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Glucocorticoids – Efficient analgesics against postherpetic neuralgia?

  • Mette Richner EMAIL logo and Christian Bjerggaard Vaegter
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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 16 Issue 1

In this issue of the Scandinavian Journal of Pain, Mienke Rijsdijk, MD, presents the original experiments entitled “Effect of intrathecal glucocorticoids on the central glucocorticoid receptor in a rat nerve ligation model” [1]. Intrathecal administration of methylprednisolone acetate (MPA) in a randomized controlled clinical trial on intractable postherpetic neuralgia (PHN) patients did not result in any analgesic effects [2], which is in contrast to findings by others [3, 4, 5, 6]. Consequently, studies on rats seek to explain these observations further.

1 The clinical problem

PHN is one of many forms of neuropathic pain and is characterized by severe burning pain, hypersensitivity and/or numbness in affected areas. PHN is caused by the varicella zoster virus (VZV), to which >95% of the world’s population has been exposed [7,8]. Varicella, also known as chickenpox, is a generally harmless childhood illness that manifests itself through fever and small fluid-filled vesicles that can cover the entire body. VZV further infects multiple cranial nerve ganglia, dorsal root ganglia as well as autonomic and enteric ganglia [9,10,11]. After the varicella outbreak, the immune system maintains a host-virus equilibrium (latent infection) commonly providing lifelong VZV immunity [12,13]. Herpes zoster (HZ), also known as shingles, occurs when the virus is reactivated, typically when the immune system is weakened [14], and painful clustered blisters emerge usually one-sided on the trunk or on the face. Across Europe, the risk of developing HZ is estimated to affect almost one third of the population at some point in their life [15] with markedly increased incidence rates in people aged 60 years or over [16]. The acute pain from the HZ outbreak gradually resolves for most patients, but approximately 20% of HZ patients develop PHN [17], defined as “significant pain or abnormal sensation 120 days or more after the presence of the initial rash” [18]. PHN is often confined to a dermatome reflecting the affected nerve pathways and the symptoms may improve over time but recur in some patients throughout life.

As for other forms of neuropathic pain, there is no targeted treatment option against PHN since the main part of the underlying pain mechanisms is unknown. Various VZV vaccination programmes with varying outcomes have been initiated in recent years [8,19,20]. Nevertheless, common treatment options still rely on symptom suppression and include antidepressants (e.g. amitriptyline, nortriptyline, and duloxetine), anticonvulsants (e.g. gabapentin, pregabalin, and topiramate), topical agents (lidocaine patches and capsaicin patch or lotion), and opioids (e.g. morphine, oxycodone, and methadone), all with varying success rates and potential side effects (Table 1).

Table 1

Recommended line of use [21], functions, and side effects of common agents for PHN relieve.

Drug Line of use Mechanism of action Side effects
Antidepressants First-line Mainly block reuptake of noradrenalin and serotonin thereby increasing the synaptic gap levels Drowsiness, lightheadedness, constipation, dry mouth, weight gain
Anticonvulsants First-line Decrease calcium influx into the nerve ending thereby diminishing release of excitatory neurotransmitters Drowsiness, lightheadedness, unclear thinking, swelling in the feet, weight gain
Lidocaine patch First-line Voltage-gated sodium channel blockade Temporary relief
Opioids Second- or third-line Act on G-protein coupled receptors; mostly result in neuronal hyperpolarization and in modulation of nociceptive neurotransmitter release Suicidal thoughts, emotional disturbances, addictive over time
Capsaicin Second- or third-line Initially activate TRPV1 cation channels, then render them inactive Burning pain, skin irritation

2 What makes glucocorticoids a potential treatment option?

An important player in development and sustainment of neuropathic pain is inflammation [22,23]. Corticosteroids (glucocorticoids) are well known for their anti-inflammatory effects [24], as thoroughly reviewed by Rijsdijk et al. [25]. They can alter the cellular response to inflammatory stimuli by three mechanisms: (1) repression of pro-inflammatory gene cascades, (2) activation of anti-inflammatory gene cascades, and (3) non-genomically by directly affecting already expressed proteins. Binding of glucocorticoids to their glucocorticoid receptor on the cell surface triggers translocation of the ligand-receptor complex to the cell nucleus [26] where the complex regulates transcription of multiple genes [27]. On a non-genomic level, glucocorticoids can affect membrane bound proteins such as G-protein coupled receptors as well as intracellular proteins by direct interaction [28,29,30].

In recent years, the importance of glial cells for development and sustainment of neuropathic pain has become evident [31,32] and it has been reported that glucocorticoids attenuate activation of glial cells in rodent models of neuropathic pain [33,34,35,36].

Albeit not a standard recommended treatment option, various forms of glucocorticoids (MPA, triamcinolone acetonide and dexamethasone) have since the 1960s to some extent been used to alleviate pain syndromes in humans by administration to the intrathecal space [37,38,39,40,41]. MPA is a less hydrophilic glucocorticoid formulation and therefore functions as a depot drug extending tissue exposure after a single application [42]. However, there is evidence in both preclinical and clinical studies that glucocorticoids have no effect or even increase neuropathic pain symptoms [25]. Further conflicting results have been added by a replication trial of Rijsdijk and colleagues, who found lack of analgesic effects upon intrathecal MPA administration in patients suffering from PHN [2] in sharp contrast to Kotani and colleagues, who found MPA to be an effective treatment agent [3].

3 Are glucocorticoids only a treatment option for some patients?

How can such contradictory results arise in seemingly similar experiments? The question highlights the need of systematic investigations on cellular and molecular levels. Currently there is no suitable animal model to study VZV reactivation [43,44] as VZV replication is host restricted, growing efficiently only in human cells. Rijsdijk and colleagues therefore investigated MPA actions in three well-established rodent neuropathic pain models: carrageenan injection, formalin injection, and spared nerve ligaton (SNL), of which the first two models are inflammation-models and the latter comprises a direct nerve injury with an inevitable inflammatory component. They reported MPA not to have any acute analgesic effects in any of the three models [45]. Further investigations on MPA actions were performed in the SNL model, showing unaltered levels of total and phosphorylated glucocorticoid receptor in tissue of the spinal cord and dorsal root ganglia, reflecting lack of MPA effects in line with their previous study [1].

4 Is time of MPA-treatment during an inflammatory process important?

Perhaps an explanation for the data inconsistencies lies already in the test-cohorts both for patients and rodents: Emerging evidence points in the direction of immune cells and glial cells displaying a biphasic course of activation during development of neuropathic pain reflecting a change from an acute phase to a sustainment phase in a matter of days [46]. Given the likely phasic nature of the inflammatory aspects of both initial VZV infection as well as reactivation, it is very likely that MPA only is able to trigger a beneficial response when injected at a specific time point thereby inhibiting cellular activity necessary for disease progression.

5 Are gender and age important?

Another critical factor may be the gender difference. It is well known that general pain prevalence as well as the risk for PHN development is higher in women than in men, and emerging evidence in rodents indicates a differing immune response to nerve damage between males and females [47,48,49,50] potentially influencing the effect of MPA treatment. Further, the immune system weakens with age, necessitating adjustment of pain treatment recommendations as reviewed in [51]. Standard rodent experiments are executed on young adults, but as VZV reactivation is often observed in elderly patients, it may prove important to perform preclinical studies on older animals in order to gain representable drug effects.

6 Perspectives

To date, no adequate treatment options for PHN are known. The work of Rijsdijk and colleagues highlights the controversy about the ability of MPA to alleviate pain. This strongly emphasizes the importance and necessity of further systematic investigations of MPA action. Since PHN is only one of several known painful neuropathies, such experiments may also shed further light on inflammatory and glial involvement in development and sustainment of other neuropathic pain conditions, thereby potentially identifying new treatment targets against various types of neuropathic pain.

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2016.12.008.

Department of Biomedicine, Aarhus University, Ole Worms Allé 3, Aarhus DK-8000, Denmark.

  1. Conflict of interest: None declared.

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Published Online: 2017-07-01
Published in Print: 2017-07-01

© 2017 Scandinavian Association for the Study of Pain

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  126. Assessing Offset Analgesia through electrical stimulations in healthy volunteers
  127. Abstracts
  128. Metastatic lung cancer in patient with non-malignant neck pain: A case report
  129. Abstracts
  130. The size of pain referral patterns from a tonic painful mechanical stimulus is increased in women
  131. Abstracts
  132. Oxycodone and macrogol 3350 treatment reduces anal sphincter relaxation compared to combined oxycodone and naloxone tablets
  133. Abstracts
  134. The effect of UVB-induced skin inflammation on histaminergic and non-histaminergic evoked itch and pain
  135. Abstracts
  136. Topical allyl-isothiocyanate (mustard oil) as a TRPA1-dependent human surrogate model of pain, hyperalgesia, and neurogenic inflammation – A dose response study
  137. Abstracts
  138. Dissatisfaction and persistent post-operative pain following total knee replacement – A 5 year follow-up of all patients from a whole region
  139. Abstracts
  140. Paradoxical differences in pain ratings of the same stimulus intensity
  141. Abstracts
  142. Pain assessment and post-operative pain management in orthopedic patients
  143. Abstracts
  144. Combined electric and pressure cuff pain stimuli for assessing conditioning pain modulation (CPM)
  145. Abstracts
  146. The effect of facilitated temporal summation of pain, widespread pressure hyperalgesia and pain intensity in patients with knee osteoarthritis on the responds to Non-Steroidal Anti-Inflammatory Drugs – A preliminary analysis
  147. Abstracts
  148. How to obtain the biopsychosocial record in multidisciplinary pain clinic? An action research study
  149. Abstracts
  150. Experimental neck muscle pain increase pressure pain threshold over cervical facet joints
  151. Abstracts
  152. Are we using Placebo effects in specialized Palliative Care?
  153. Abstracts
  154. Prevalence and pattern of helmet-induced headache among Danish military personnel
  155. Abstracts
  156. Aquaporin 4 expression on trigeminal satellite glial cells under normal and inflammatory conditions
  157. Abstracts
  158. Preoperative synovitis in knee osteoarthritis is predictive for pain 1 year after total knee arthroplasty
  159. Abstracts
  160. Biomarkers alterations in trapezius muscle after an acute tissue trauma: A human microdialysis study
  161. Abstracts
  162. PainData: A clinical pain registry in Denmark
  163. Abstracts
  164. A novel method for investigating the importance of visual feedback on somatosensation and bodily-self perception
  165. Abstracts
  166. Drugs that can cause respiratory depression with concomitant use of opioids
  167. Abstracts
  168. The potential use of a serious game to help patients learn about post-operative pain management – An evaluation study
  169. Abstracts
  170. Modelling activity-dependent changes of velocity in C-fibers
  171. Abstracts
  172. Choice of rat strain in pre-clinical pain-research – Does it make a difference for translation from animal model to human condition?
  173. Abstracts
  174. Omics as a potential tool to identify biomarkers and to clarify the mechanism of chronic pain development
  175. Abstracts
  176. Evaluation of the benefits from the introduction meeting for patients with chronic non-malignant pain and their relatives in interdisciplinary pain center
  177. Observational study
  178. The changing face of acute pain services
  179. Observational study
  180. Chronic pain in multiple sclerosis: A10-year longitudinal study
  181. Clinical pain research
  182. Functional disability and depression symptoms in a paediatric persistent pain sample
  183. Observational study
  184. Pain provocation following sagittal plane repeated movements in people with chronic low back pain: Associations with pain sensitivity and psychological profiles
  185. Observational study
  186. A longitudinal exploration of pain tolerance and participation in contact sports
  187. Original experimental
  188. Taking a break in response to pain. An experimental investigation of the effects of interruptions by pain on subsequent activity resumption
  189. Clinical pain research
  190. Sex moderates the effects of positive and negative affect on clinical pain in patients with knee osteoarthritis
  191. Original experimental
  192. The effects of a brief educational intervention on medical students’ knowledge, attitudes and beliefs towards low back pain
  193. Observational study
  194. The association between pain characteristics, pain catastrophizing and health care use – Baseline results from the SWEPAIN cohort
  195. Topical review
  196. Couples coping with chronic pain: How do intercouple interactions relate to pain coping?
  197. Narrative review
  198. The wit and wisdom of Wilbert (Bill) Fordyce (1923 - 2009)
  199. Letter to the Editor
  200. Unjustified extrapolation
  201. Letter to the Editor
  202. Response to: “Letter to the Editor entitled: Unjustified extrapolation” [by authors: Supp G., Rosedale R., Werneke M.]
https://doi.org/10.1016/j.sjpain.2017.03.003

Articles in the same Issue

  2. Scandinavian Journal of Pain
  3. Editorial comment
  4. Glucocorticoids – Efficient analgesics against postherpetic neuralgia?
  5. Original experimental
  6. Effect of intrathecal glucocorticoids on the central glucocorticoid receptor in a rat nerve ligation model
  7. Editorial comment
  8. Important new insight in pain and pain treatment induced changes in functional connectivity between the Pain Matrix and the Salience, Central Executive, and Sensorimotor networks
  9. Original experimental
  10. Salience, central executive, and sensorimotor network functional connectivity alterations in failed back surgery syndrome
  11. Editorial comment
  12. Education and support strategies improve assessment and management of pain by nurses
  13. Clinical pain research
  14. Using education and support strategies to improve the way nurses assess regular and transient pain – A quality improvement study of three hospitals
  15. Editorial comment
  16. The interference of pain with task performance: Increasing ecological validity in research
  17. Original experimental
  18. The disruptive effects of pain on multitasking in a virtual errands task
  19. Editorial comment
  20. Analyzing transition from acute back pain to chronic pain with linear mixed models reveals a continuous chronification of acute back pain
  21. Observational study
  22. From acute to chronic back pain: Using linear mixed models to explore changes in pain intensity, disability, and depression
  23. Editorial comment
  24. NSAIDs relieve osteoarthritis (OA) pain, but cardiovascular safety in question even for diclofenac, ibuprofen, naproxen, and celecoxib: what are the alternatives?
  25. Clinical pain research
  26. Efficacy and safety of diclofenac in osteoarthritis: Results of a network meta-analysis of unpublished legacy studies
  27. Editorial comment
  28. Editorial comment on Nina Kreddig’s and Monika Hasenbring’s study on pain anxiety and fear of (re) injury in patients with chronic back pain: Sex as a moderator
  29. Clinical pain research
  30. Pain anxiety and fear of (re) injury in patients with chronic back pain: Sex as a moderator
  31. Editorial comment
  32. Intraoral QST – Mission impossible or not?
  33. Clinical pain research
  34. Multifactorial assessment of measurement errors affecting intraoral quantitative sensory testing reliability
  35. Editorial comment
  36. Objective measurement of subjective pain-experience: Real nociceptive stimuli versus pain expectation
  37. Clinical pain research
  38. Cerebral oxygenation for pain monitoring in adults is ineffective: A sequence-randomized, sham controlled study in volunteers
  39. Editorial comment
  40. Association between adolescent and parental use of analgesics
  41. Observational study
  42. The association between adolescent and parental use of non-prescription analgesics for headache and other somatic pain – A cross-sectional study
  43. Editorial comment
  44. Cancer-pain intractable to high-doses systemic opioids can be relieved by intraspinal local anaesthetic plus an opioid and an alfa2-adrenoceptor agonist
  45. Clinical pain research
  46. Spinal analgesia for severe cancer pain: A retrospective analysis of 60 patients
  47. Editorial comment
  48. Specific symptoms and signs of unstable back segments and curative surgery?
  49. Clinical pain research
  50. Symptoms and signs possibly indicating segmental, discogenic pain. A fusion study with 18 years of follow-up
  51. Editorial comment
  52. Local anaesthesia methods for analgesia after total hip replacement: Problems of anatomy, methodology and interpretation?
  53. Clinical pain research
  54. Local infiltration analgesia or femoral nerve block for postoperative pain management in patients undergoing total hip arthroplasty. A randomized, double-blind study
  55. Editorial
  56. Scientific presentations at the 2017 annual meeting of the Scandinavian Association for the Study of Pain (SASP)
  57. Abstracts
  58. Correlation between quality of pain and depression: A post-operative assessment of pain after caesarian section among women in Ghana
  59. Abstracts
  60. Dynamic and static mechanical pain sensitivity is associated in women with migraine
  61. Abstracts
  62. The number of active trigger points is associated with sensory and emotional aspects of health-related quality of life in tension type headache
  63. Abstracts
  64. Chronic neuropathic pain following oxaliplatin and docetaxel: A 5-year follow-up questionnaire study
  65. Abstracts
  66. Expression of α1 adrenergic receptor subtypes by afferent fibers that innervate rat masseter muscle
  67. Abstracts
  68. Buprenorphine alleviation of pain does not compromise the rat monoarthritic pain model
  69. Abstracts
  70. Association between pain, disability, widespread pressure pain hypersensitivity and trigger points in subjects with neck pain
  71. Abstracts
  72. Association between widespread pressure pain hypersensitivity, health history, and trigger points in subjects with neck pain
  73. Abstracts
  74. Neuromas in patients with peripheral nerve injury and amputation - An ongoing study
  75. Abstracts
  76. The link between chronic musculoskeletal pain and sperm quality in overweight orthopedic patients
  77. Abstracts
  78. Several days of muscle hyperalgesia facilitates cortical somatosensory excitability
  79. Abstracts
  80. Social stress, epigenetic changes and pain
  81. Abstracts
  82. Characterization of released exosomes from satellite glial cells under normal and inflammatory conditions
  83. Abstracts
  84. Cell-based platform for studying trigeminal satellite glial cells under normal and inflammatory conditions
  85. Abstracts
  86. Tramadol in postoperative pain – 1 mg/ml IV gave no pain reduction but more side effects in third molar surgery
  87. Abstracts
  88. Tempo-spatial discrimination to non-noxious stimuli is better than for noxious stimuli
  89. Abstracts
  90. The encoding of the thermal grill illusion in the human spinal cord
  91. Abstracts
  92. Effect of cocoa on endorphin levels and craniofacial muscle sensitivity in healthy individuals
  93. Abstracts
  94. The impact of naloxegol treatment on gastrointestinal transit and colonic volume
  95. Abstracts
  96. Preoperative downregulation of long-noncoding RNA Meg3 in serum of patients with chronic postoperative pain after total knee replacement
  97. Abstracts
  98. Painful diabetic polyneuropathy and quality of life in Danish type 2 diabetic patients
  99. Abstracts
  100. “What about me?”: A qualitative explorative study on perspectives of spouses living with complex chronic pain patients
  101. Abstracts
  102. Increased postural stiffness in patients with knee osteoarthritis who are highly sensitized
  103. Abstracts
  104. Efficacy of dry needling on latent myofascial trigger points in male subjects with neck/shoulders musculoskeletal pain. A case series
  105. Abstracts
  106. Identification of pre-operative of risk factors associated with persistent post-operative pain by self-reporting tools in lower limb amputee patients – A feasibility study
  107. Abstracts
  108. Renal function estimations and dose recommendations for Gabapentin, Ibuprofen and Morphine in acute hip fracture patients
  109. Abstracts
  110. Evaluating the ability of non-rectangular electrical pulse forms to preferentially activate nociceptive fibers by comparing perception thresholds
  111. Abstracts
  112. Detection of systemic inflammation in severely impaired chronic pain patients, and effects of a CBT-ACT-based multi-modal pain rehabilitation program
  113. Abstracts
  114. Fixed or adapted conditioning intensity for repeated conditioned pain modulation
  115. Abstracts
  116. Combined treatment (Norspan, Gabapentin and Oxynorm) was found superior in pain management after total knee arthroplasty
  117. Abstracts
  118. Effects of conditioned pain modulation on the withdrawal pattern to nociceptive stimulation in humans – Preliminary results
  119. Abstracts
  120. Application of miR-223 onto the dorsal nerve roots in rats induces hypoexcitability in the pain pathways
  121. Abstracts
  122. Acute muscle pain alters corticomotor output of the affected muscle stronger than a synergistic, ipsilateral muscle
  123. Abstracts
  124. The subjective sensation induced by various thermal pulse stimulation in healthy volunteers
  125. Abstracts
  126. Assessing Offset Analgesia through electrical stimulations in healthy volunteers
  127. Abstracts
  128. Metastatic lung cancer in patient with non-malignant neck pain: A case report
  129. Abstracts
  130. The size of pain referral patterns from a tonic painful mechanical stimulus is increased in women
  131. Abstracts
  132. Oxycodone and macrogol 3350 treatment reduces anal sphincter relaxation compared to combined oxycodone and naloxone tablets
  133. Abstracts
  134. The effect of UVB-induced skin inflammation on histaminergic and non-histaminergic evoked itch and pain
  135. Abstracts
  136. Topical allyl-isothiocyanate (mustard oil) as a TRPA1-dependent human surrogate model of pain, hyperalgesia, and neurogenic inflammation – A dose response study
  137. Abstracts
  138. Dissatisfaction and persistent post-operative pain following total knee replacement – A 5 year follow-up of all patients from a whole region
  139. Abstracts
  140. Paradoxical differences in pain ratings of the same stimulus intensity
  141. Abstracts
  142. Pain assessment and post-operative pain management in orthopedic patients
  143. Abstracts
  144. Combined electric and pressure cuff pain stimuli for assessing conditioning pain modulation (CPM)
  145. Abstracts
  146. The effect of facilitated temporal summation of pain, widespread pressure hyperalgesia and pain intensity in patients with knee osteoarthritis on the responds to Non-Steroidal Anti-Inflammatory Drugs – A preliminary analysis
  147. Abstracts
  148. How to obtain the biopsychosocial record in multidisciplinary pain clinic? An action research study
  149. Abstracts
  150. Experimental neck muscle pain increase pressure pain threshold over cervical facet joints
  151. Abstracts
  152. Are we using Placebo effects in specialized Palliative Care?
  153. Abstracts
  154. Prevalence and pattern of helmet-induced headache among Danish military personnel
  155. Abstracts
  156. Aquaporin 4 expression on trigeminal satellite glial cells under normal and inflammatory conditions
  157. Abstracts
  158. Preoperative synovitis in knee osteoarthritis is predictive for pain 1 year after total knee arthroplasty
  159. Abstracts
  160. Biomarkers alterations in trapezius muscle after an acute tissue trauma: A human microdialysis study
  161. Abstracts
  162. PainData: A clinical pain registry in Denmark
  163. Abstracts
  164. A novel method for investigating the importance of visual feedback on somatosensation and bodily-self perception
  165. Abstracts
  166. Drugs that can cause respiratory depression with concomitant use of opioids
  167. Abstracts
  168. The potential use of a serious game to help patients learn about post-operative pain management – An evaluation study
  169. Abstracts
  170. Modelling activity-dependent changes of velocity in C-fibers
  171. Abstracts
  172. Choice of rat strain in pre-clinical pain-research – Does it make a difference for translation from animal model to human condition?
  173. Abstracts
  174. Omics as a potential tool to identify biomarkers and to clarify the mechanism of chronic pain development
  175. Abstracts
  176. Evaluation of the benefits from the introduction meeting for patients with chronic non-malignant pain and their relatives in interdisciplinary pain center
  177. Observational study
  178. The changing face of acute pain services
  179. Observational study
  180. Chronic pain in multiple sclerosis: A10-year longitudinal study
  181. Clinical pain research
  182. Functional disability and depression symptoms in a paediatric persistent pain sample
  183. Observational study
  184. Pain provocation following sagittal plane repeated movements in people with chronic low back pain: Associations with pain sensitivity and psychological profiles
  185. Observational study
  186. A longitudinal exploration of pain tolerance and participation in contact sports
  187. Original experimental
  188. Taking a break in response to pain. An experimental investigation of the effects of interruptions by pain on subsequent activity resumption
  189. Clinical pain research
  190. Sex moderates the effects of positive and negative affect on clinical pain in patients with knee osteoarthritis
  191. Original experimental
  192. The effects of a brief educational intervention on medical students’ knowledge, attitudes and beliefs towards low back pain
  193. Observational study
  194. The association between pain characteristics, pain catastrophizing and health care use – Baseline results from the SWEPAIN cohort
  195. Topical review
  196. Couples coping with chronic pain: How do intercouple interactions relate to pain coping?
  197. Narrative review
  198. The wit and wisdom of Wilbert (Bill) Fordyce (1923 - 2009)
  199. Letter to the Editor
  200. Unjustified extrapolation
  201. Letter to the Editor
  202. Response to: “Letter to the Editor entitled: Unjustified extrapolation” [by authors: Supp G., Rosedale R., Werneke M.]
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