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Finally a promising analgesic signal in a long-awaited new class of drugs: TRPV1 antagonist mavatrep in patients with osteoarthritis (OA)

  • Rolf Karlsten EMAIL logo
Published/Copyright: October 1, 2017
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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 17 Issue 1

In this issue of Scandinavian Journal of Pain, Mayorga et al. report positive efficacy data of mavatrep, a transient receptor potential vanilloid subtype 1 (TRPV1) antagonist, in OA pain [1]. A positive signal of efficacy has been reported previously in dental extraction pain [2], but this is the first report of a signal of efficacy with a TRPV1 antagonist in a chronic pain condition.

1 What is transient receptor potential vanilloid subtype 1 (TRPV1)?

TRPV1 is a cation channel located on peripheral nociceptive fibres, but also in areas involved in nociception in the central nervous system [3,4]. The receptor is activated by heat, capsaicin and low pH and the activity is regulated by inflammatory regulators [5]. The TRPV1 receptor acts as a polymodal signal detector and may be influenced by several simultaneous stimuli, e.g. the thermal activation curve for the TRPV1 receptor is shifted to the left by capsaicin [6].

2 Difficulties in developing this class of analgesic drugs – the TRPVl-anatagonists

Based on these properties, indicating a pivotal role for TRPV1 in nociception, many TRPV1 antagonists have been developed displaying efficacy in animal models of a variety of pain conditions, like inflammatory, osteoarthritis, and neuropathic pain models [5,7]. The clinical development of this class of compounds has so far been challenging, mainly due side effects. The first is an increase in core body temperature, usually mild but sometimes exceeding 39 °C. The other problem has been that subjects experience increased detection thresholds for warmth and pain thresholds for heat pain [7]. The implication of the deficit to sense noxious heat is the possibility for burns in real life situations e.g. when drinking hot beverage or taking a hot shower.

3 Previous aborted attempts to develop TRPVl-anatagonist-analgesic drugs

In a previous study in OA with a TRPV1 antagonist (AZD1386), no signal of efficacy was seen and the study was halted due to elevated liver enzymes in a subset of patients [8]. In that 4-week phase IIA/B study (combined proof of concept and dose-finding), patients were included that had failed treatment with paracetamol and/or NSAIDs. The reason behind the patient selection was a combination of scientific and commercial aspects, potentially positioning the drug as an alternative for patients failing first line treatments of OA pain. The primary variable was the WOMAC pain subscale with 48 h recall, change from baseline to mean of week 2 and 4 [8]. This is an unreliable analgesic effect measurement: Patients are not good at remembering “average” pain.

4 A smart design for developing the TRPVl-antagoist mavatrep

The study by Mayorga et al. [1] is interesting in several aspects, applying measures to reduce variability and thereby increase the possibility to show a potential signal of efficacy. In this case by means of selecting the study population, choosing the primary variable and a 3-way cross-over design.

  • In the study only patients that had responded to previous treatment with non-opioid analgesics are included. They were also tested for their ability to report pain in a consistent manner using the focused analgesia selection test (FAST), recently published [9]. Subjects defined as “poor pain reporters” (17/63 screened), were excluded.

  • The primary variable in OA-studies has historically mainly been based on recall of mean pain during a period 12–24 h or a combination of items as in the WOMAC pain subscale (walking, using stairs, in bed, sitting/lying and standing). In the present study the primary variable is based on evoked pain, the sum of pain intensity difference (4-h post-dose) following stair-climbing, using an 11-point (0–10) numeric rating score. Only patients experiencing an increase of pain (PGIC) and with a minimum pain post-stairclimbing ≤4 were included in the study.

  • Cross-over designs are often used in order to reduce variability [10]. In this case the patients were randomly assigned to 1 of 6 treatment sequences, representing all possible combinations of placebo, naproxen (500 mg bid) and mavatrep (50 mg single dose, due to long half-life). Each sequence was 1 week of treatment followed by one week of wash-out.

To prevent burns, the patients were well informed and were also quizzed to ensure the understanding of the burn prevention measures. Also, patients that were routinely exposed to situations in which they had a risk of sustaining burns were excluded.

5 Mavatrep is superior to the traditional NSAID naproxen (and placebo)

The results shows that mavatrep significantly reduced pain after stair climbing 4h post-dose (p = 0.005), while no significant effect was seen on naproxen (p = 0.229). The analgesic efficacy was further supported by secondary variables, WOMAC (24 h recall) pain, function and stiffness at 2 and 7 days. For this variable also naproxen was effective. Notably, no effect could be seen on pain at rest (4-h SPID) or mean average current pain (NRS-scores, 7 day mean) with mavatrep or naproxen.

6 Mechanism-based, expected adverse effects of mavatrep

Although measures had been taken to reduce burns, 3/33 patients reported mild burns. All patients receiving mavatrep reported adverse events. 79% feeling cold, 61% thermohypoes- thesia, 58% dysgeusia (=distortion of the sense of taste), 36% paresthesia, and 15% feeling warm, all related to the mechanism of action. One patient had a body temperature of 38 °C 2-h post- dosing, that returned to normal within 4 h.

7 Finally a hope for this class of analgesic drugs

The study by Mayorga et al. [1] shows that TRPV1 antagonists may have a role in reducing pain in OA. The study was designed for signal detection and must be seen as such. The study population was highly selected and the high number of target related adverse events might have had impact, as it could un-mask the drug. Even if further studies will prove the efficacy in OA patients, there will still be a substantial challenge to manage the potential for burns in real life situations, when larger numbers of patients will be treated.

There might be a way forward for TRPV1 antagonists if it would be possible to modulate the effects on thermoregulation and the risk for burns associated with the impaired detection of warmth and heat pain. Not only would it reduce those specific side effects, but possibly allow higher exposure and increase the possibility for analgesic efficacy in the clinical setting. In later years a new set of substances, second generation compounds, have been developed that are designed to be modality specific molecules, acting on the capsaicin site, but with or without effects on acid induced TRPV1 activation. The compounds that block acid induced TRPV1 activation elicit profound hyperthermia in rats (for review see [7]). In a recently published study, NEO6860 a TRPV1 antagonist inhibiting capsaicin activation but with little or no effect against heat or acid activation, was studied in healthy subjects. The authors report minor effects on heat pain thresholds and an effect on capsaicin evoked pain and hyperalgesia [11]. Further studies are needed to explore the potential analgesic efficacy in chronic pain patients as well as the safety profile of these types of compounds.

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2017.07.021.

Pain Center, Akademisk Sjukhuset, 751 85 Uppsala, Sweden

  1. Conflict of interest: None declared.

References

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Published Online: 2017-10-01
Published in Print: 2017-10-01

© 2017 Scandinavian Association for the Study of Pain

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https://doi.org/10.1016/j.sjpain.2017.08.015

Articles in the same Issue

  1. Observational study
  2. Perceived sleep deficit is a strong predictor of RLS in multisite pain – A population based study in middle aged females
  3. Clinical pain research
  4. Prospective, double blind, randomized, controlled trial comparing vapocoolant spray versus placebo spray in adults undergoing intravenous cannulation
  5. Clinical pain research
  6. The Functional Barometer — An analysis of a self-assessment questionnaire with ICF-coding regarding functional/activity limitations and quality of life due to pain — Differences in age gender and origin of pain
  7. Clinical pain research
  8. Clinical outcome following anterior arthrodesis in patients with presumed sacroiliac joint pain
  9. Observational study
  10. Chronic disruptive pain in emerging adults with and without chronic health conditions and the moderating role of psychiatric disorders: Evidence from a population-based cross-sectional survey in Canada
  11. Educational case report
  12. Management of patients with pain and severe side effects while on intrathecal morphine therapy: A case study
  13. Clinical pain research
  14. Behavioral inhibition, maladaptive pain cognitions, and function in patients with chronic pain
  15. Observational study
  16. Comparison of patients diagnosed with “complex pain” and “somatoform pain”
  17. Original experimental
  18. Patient perspectives on wait times and the impact on their life: A waiting room survey in a chronic pain clinic
  19. Topical review
  20. New evidence for a pain personality? A critical review of the last 120 years of pain and personality
  21. Clinical pain research
  22. A multi-facet pain survey of psychosocial complaints among patients with long-standing non-malignant pain
  23. Clinical pain research
  24. Pain patients’ experiences of validation and invalidation from physicians before and after multimodal pain rehabilitation: Associations with pain, negative affectivity, and treatment outcome
  25. Observational study
  26. Long-term treatment in chronic noncancer pain: Results of an observational study comparing opioid and nonopioid therapy
  27. Clinical pain research
  28. COMBAT study – Computer based assessment and treatment – A clinical trial evaluating impact of a computerized clinical decision support tool on pain in cancer patients
  29. Original experimental
  30. Quantitative sensory tests fairly reflect immediate effects of oxycodone in chronic low-back pain
  31. Editorial comment
  32. Spatial summation of pain and its meaning to patients
  33. Original experimental
  34. Effects of validating communication on recall during a pain-task in healthy participants
  35. Original experimental
  36. Comparison of spatial summation properties at different body sites
  37. Editorial comment
  38. Behavioural inhibition in the context of pain: Measurement and conceptual issues
  39. Clinical pain research
  40. A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis
  41. Editorial comment
  42. Quantitative sensory tests (QST) are promising tests for clinical relevance of anti–nociceptive effects of new analgesic treatments
  43. Educational case report
  44. Pregabalin as adjunct in a multimodal pain therapy after traumatic foot amputation — A case report of a 4-year-old girl
  45. Editorial comment
  46. Severe side effects from intrathecal morphine for chronic pain after repeated failed spinal operations
  47. Editorial comment
  48. Opioids in chronic pain – Primum non nocere
  49. Editorial comment
  50. Finally a promising analgesic signal in a long-awaited new class of drugs: TRPV1 antagonist mavatrep in patients with osteoarthritis (OA)
  51. Observational study
  52. The relationship between chronic musculoskeletal pain, anxiety and mindfulness: Adjustments to the Fear-Avoidance Model of Chronic Pain
  53. Clinical pain research
  54. Opioid tapering in patients with prescription opioid use disorder: A retrospective study
  55. Editorial comment
  56. Sleep, widespread pain and restless legs — What is the connection?
  57. Editorial comment
  58. Broadening the fear-avoidance model of chronic pain?
  59. Observational study
  60. Identifying characteristics of the most severely impaired chronic pain patients treated at a specialized inpatient pain clinic
  61. Editorial comment
  62. The burden of central anticholinergic drugs increases pain and cognitive dysfunction. More knowledge about drug-interactions needed
  63. Editorial comment
  64. A case-history illustrates importance of knowledge of drug-interactions when pain-patients are prescribed non-pain drugs for co-morbidities
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  66. Why can multimodal, multidisciplinary pain clinics not help all chronic pain patients?
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  68. Individual variability in clinical effect and tolerability of opioid analgesics – Importance of drug interactions and pharmacogenetics
  69. Editorial comment
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  73. Clinical pain research
  74. Lateral Cutaneous Nerve Entrapment Syndrome (LACNES): A previously unrecognized cause of intractable flank pain
  75. Editorial comment
  76. Towards a structured examination of contextual flexibility in persistent pain
  77. Clinical pain research
  78. Context sensitive regulation of pain and emotion: Development and initial validation of a scale for context insensitive avoidance
  79. Editorial comment
  80. Is the search for a “pain personality” of added value to the Fear-Avoidance-Model (FAM) of chronic pain?
  81. Editorial comment
  82. Importance for patients of feeling accepted and understood by physicians before and after multimodal pain rehabilitation
  83. Editorial comment
  84. A glimpse into a neglected population – Emerging adults
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  86. Assessment and treatment at a pain clinic: A one-year follow-up of patients with chronic pain
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  92. The use of rapid onset fentanyl in children and young people for breakthrough cancer pain
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  97. Clinical pain research
  98. The cognitive impact of chronic low back pain: Positive effect of multidisciplinary pain therapy
  99. Clinical pain research
  100. Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia
  101. Topical review
  102. Targeting cytokines for treatment of neuropathic pain
  103. Original experimental
  104. What constitutes back pain flare? A cross sectional survey of individuals with low back pain
  105. Original experimental
  106. Coping with pain in intimate situations: Applying the avoidance-endurance model to women with vulvovaginal pain
  107. Clinical pain research
  108. Chronic low back pain and the transdiagnostic process: How do cognitive and emotional dysregulations contribute to the intensity of risk factors and pain?
  109. Original experimental
  110. The impact of the Standard American Diet in rats: Effects on behavior, physiology and recovery from inflammatory injury
  111. Educational case report
  112. Erector spinae plane (ESP) block in the management of post thoracotomy pain syndrome: A case series
  113. Original experimental
  114. Hyperbaric oxygenation alleviates chronic constriction injury (CCI)-induced neuropathic pain and inhibits GABAergic neuron apoptosis in the spinal cord
  115. Observational study
  116. Predictors of chronic neuropathic pain after scoliosis surgery in children
  117. Clinical pain research
  118. Hospitalization due to acute exacerbation of chronic pain: An intervention study in a university hospital
  119. Clinical pain research
  120. A novel miniature, wireless neurostimulator in the management of chronic craniofacial pain: Preliminary results from a prospective pilot study
  121. Clinical pain research
  122. Implicit evaluations and physiological threat responses in people with persistent low back pain and fear of bending
  123. Original experimental
  124. Unpredictable pain timings lead to greater pain when people are highly intolerant of uncertainty
  125. Original experimental
  126. Initial validation of the exercise chronic pain acceptance questionnaire
  127. Clinical pain research
  128. Exploring patient experiences of a pain management centre: A qualitative study
  129. Clinical pain research
  130. Narratives of life with long-term low back pain: A follow up interview study
  131. Observational study
  132. Pain catastrophizing, perceived injustice, and pain intensity impair life satisfaction through differential patterns of physical and psychological disruption
  133. Clinical pain research
  134. Chronic pain disrupts ability to work by interfering with social function: A cross-sectional study
  135. Original experimental
  136. Evaluation of external vibratory stimulation as a treatment for chronic scrotal pain in adult men: A single center open label pilot study
  137. Observational study
  138. Impact of analgesics on executive function and memory in the Alzheimer’s Disease Neuroimaging Initiative Database
  139. Clinical pain research
  140. Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [11C]-D-deprenyl PET/CT
  141. Original experimental
  142. Developing a model for measuring fear of pain in Norwegian samples: The Fear of Pain Questionnaire Norway
  143. Topical review
  144. Psychoneuroimmunological approach to gastrointestinal related pain
  145. Letter to the Editor
  146. Do we need an updated definition of pain?
  147. Narrative review
  148. Is acetaminophen safe in pregnancy?
  149. Book Review
  150. Physical Diagnosis of Pain
  151. Book Review
  152. Advances in Anesthesia
  153. Book Review
  154. Atlas of Pain Management Injection Techniques
  155. Book Review
  156. Sedation: A Guide to Patient Management
  157. Book Review
  158. Basics of Anesthesia
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