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Latest Updates

Placebo Effect and Pain – Part 3

In this latest article on the placebo effect and pain, we look at the findings from a recently published trial supported by Grünenthal that shows promise for reducing the likelihood of clinical trial failure due to variations and bias in symptom reporting by participants. The background to this study and its implications are discussed.

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IMI-PainCare Initiative

The Innovative Medicines Initiative (IMI) PainCare initiative is a consortium composed of 40 participants from 14 countries, co-led by Grünenthal and the University of Heidelberg. The three sub-projects, PROMPT, BioPain and TRiPP, aim to revolutionise different aspects of pain research and development, and pain management with the aim of improving the care of patients suffering from acute or chronic pain.

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CGRP Antibodies in Migraine

Calcitonin gene-related peptide (CGRP)-targeted antibodies represent the first in a new class of drugs designed for the preventive treatment of migraine in adults. Following the recent FDA approval in this drug group, we review the pathophysiology of migraine and how these novel treatments can revolutionise prevention of this debilitating condition.

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Placebo Effect and Pain - Part 1

May 2018

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

  1. 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.
  2. 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.
  3. 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

References

  1. Tuttle AH, et al. Pain 2015; 156: 2616–26
  2. Frisaldi e, et al. Pain Ther 2017; 6: 107–110
  3. 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)
  4. Blease CR, et al. BMJ 2017; 356: j463
  5. Bhardwaj P, Yadav RK. Int J Clin Exp Physiology 2017; 4: 123–128
  6. Kaptchuk TJ, Miller FG. N Engl J Med 2015; 373: 8–9
  7. 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

May 2018

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

References

  1. Crofford LJ. Trans Am Clin Climatol Assoc 2015; 126: 167–183
  2. Goldberg DS, McGee SJ. BMC Public Health 2011; 11: 770
  3. Lumley MA, et al. J Clin Psychol 2011; 67: 942–968
  4. Jensen MP & Turk DC. Am Psychol 2014; 69: 105–118
  5. 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)
  6. Eccleston C, et al. Br J Anaesth 2013; 111: 59–63
  7. Sturgeon JA, et al. Psychol Res Behav Manag 2014; 7: 115–124
  8. Barker E & McCracken LM. Br J Pain 2014; 8: 98–106
  9. Ehde DM, et al. Am Psychol 2014; 69: 153–166
  10. Roditi D & Robinson ME. Psychol Res Behav Manag 2011; 4: 41–49
  11. Fisher E, et al. Cochrane Database Syst Rev. 2015; 3: CD011118
  12. Hoch DB, et al. PLoS ONE 7: e33843

The placebo effect and pain - Part 2

June 2018

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

Approach Potential benefit
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.

References

  1. Gilron I. Expert Rev Clin Pharmacol 2016; 9: 1399–1402
  2. Harden RN, et al. Pain Medicine 2016; 17: 2305–2310
  3. Blease CR, et al. BMJ 2017; 356: j463
  4. Frisaldi e, et al. Pain Ther 2017; 6: 107–110
  5. Arakawa A, et al. Clin Drug Investig 2015; 35: 67–81
  6. Wanigasekera V, et al. Br J Anaesth 2018; 120: 299–307
  7. Chen X, et al, Clin Rheumatol 2017; 36: 1623–1630
  8. 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

June 2018

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
TRPC (Canonical)
TRPV (Vanilloid) TRPV1 Inflammatory pain, neuropathic pain, visceral pain
TRPV2 Inflammatory pain
TRPV3 Nociceptive pain, inflammatory pain
TRPV4 Mechanically-evoked pain, inflammatory pain, neuropathic pain, visceral pain, headache
TRPM (Melastatin) TRPM2 Inflammatory pain
TRPM3 Neurogenic pain
TRPM8 Cold hypersensitivity, neuropathic pain
TRPP (Polycystin)
TRPML (Mucolipin)
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).

References

  1. Carnevale V, Rohacs T. Pharmaceuticals (Basel). 2016; 9: pii: E52
  2. Dai Y. Semin Immunopathol. 2016; 38: 277-91
  3. 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
  4. Huang S, Szallasi A. Pharmaceuticals (Basel). 2017; 10: pii: E64
  5. Kaneko Y, Szallasi A. Br J Pharmacol. 2014; 171: 2474–507
  6. 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)
  7. Manitpisitkul P, et al. Pain Rep. 2016; 1: e576.
  8. Manitpisitkul P, et al. Scand J Pain. 2018; 18: 151–164
  9. Moran MM, Szallasi A. Br J Pharmacol. 2017; doi: 10.1111/bph.14044
  10. Neomed Institute. NEO6860 Transient receptor potential vanilloid type 1 (TRPV1) antagonist. Available at: http://neomed.ca/en/projects/neo6860/ (accessed 06 June 2018)
  11. Sousa-Valente J, et al. Br J Pharmacol. 2014; 171: 2508–27

2018: The Global Year for Excellence in Pain Education

June 2018

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."

Prof. dr. Bart Morlion

President of the European Pain Federation EFIC®

CGRP Antibodies for the Treatment of Migraine

October 2018

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.

References

  1. FDA. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm608120.htm
  2. Science. Available at: http://www.sciencemag.org/news/2018/05/will-antibodies-finally-put-end-migraines
  3. Tso AR & Goadsby PJ. Curr Treat Options Neurol. 2017; 19(8): 27.
  4. Russo AF. Annu Rev Pharmacol Toxicol. 2015; 55: 533–552.
  5. Noseda R & Burstein R. Pain. 2013 Dec; 154 Suppl 1: 10.1016/j.pain.2013.07.021.
  6. Russell FA et al. Physiol Rev. 2014 Oct;94(4):1099-142. doi: 10.1152/physrev.00034.2013.
  7. Schuster NM & Rapoport AM. Clin Neuropharmacol. 2017 Jul/Aug;40(4):169-174. doi: 10.1097/WNF.0000000000000227.
  8. Durham PL. Headache. 2008 Sep; 48(8): 1269–1275.
  9. Bigal ME et al. Br J Clin Pharmacol. 2015 Jun; 79(6): 886–895.
  10. 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

October 2018

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.

Placebo Effect and Pain – Part 3

October 2018

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

References

  1. Pankevich DE, et al. Neuron 2014; 84(3): 546–53
  2. Harrison RK. Nat Rev Drug Discov 2016; 15(12): 817–8
  3. Heneghan C, et al. Trials 2017; 18: 122
  4. Farrar JT, et al. Pain 2014; 155: 1622–31
  5. Tuttle AH, et al. Pain 2015; 156(12):2616–26
  6. 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
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