Leuven join forces to develop an innovative non-opioid pain treatment. Available at:https://lrd.kuleuven.be/en/news/grunenthal-and-ku-leuven-join-forces-to-develop-an-innovative-non-opioid-pain-treatment (accessed 06 June 2018)
- Manitpisitkul P, et al. Pain Rep. 2016; 1: e576.
- Manitpisitkul P, et al. Scand J Pain. 2018; 18: 151–164
- Moran MM, Szallasi A. Br J Pharmacol. 2017; doi: 10.1111/bph.14044
- Neomed Institute. NEO6860 Transient receptor potential vanilloid type 1 (TRPV1) antagonist. Available at: http://neomed.ca/en/projects/neo6860/ (accessed 06 June 2018)
- Sousa-Valente J, et al. Br J Pharmacol. 2014; 171: 2508–27
2018: The Global Year for Excellence in Pain Education
PainSolve Editorial Team
IASP Global Year
Every year, the International Association for the Study of Pain (IASP) hosts a Global Year to disseminate knowledge and raise awareness across a range of issues related to pain. This year, the theme is ‘Bridging the gap between knowledge and practice’, with an overarching goal to make a difference in four key domains:
- Public and Government Education
- Patient Education
- Professional Education
- Pain Education Research
EFIC® Education Platform
The European Pain Federation EFIC® is a multidisciplinary professional organisation in the field of pain science and medicine, representing 37 European National Pain Societies. As part of their commitment to furthering pain understanding, and of particular relevance during the Global Year for Excellence in Pain Education, they have developed the EFIC® Education Platform .
This resource compiles dozens of videos from EFIC® congresses and other scientific initiatives across a range of pain topics, with the primary aim of disseminating knowledge and initiating conversations. Professionally filmed symposia, lectures and debates from world-renowned experts in pain allow you to experience or relive these important events, and comments boxes on each video open a dialogue across a network of pain professionals.
Videos are viewable to all registered users free of charge, and searchable by title, author and topic.
"Education is, among research and advocacy, one of the three core missions of the European Pain Federation EFIC®. Indeed, by investing into a performant e-learning platform, we offer a service to our community. Furthermore, we try to fill the gap of inequity of the access to excellent pain education of all HCPs in Europe and the rest of the world. I thank all presenters for their generous contributions to the platform and encourage you to sign-in."
CGRP Antibodies for the Treatment of Migraine
Can the first migraine-specific therapeutics change the treatment landscape?
PainSolve Editorial Team
State of the art in migraine
Migraine is one of the most prevalent and disabling disorders in the world, yet, until recently, no preventive treatments in clinical use were developed specifically for migraine. In May 2018, the FDA approved the first in a new class of drugs designed for the preventive treatment of migraine in adults.1 Erenumab, administered as a once-monthly self-injection, acts by blocking the activity of calcitonin gene-related peptide (CGRP), a molecule that spikes during migraine attacks.1,2 Three other CGRP-targeted monoclonal antibodies are also under investigation for their potential in the treatment of migraine: galcanezumab, eptinezumab and fremanezumab.3
The pathophysiology of migraine
Migraine is a neurological disorder characterised by debilitating headache accompanied by sensory alterations.4 The trigeminovascular system is intricately involved in the pathophysiology of migraine; it is thought that migraine headache is a manifestation of altered brain excitability activating the trigeminovascular system in genetically susceptible individuals.4,5 The system is centred around the trigeminal nerve, the efferent projections of which synapse with second-order neurons in the trigeminal nucleus caudalis (TNC) of the brainstem.4 These neurons project to the thalamus, where ascending input is integrated and relayed to higher cortical areas.4 Activation of the trigeminovascular system most likely involves peripheral mechanisms, such as inflammatory mediators and agents released during neurogenic inflammation and cortical spreading depression (CSD).4 The most abundant neuropeptide in the trigeminal nerve is CGRP, which is expressed in 35–50% of neurons in the trigeminal ganglia.4
CGRP and its role in migraine
CGRP is a 37-amino acid discovered over 30 years ago that is widely distributed throughout the central and peripheral nervous systems.6 It has been implicated in the pathophysiology of migraine and evidence suggests it also plays a role in other headache and facial pain disorders.6,7 CGRP exists in 2 isoforms: α-CGRP (found in both the central and peripheral nervous systems and preferentially expressed in sensory neurons) and β-CGRP (preferentially expressed in enteric nerves and the pituitary gland).8 α-CGRP is more abundantly expressed than β-CGRP and has a 3- to 6-fold higher concentration.8
CGRP acts on an unusual receptor family that consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP).3,8 The CGRP receptor is expressed throughout the nervous system and is also found throughout the arterial system in the smooth muscle cell layer, including the cardiovascular and cerebrovascular systems, in addition to the adrenal glands, kidneys, and pancreas.3 During a migraine, CGRP is released from trigeminal afferent nerve fibres, causing vasodilatation and neurogenic inflammation. CGRP-targeted antibodies are believed to work by blocking the activity of CGRP, reducing migraine symptoms.6
The evidence for CGRP antibodies in migraine
The use of monoclonal antibodies for the treatment of neurological disorders has increased in recent years, partly due to their highly specific activity and long half-life, making them suitable for conditions such as migraine and allowing for less frequent dosing (i.e. once or twice monthly).3 There are 4 CGRP-targeted monoclonal antibodies currently under investigation for migraine prevention (see table below).9,10 Erenumab is the only antibody that targets the CGRP receptor and has recently been approved by the FDA; the other drugs (galcanezumab, eptinezumab and fremanezumab) target CGRP itself and have received approval from regulatory authorities.1–3
|Drug name||Target||Half-life||Key phase 3 trials|
|Erenumab(AMG-334)||CGRP receptor with a human antibody||21 days||STRIVE (completed in EM) ARISE (completed in EM) LIBERTY (ongoing in refractory EM) EMPOwER (ongoing in EM)|
|Galcanezumab(LY2951742)||CGRP with a humanised antibody||28 days||EVOLVE-1 and EVOLVE-2 (ongoing trials in EM)REGAIN (ongoing in CM)|
|Eptinezumab(ALD403)||CGRP with a humanised antibody||31 days||PROMISE 1 (ongoing in frequent EM)PROMISE 2 (ongoing in CM)|
|Fremanezumab(TEV-48215)||CGRP with a fully humanised antibody||40–48 days||HALO (ongoing long-term safety)FOCUS (ongoing in refractory EM or CM)|
CM: Chronic migraine; EM: Episodic migraine
Evidence for these innovative treatments in migraine have been positive; phase 2 and phase 3 trials versus placebo treatments indicate efficacy from approximately 4 weeks (current preventative treatments typically take up to 8 weeks), although these results should be interpreted with caution.3 Statistical analyses suggest that these therapies are associated with significantly fewer days with migraine.3,10 Safety and tolerability data appear promising with no major safety signals identified.3,10
The future of migraine therapies
The CGRP-targeted monoclonal antibodies represent the first class of therapeutics targeted at a migraine-specific mechanism and may well shape the future of migraine prevention. The recent FDA approval of erenumab paves the way for more widespread adoption of CGRP antibodies and will allow for the collection of real-world data to better analyse the impact on patients, as well as potential expansions into other indications such as cluster headache.
- FDA. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm608120.htm
- Science. Available at: http://www.sciencemag.org/news/2018/05/will-antibodies-finally-put-end-migraines
- Tso AR & Goadsby PJ. Curr Treat Options Neurol. 2017; 19(8): 27.
- Russo AF. Annu Rev Pharmacol Toxicol. 2015; 55: 533–552.
- Noseda R & Burstein R. Pain. 2013 Dec; 154 Suppl 1: 10.1016/j.pain.2013.07.021.
- Russell FA et al. Physiol Rev. 2014 Oct;94(4):1099-142. doi: 10.1152/physrev.00034.2013.
- Schuster NM & Rapoport AM. Clin Neuropharmacol. 2017 Jul/Aug;40(4):169-174. doi: 10.1097/WNF.0000000000000227.
- Durham PL. Headache. 2008 Sep; 48(8): 1269–1275.
- Bigal ME et al. Br J Clin Pharmacol. 2015 Jun; 79(6): 886–895.
- Edvinsson L. Headache. 2018 May;58 Suppl 1:33-47. doi: 10.1111/head.13305.
IMI-PainCare – Improving the Care of Patients Suffering from Acute or Chronic Pain
Can the ambitious goals of the IMI-PainCare public-private partnership revolutionise pain research and development?
PainSolve Editorial Team
Aims of the IMI and the Pain Group collaboration
Established ten years ago, the Innovative Medicines Initiative (IMI) is a partnership between the European Commission and the European pharmaceutical industry, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA).1 The IMI works to improve health by speeding up the development of, and patient access to, innovative medicines, particularly in areas where there is an unmet medical or social need.1 The IMI-2 is the world’s biggest public-private partnership in life sciences, with a €3.3 billion budget for the period 2014–2020.1 Grünenthal have been involved in the ‘Patients Active in Research and Dialogues for an Improved Generation of Medicines’ (PARADIGM) project and will also join other initiatives to establish networks of specialists, including the ‘European Screening Center Unique Library of Attractive Biology’ (ESCulab), and ‘Linking digital assessment of mobility to clinical endpoints to drive regulatory acceptance and clinical practice’. Pain remains at the forefront of Grünenthal’s priorities, and the IMI Pain Group provides opportunities to further advance research in this area.
The IMI Pain Group unites companies of the EFPIA who are dedicated to better understand, treat and manage pain. It was founded in 2015 as a section of the IMI Strategic Governance Group Neurodegeneration.2 The IMI offers a framework to achieve this aim, as it facilitates collaboration between pharmaceutical companies, universities, small-midsized enterprises, patient organisations, regulators, and others.2 The Pain Group establishes a portfolio of pain projects, organised as public-private partnerships, that address a broad spectrum of challenges with particular societal value. The first collaborative project, NGN-PET, of the IMI Pain Group with renowned public partners was started in April 2017 and applies novel approaches to understanding neuropathic pain. Now a second project, IMI-PainCare, aims to address specific scientific challenges.
The IMI-PainCare Public-Private Partnership
Co-led by Petra Bloms-Funke, Grünenthal, and Rolf-Detlef Treede, University of Heidelberg, IMI-PainCare is a consortium composed of 40 participants from 14 countries, which is aimed at improving the care of patients suffering from acute or chronic pain.3 This initiative will involve the development of a toolbox that can streamline the research and development process for novel analgesic drugs and improve treatment quality in clinical practice.3 The project comprises three sub-projects: PROMPT, BioPain and TRiPP.3
PROMPT – providing a core set of patient-reported outcome measures
Led by Winfried Meissner, University of Jena, and Hiltrud Liedgens, Grünenthal, PROMPT aims to improve the management of pain by defining a core set of patient-reported outcome measures (PROMs) that are predictive indicators of treatment success in controlled trials as well as real-world conditions. This core set of PROMs will address pain intensities, functional consequences of pain and help identify patients at risk of experiencing chronification of acute post-operative pain. The objective is to implement the standard use of the core set of PROMs in randomised controlled trials and care of pain patients in clinical practice. It is hoped that the outputs of the initiative will help healthcare professionals to improve pain management and the patient’s quality of life.
BioPain – pharmacological validation of functional pain biomarkers in healthy subjects and animals
Led by Rolf-Detlef Treede, University of Heidelberg, and Keith Phillips, Eli Lilly and Company, BioPain aims to validate functional biomarkers and establish pharmacokinetic/pharmacodynamic models in healthy humans and back-translate to rodents to improve candidate selection and increase the chance of a successful translation from pre-clinical to clinical development. The main hypothesis driving this work is that effect sizes of analgesic actions on at least some objective biomarkers of nociceptive signal processing can be translated between rodents, healthy volunteers undergoing surrogate models of pain sensitisation and patients suffering from chronic pain.
TRiPP – improving translation in chronic pelvic pain
Led by Katy Vincent, University of Oxford, and Jens Nagel, Bayer, TRiPP aims to determine subgroups within endometriosis and interstitial cystitis/bladder pain syndrome and identify biomarkers of these clinical phenotypes. The main hypothesis driving this project is that the symptoms of pain experienced by women suffering from these conditions are generated and maintained by mechanisms similar to those found in other chronic pain conditions, but occur in combination with specific pathological lesions and symptoms. By reconceptualising these conditions, meaningful subgroups of patients can be identified and better pre-clinical models developed, ultimately helping to facilitate drug development in this field.
Staying up to date with IMI-PainCare
More information on IMI-PainCare can be found at https://www.imi-paincare.eu/ including a calendar of events and list of partners for each sub-project. We look forward to seeing the progress made in these initiatives, and updates are expected to be published online towards the end of 2018.
- IMI. Available at: https://www.imi.europa.eu/about-imi/history-imi-story-so-far
- IMI. Available at: https://www.imi.europa.eu/about-imi/governance/strategic-governing-groups
- IMI PainCare. Available at: https://www.imi-paincare.eu/
Placebo Effect and Pain – Part 3
Can patient training help address symptom reporting challenges in analgesic clinical trials?
PainSolve Editorial Team
Why may analgesic drugs fail to show efficacy in clinical trials?
Across all therapy areas, a global analysis for the period 2013–2015 shows that failure to demonstrate efficacy in phase 2 or phase 3 studies was the leading reason for discontinuing development of drugs (both investigational agents, and marketed drugs under evaluation for new indications).1 For neurologic and psychiatric disease, late-stage clinical trial failure rates are disproportionately high when compared with those for other disease areas.2
A key challenge in studies for indications such as mood disorders, Alzheimer’s disease, and pain, is that subjective outcome measures, which are known to be vulnerable to bias3 and variance,4 may be endpoints for efficacy. The placebo response is also relevant, particularly in trials of novel analgesics, where patient responses to placebo can reduce the differences observed between outcomes for the active versus control arms.5
How can inaccurate self-reporting of pain in trials be addressed?
Patient training to improve the accuracy of their pain reporting has recently been applied in an analgesic clinical trial setting in the USA, where it has shown promise for increasing the likelihood of success in such trials.6 This Grünenthal-supported pilot study (NCT02842554) was a 2-stage randomised, double-blind trial in 51 adults who had peripheral diabetic neuropathy for at least 6 months (Figure 1). In Stage-1 (Training), subjects were randomised to accurate-pain-reporting-training (APRT) or control (No-Training). The APRT participants received feedback on the accuracy of their pain reports in response to mechanical stimuli applied multiple times at different intensities, with the correlation between stimuli intensities and pain intensity reports measured using Pearson’s R2 score.
In Stage-2 (Evaluation), all participants entered a placebo-controlled, crossover trial. They received treatment with pregabalin or placebo for 10–13 days, before crossover to the alternative treatment for a similar period (a washout interval of at least 6 days separated the 2 treatment periods). Primary (24-hour average pain intensity [0–10 scale]) and secondary (current, 24-hour worst, and 24-hour walking pain intensity) outcome measures were reported at the beginning and end of each treatment period.6
APRT study findings and future perspectives
In Stage-1 of the study, the APRT patients (n=28) demonstrated significant (p=0.036) increases in R2 scores indicating improvements in pain reporting accuracy due to training. This effect was demonstrated for 70.8% of these subjects. In the second study stage, the APRT group demonstrated significantly (p=0.018) lower placebo response for the primary outcome measure versus the No-Training group (0.29 ± 1.21 vs. 1.48 ± 2.21 respectively, mean difference ± SD=-1.19 ± 1.73). No relationships were found between the R2 scores and changes in pain intensity in the treatment arm.6
This pilot study shows that pain reporting accuracy is a trainable skill that can be improved, and that this improvement in turn reduces the placebo response. The findings support further research in a larger study to confirm these observations, and have implications for future analgesic, and potentially other neurological and psychiatric clinical trials. Potential benefits of training trial participants to improve their symptom reporting include improved assay sensitivity, reduced sample size requirements, increased likelihood of trial success, and accelerated development of new treatment options for patients whose clinical needs are currently unmet.6
- Pankevich DE, et al. Neuron 2014; 84(3): 546–53
- Harrison RK. Nat Rev Drug Discov 2016; 15(12): 817–8
- Heneghan C, et al. Trials 2017; 18: 122
- Farrar JT, et al. Pain 2014; 155: 1622–31
- Tuttle AH, et al. Pain 2015; 156(12):2616–26
- Treister R, et al. PLoS ONE 2018; 13(5): e0197844. Full article online at: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197844
Lack of clear and consistent definition for chronic neuropathic intractable or refractory pain
What are the implications for a lack of a clear definition?
PainSolve Editorial Team
Unmet need in chronic neuropathic pain treatment
Most patients with chronic neuropathic pain are treated with medications as the mainstay of therapy, and yet most medically treated patients continue to report ongoing pain. A recent evidence-based review of medical therapy for neuropathic pain concluded that “existing pharmacologic treatments for neuropathic pain are limited, with no more than 40-60% of patients obtaining partial relief of their pain.”1 This means that roughly half of all patients with common conditions, such as diabetic peripheral neuropathy, lumbar radiculopathy or postsurgical neuropathic pain will not have sufficient improvement with conservative pain care measures.2
What is refractory and intractable pain?
Chronic neuropathic pain not responding to multiple treatment options is often called “refractory” or “intractable” pain. According to medical dictionary, intractable pain is “Chronic pain that is difficult or impossible to manage with standard interventions”, whereas the term refractory stands for “not responding to treatment”. Both terms are generally used synonymously. However, different definitions have been given in the literature, and whilst these definitions share some common features, issues arise when they are not used consistently across publications and there is divergence across sources.3 Treatments often state specific indications for either refractory or intractable pain, which can cause confusion for clinicians. For example, in 2004, Ziconotide (Prialt®) was approved by the FDA for treatment of severe refractory pain, and more recently in 2015 the spinal cord stimulation system (Senza System) was approved for intractable pain of the trunk and/or limbs.
Refractory or intractable – choose your words carefully
The term “intractable” may have a negative association for both the treating physician and the patient, because it gives the impression that the pain cannot be adequately relieved anymore. For the clinician it may also mean: “I am not going to treat you because it is not going to work”. The term “refractory” may be understood as pain which is not adequately controlled by some treatments but may be relieved by others.
The importance of a clear definition
A continued pharmacological drug rotation, strong opioids, spinal cord stimulation or intrathecal drug delivery are indicated for patients with chronic refractory or intractable pain.2,4 However, the lack of clear definition makes it challenging for the clinicians to decide when to prescribe more invasive treatment options. There are guidelines for chronic pain management, but there are no guidelines for the treatment of chronic refractory or intractable pain.
A consistent, clinically relevant definition of chronic refractory or refractory neuropathic pain would facilitate selection of appropriate interventions to enhance patient outcomes, as well as provide a foundation for future clinical research. A clear definition would also allow the prevalence of patients within different chronic neuropathic pain indications to be assessed.
- Dworkin RH, et al. Pain 2007; 132: 237-51
- Lamer TJ, et al. Mayo Clin Proc 2016; 91: 246-58
- Deer TR, et al. Neuromodulation 2014; 17: 711-5
- Wallace MS. Expert Rev Neurother 2006; 6: 1423-8
The future of pain management: Exploring the genome to identify new targets and inform treatment selection
Does current research represent the dawn of precision medicine in pain management?
PainSolve Editorial Team
Pain – an individual experience
Pain is a subjective experience. It is influenced by multiple factors including sex, race, ethnicity, psychological and social contexts and interpretation of pain, not to mention the environment.1 There exists interindividual variability in pain sensitivity, tolerance, the response to treatments and the propensity to develop chronic pain conditions.1–3 It is, therefore, challenging both to study pain and to manage it effectively.
Current pain-relieving treatments can be rather blunt tools and are often associated with side effects.4 There is a need to identify targets and treatments that are as individual as the experience of pain. Studies of twins have provided insight into the interindividual variability that can be explained by genetic factors.2,5 Thus, innovation in this area will likely come via a deeper understanding of the genetic contribution to individual differences in the pain experience, as well as the molecular mechanisms underlying chronic pain conditions. This article aims to summarise some of the current approaches.
Exploring the genome for novel pain targets
Currently, the genetics of pain is investigated in three main ways. Firstly, there is the study of rare inherited pain conditions. This has led to the identification of some specific important mutations. For example, mutations in the gene for the sodium channel Nav1.7 (SCN9A) have been associated with insensitivity to pain, informing the development of sodium channel blockers with greater selectivity.5,6 In addition, loss-of-function mutations in the gene encoding the neurotrophic receptor tyrosine kinase 1 (TrkA), a receptor tyrosine kinase for NGF, have been associated with an absence of small diameter sensory neurons, leading to the development of TrkA inhibitors.5,7
Secondly, there is linkage analysis to determine which genes are linked, i.e. inherited together based on their proximity on the same chromosome, through the study of large families.8 Family members who do and do not have pain are phenotyped and genotyped to determine which genes separate out with the disease.8
Finally, there are genetic association studies of large cohorts of matched, but unrelated, individuals to identify genetic variants that are distributed unevenly in those with pain and those without.5 Association studies test either a limited number of pre-selected genes (a candidate gene approach) or all variants in an unbiased screen (a genome-wide approach). These approaches are more relevant to the general population than is the study of rare conditions. While the study of familial pain conditions reveals ‘rare, high-impact mutations’, most genetic association studies reveal common single nucleotide polymorphisms (SNPs), found in >1% of the population, that modulate susceptibility to a given pain condition rather than cause it.8
In the public GWAS databases, numerous genes have been reported in genetic association studies across multiple chronic pain conditions, including cancer pain, low back pain, migraine, peripheral neuropathy, postoperative pain and temporomandibular disorder.8 The most recent studies have presented associations with neuropathic pain in post total joint replacement surgery for osteoarthritis9 and head and neck cancer10 (see the GWAS Catalog, GWAS Central, Human Genome Variation Database and National Human Genome Research Institute). However, to date, the results of association studies have been largely difficult to reproduce. This can reflect the large interindividual variability, suggesting the need for more rigorous phenotyping, use of a broader spectrum of -omics methods, cutting-edge analysis methods, as well as more homogeneous populations.5
Grünenthal’s expertise in pain research
Grünenthal is focused on improving the understanding of the biology of pain to uncover insights for patient stratification and biomarkers, identify pathways in which existing drugs are likely to be effective, and identify and validate new targets for treatment. Researchers are currently concentrating on genetic linkage studies, conducting detailed phenotyping and collecting tissue that undergoes multiple ‘omics’ analyses to identify which genes, RNAs, proteins or metabolites are associated with which phenotypical characteristics. In a next step, the so called ‘omics’ findings are enriched via pathway analysis to understand the underlying relevant biological pathways that are linked to the respective phenotypical characteristics. Examples of Grünenthal’s research can be accessed through links to the posters below.
- Preliminary Results of Comparative Proteomic Profiling of Sciatic Nerve, Plasma and Csf in a Rat Model of Neuropathic Pain
- Pain Testing@Home – The Cold Pressor Test as a first example
- Validity of online, self-administered Pain Sensitivity Questionnaire
In line with this strategy, the paper of Themistocleous et al. (2018) describes the ways in which patients with neuropathic pain may be stratified and the benefits of this stratification to reduce the uncertainty in diagnosis and help improve prevention, prognostication, and treatment selection.11 Figure 1 summarises some of the ways in which patients can be stratified.11
Figure 1.11 Schematic representations of some of the techniques that can be used to stratify patients with neuropathic pai. QST: quantitative sensory testing
The recent findings of Cobos et al. (2018) who correlated gene expression with behaviour following nerve injury in a mouse model validate this approach.12 They found that two common manifestations of neuropathic pain, cold and tactile allodynia, which develop at different timepoints after injury are associated with two distinct cellular and molecular mechanisms. One mechanism occurs in neurons, leading to cold allodynia, and the other includes immune cells and neurons, leading to tactile allodynia. The authors describe the potential to target drug development to each of these types of allodynia.12
As a basis to start this approach, Grünenthal conducted research using specific search terms combining -omics results with disease indications in pain to extract knowledge from relevant literature. This database has been used for gene set enrichment analysis to identify relevant biological pathways, which enhances the understanding of pathophysiologies of pain at the molecular level. Grünenthal is building a big picture of relevant biological pathways that enables the identification of unique and overlapping pathways for several pain indications that we will share with the PainSolve community in Q1 2019. As an example, we have shared a relevant pathway from our chronic constriction injury (CCI) experiments, which was reported at the IASP meeting in September (Figure 2). Such information can also be used to determine where existing drugs may be repurposed; we will report on our approach to drug repurposing in a future article. To date, a pilot in complex regional pain syndrome (CRPS) has been completed and analyses are ongoing for several other pain indications, with a particular focus on the processes behind molecular mechanisms of chronification in pain.
Figure 2: Pathway analysis of data sets revealed several proteins within the complement system that highlight neuropathic and postoperative pain involvement
Future directions – looking towards precision medicine for pain
While -omics studies in pain indications are still at their beginning, results to date suggest it may lead to promising new strategies for the assessment and treatment of pain conditions in the future. New patient stratification techniques and novel treatment options may translate into the development of drugs targeted to molecular pathways unique to particular conditions and pathologies, and the realisation of precision medicine in pain.
- James S. Br J Pain 2013; 7: 171–8
- Coghil RC. Headache 2010; 50: 1531–5
- LaCroix-Fralish ML, et al. Annu Rev Pharmacol Toxicol 2009; 49: 97–121
- Mayo Clinic (2018). Available at: https://www.mayoclinic.org/chronic-pain-medication-decisions/art-20360371
- Crow M, et al. Genome Medicine 2013; 5:12
- Versavel M. J. Pain Relief 2015; 4:3
- Bagal SK, et al. J Med Chem 2018; 61: 6779–800
- Zorina-Lichtenwalter K, et al. Neuroscience 2016; 338: 36–62
- Warner SC, et al. Eur J Hum Genet 2017; 25(4): 446-451
- Reyes-Gibby CC, et al. Sci Rep 2018; 8(1): 8789
- Themistocleous AC, et al. Pain 2018; 159: S31–S42
- Cobos EJ, et al. Cell Rep 2018; 22: 1301–12
Chronic Overlapping Pain Conditions
Christin Veasley, Co-Founder & Director, Chronic Pain Research Alliance
Impact vs Belief – a disconnect in chronic pain
The Institute of Medicine’s (IOM) historic 2011 report, Relieving Pain in America, documented the profound cumulative impact of chronic pain on our nation, finding that four in ten American adults live with chronic pain disorders, with annual costs exceeding $500 billion.1
In March 2013, the National Poll on Chronic Pain was conducted online by Zogby Analytics for Research!America. The survey had a sample size of 1,016 with a theoretical sampling error of +/- 3.1%.2 A major highlight of the survey was that most Americans (63%) reported knowing someone with pain so severe that s/he sought prescription medications to treat it. Further, the majority, 60%, reported thinking that chronic pain tends to be dismissed by doctors and the general public. However, when respondents were asked to select health conditions they considered to be major health problems in the US, only 18% listed chronic pain as a major health problem, demonstrating a major public disconnect.
One reason for this disconnect can be traced back to a longstanding underinvestment in pain research by the U.S. federal government. Chronic pain affects the same number of people as cancer, heart disease and diabetes combined (100 million), and in 2016, the National Institutes of Health (NIH) invested 95% less on pain research than it did on research for these three conditions ($483 million on pain research vs. $7.9 billion on cancer, diabetes and heart disease research).3 The disparity is even more glaring when one compares the research investment to financial burden – with a federal investment of less than 1% of the annual cost of chronic pain ($560-635 billion).
Current initiatives to improve chronic pain management in the US
Nevertheless, positive initiatives are in development. In March 2016, the Department of Health and Human Services released the first federal interagency plan to develop a new system of pain care in the United States, called the National Pain Strategy. Further, the development of the first federal interagency pain research strategy is underway. Also, for the first time, the Department of Health and Human Services has included pain in its plan to address the opioid epidemic, and the NIH, along with the U.S. Food and Drug Administration and pharmaceutical industry is developing the first public-private partnership to develop novel treatments for both chronic pain and opioid addiction.
Chronic Overlapping Pain Conditions – emergence, symptoms, mechanisms & unmet need
Coming back to the beginning of this article, the IOM report noted the increasing recognition and importance of a cluster of prevalent pain conditions that frequently co-occur, share common underlying disease mechanisms, and either solely or predominantly affect women.1 The concept of coexisting pain conditions was recognized by the National Institutes of Health and the US Congress as a set of disorders that co-aggregate and include, but are not limited to temporomandibular disorder (TMD), fibromyalgia (FM), irritable bowel syndrome (IBS), vulvodynia, myalgic encephalomyelichronic fatigue syndrome (ME/CFS), interstitial cystitis/painful bladder syndrome (IC/PBS), endometriosis, chronic tension-type headache, migraine headache, and chronic low back pain. Collectively, the state of clinical overlap of these conditions are increasingly referred to as Chronic Overlapping Pain Conditions (COPCs).4
Not everyone who develops one of these conditions will go on to develop more, however many do, particularly women. The complexity of overlap makes any combination and number of conditions possible. Some people develop multiple conditions around the same time, while others develop them in succession over many years.5
It’s common for COPCs patients to suffer from other chronic conditions, such as sleep or mood disorders. Also, chronic pain has a far-reaching impact, causing fatigue, difficulty with thinking and understanding, and varying degrees of physical, social and sexual dysfunction. These conditions can develop before chronic pain starts, at the same time, or afterwards.
Mounting publications further substantiate that these conditions share common underlying disease mechanisms, mainly in the immune, neural and endocrine systems. Cumulatively, evidence suggests that multiple genetic factors, when coupled with environmental exposures (eg, injury, infections, and physical and psychological stress), increase the susceptibility to highly prevalent COPCs by enhancing pain sensitivity and/or affecting psychological vulnerability.6
A delay in accurate diagnosis and effective treatment commonly experienced by individuals with COPCs can have serious consequences, including worsening of both site-specific and body-wide symptoms, which in turn, makes COPCs more difficult to effectively treat. A vicious cycle ensues, leading to poorer health outcomes, diminished quality of life and increased disability. The toll extends far beyond the affected and their families, substantially impacting the health, workforce and productivity of the nation as a whole.3
Given their widespread prevalence and financial toll, significant rates of overlap, similar symptom presentation, common disease mechanisms and appreciable unmet treatment demand, there is a tremendous opportunity for research and development of safe and effective treatments for COPCs. As a result of the meager federal, private and industry research investment in COPCs to date, evidence-based treatment options are woefully few and inadequate. Furthermore, only a handful of FDA-approved pharmaceutical treatments exist for half of these conditions, only two of which have been approved in the last five years. None are indicated for more than one COPC, although several are used off-label to treat a number of these conditions. The resultant situation is that COPCs sufferers and their clinicians must use trial‑and‑error methods selected from a myriad of treatments, most with unknown safety and efficacy data (especially when combined), until they identify a combination that brings some relief.4
Presently, there are four national multi-center studies in various stages of development, execution and publication: MAPP, OPPERA, Complex Persistent Pain Conditions: Unique & Shared Pathway of Vulnerability and Pain, and The Interoception Imaging Network (PAIN) Repository.
Although the mechanisms that underlie most of these conditions are still poorly understood, COPCs have been associated with a state of pain amplification resulting from either peripheral and/or central mechanisms manifested as widespread hyperalgesia on the basis of quantitative sensory testing, with sensory and also affective perturbation. Although assessing all of these domains is not practical clinically, screening methods are needed that permit the identification of patients requiring more intensive treatments. Computer adaptive testing approaches also can be implemented, which greatly reduce respondent burden.7,8
Despite our ability to assess multiple facets relevant to COPCs, treatment of COPCs and chronic pain more generally, remains challenging. Current interventions retain a focus on sensory aspects of pain despite the knowledge that chronic pain is heavily influenced by biopsychosocial factors. Regardless, some positive evidence for combination therapy for COPCs, clinical outcomes remain suboptimal and additional research and stratification methods are needed. This may be in part attributable to the failure to appropriately incorporate COPCs into the design and conduct of most clinical trials.9
Future research direction
Obviating how future trials will account for COPCs, an important step will be to collect more comprehensive biopsychosocial and molecular data, across multiple domains, to allow investigators to identify subgroups that reflect potentially distinct pathophysiologic mechanisms. Broad-based information regarding clinical features, pain amplification, and psychosocial functioning can be subjected to sophisticated statistical approaches (e.g., cluster analysis, latent class analysis) to permit identification of phenotypic profiles. These phenotypic data can then be combined with genetic and other biomarker data to characterize the biological mechanisms contributing to the empirically defined subgroups. Stratified analysis can then be performed to identify subgroups that are particularly responsive (or nonresponsive) to treatment.
- Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education: Relieving Pain in America, A Blueprint for Transforming Prevention, Care, Education and Research. The National Academies Press, 2011 http://books.nap.edu/openbook.php?record_id=13172&page=1.
- A Research!America poll of U.S. adults conducted in partnership with Zogby Analytics in March 2013
- NIH-Wide Strategy Plan Fiscal years 2016-2020
- Veasley C, et al. Chronic Pain Research Alliance. http://www.chronicpainresearch.org/public/CPRA_WhitePaper_2015-FINAL-Digital.pdf. Published May 2015
- Chronic overlapping pain conditions. Patient guide. Chronic Pain Research Alliance. 2018. http://www.chronicpainresearch.org/public/CPRA_Patient_Guide.pdf
- Maixner W, et al. J Pain. 2016; 17(9 Suppl):T93-T107
- Sturgeon JA, et al. J Pain 2015; 16:291-298.e1
- Sturgeon JA, et al. Pain 2015; 156:2627-2633
- Clauw DJ. JAMA 2014; 311:1547-1555
Highlights from the 2018 Convergences in Pelvi-Perineal Pain congress in Brussels
PainSolve Editorial Team
History of Convergences in Pelvi-Perineal Pain Congress
Convergences in Pelvi-Perineal (Convergences PP) Pain is a society that aims to promote knowledge about chronic pelvic perineal pain. It is a federation of learned societies involved in the field of pain and pelvic perineal functional diseases. On October 25th, this multidisciplinary society organised its 5th congress in Brussels, after Nantes in 2009, Nîmes in 2012, the World Congress on Abdominal and Pelvic Pain in Nice in 2015 and Aix en Provence in 2016. Initially French spoken, Convergences PP confirmed its European openness in 2015 with simultaneous translations.
Day 1 Highlights
During the first day “sensitisation and pelvic pain” was the main focus with an excellent conference on the physiopathology of visceral hypersensitivity, involvement of vegetative nervous system, by Prof. Qasim Aziz highlighting that visceral pain hypersensitivity (VPH) may occur due to anomalies at any level of the visceral nociceptive neuraxis. Important peripheral and central mechanisms of sensitisation that have been postulated include a wide range of ion channels, neurotransmitter receptors and trophic factors. Data from functional brain imaging studies have also provided evidence for aberrant central pain processing in cortical and subcortical regions. In addition, descending modulation of visceral nociceptive pathways by the autonomic nervous system, hypothalamo-pituitary-adrenal axis and psychological factors have all been implicated in the generation of VPH.
Elsewhere, Dr Virginie Quistrebert described the Clinical Criteria of Central Sensitisation in Chronic Pelvic and Perineal Pain (Convergences PP Criteria). Validation and Score development. Her presentation described how a list of 63 items was submitted to 22 international chronic pelvic pain experts according to the Delphi method, and how 10 clinical criteria were adopted for the creation of a clinical evaluation tool: 1) pain influenced by bladder filling and/or urination, 2) pain influenced by rectal distension and/or defecation, 3) pain during sexual activity, 4) perineal and/or vulvar pain in response to normally non-painful stimulation, 5) pelvic trigger points (e.g. in the piriformis, obturator internus, and/or levator ani muscles), 6) pain after urination, 7) pain after defecation, 8) pain after sexual activity, 9) variable (fluctuating) pain intensity and/or variable pain distribution and 10) migraine or tension headaches and/or fibromyalgia and/or chronic fatigue syndrome and/or post-traumatic stress disorder and/or restless legs syndrome and/or temporomandibular joint dysfunction and/or multiple chemical sensitivity.
Finally, Dr Gisele Pickering targeted the controversy to continue using ketamine once sensitisation occurs, and Dr Oliver Bredeu debated where botulinum toxin should be placed in the management of sensitisation.
Day 2 Highlights
On the second day, Psychosexual impact in women with pelvic pain as well as, coccydynia were the selected topics for discussion. Psychosexual impact was discussed by gynaecologist, Dr. Lara Quintas, psychotherapist, Dr Laura Beltran, physiotherapist, Alexandrine Close and the representative of the Patient Association “Les Cles de Venus”. Related to this, controlled studies have shown that vulvovaginal pain can adversely affect women and their partners' general psychological well-being, relationship adjustment and overall quality of life. These women have significantly lower levels of sexual desire, arousal and satisfaction, as well as a lower intercourse frequency than normal controls. They also report more anxiety and depression, in addition to more distress about their body image and genital self-image. Empirical studies indicate that specific psychological and relationship factors may increase vulvovaginal pain intensity and its psychosexual sequelae. Randomised clinical trials have shown that psychosexual interventions, namely cognitive behavioural therapy, are efficacious in reducing vulvovaginal pain and improving associated psychosexual outcomes. Women reporting significant psychological, sexual and/or relationship distress should be referred for psychosexual treatment. A multimodal approach to care integrating psychosexual and medical management is thought to be optimal.
Additionally, inside the general title of Psychosexual impact in women with pelvic pain, a symposium on vulvodynia and sensitisation took place. The aim of the symposium was to establish first, second and third line therapies in Spain, Italy and France with the further outcome to write a short guideline on approach to management. The session was introduced by Dr. Micheline Moyal-Barracco, with further contributions by gynaecologists, Dr Oriol Porta from Barcelona, Dr Filippo Murina from Milan and Dr Eric Bautrant from Aix en Provence. The management is very similar within these European Southern countries with tricyclic antidepressants, lidocaine gel, even in master formulations, botulinum toxin A and surgery as the recommended treatments. The only exception was the use of low-level laser therapy in Italy as an alternative previously to surgery. The final lecture during the symposium was assumed by Hanna Muhlrad, presenting the results of an exercise, of which she has been the Project Manager assigned to the National Board of Health in Sweden, mapping the presence, treatment and need of knowledge support for the healthcare sector, as well as information for females suffering from vulvodynia. The number of females aged 15–44 who have been nursed at least once for vulvodynia, in specialised outpatient care from 2001–2016 amounts to between 8,603–53,924, as it is not clear if HCPs established a differential diagnosis in between vulvodynia and vulvar pain or vaginism. The reported occurrence of vulvodynia or other vulvar pain disorders is significantly lower in comparison to previous prevalence studies from Sweden and internationally, which may be due to the lack of clarity for clinicians when registering this disease. Opportunities for calculating prevalence are therefore limited because available data is incomplete. Furthermore, activities carried out in youth reception, primary care or childbirth care are not registered in health registers or quality records. One possible reason for under-reporting, according to data from dialogue meetings and questionnaire surveys, is that the state of knowledge about the disease in several parts of the care chain is unclear. There are also regional differences in access to specialised gynaecological care at so-called vulgar receptions. Analysis of registry data and a review of data from previous studies indicate comorbidities with other pain diseases, mental health and chronic fungal infections.
The symposium concluded with an open debate including physicians, physiotherapists, psychologists and representatives of Patient Associations from Spain, Italy and France. They agreed on the importance of a multimodal approach; integrating physiotherapy (rehabilitation) of the pelvic floor, psychosexual education and medical management of knowledge concerning the disease.
Finally, coccydynia was anatomically introduced by Dr Stephane Ploteau; Dr Jean-Yves Maigne gave an update on the current situation and Drs Thiebault Riant and Levon Doursounian, commented results of pulsed radiofrequency, which represents a potentially useful treatment option in place of surgery and when other treatment options have failed. Coccygectomy is seen as a last resort that can be associated with a high complication rate and failure to relieve the pain.