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Targeting TRPV

Transient receptor potential (TRP) ion channels are involved in nociception and play roles in several types of pain, including inflammatory pain, neuropathic pain and visceral pain. Pharmacological modulation of TRP channels may provide an alternative to opioid- or NSAID-based pain treatments. Here we review developments in this promising approach to pain management.

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Placebo Effect and Pain - Part 2

In the second instalment of this 2-part article, we consider how researchers designing clinical trials for pain management can adapt their trial methodologies to take account of the placebo response. Various options to reduce the likelihood of ‘false negative’ trial outcomes when investigating novel options for chronic pain are proposed.

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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 ojective 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)

Option 4: 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®