Tuesday, 23 October 2018

Ketamine: Is That A Viable Alternative For Opioids In Treating Chronic Nerve Pain? Part Two

Today's extensive post from anesthesiology.pubs.asahq.org (see link below) follows on from yesterday's post concerning the same subject - ketamine for pain relief and in this case...ketamine for the relief of neuropathic pain. Yesterday's introduction talked about how ketamine has had a particularly bad rap over the years, mainly due to recreational drug use and abuse but now doctors and scientists alike are realising the particular pain-relieving properties this drug has, when it comes to chronic pain and especially, nerve pain. This article looks at it from the medical science angle and goes into great depth about how and why ketamine works for neuropathic pain. If you're considering ketamine as an analgesic option and alternative for opioids, you may want to show your doctor this article but be prepared for possible resistence. It's all about follow-up controls between doctor and patient. You have to hope that your doctor will monitor your progress with all the drugs you are prescribed - after all, they're supposed to do that with opioids aren't they? Ketamine should be treated no differently. This article may be somewhat difficult to follow but you'll get the gist. If new treatments are essential for neuropathic conditions and opioids are becoming less and less available, then ketamine should probably be given a chance. Maybe worth discussing with your doctor.


Brain Dynamics and Temporal Summation of Pain Predicts Neuropathic Pain Relief from Ketamine Infusion
Pain Medicine | November 2018 Rachael L. Bosma, Ph.D.; Joshua C. Cheng, Ph.D.; Anton Rogachov, B.Sc.; Junseok A. Kim, M.Sc.; Kasey S. Hemington, Ph.D.; et al Natalie R. Osborne, M.Sc.; Lakshmikumar Venkat Raghavan, M.D.; Anuj Bhatia, M.D.; Karen D. Davis, Ph.D.


Author Notes

Anesthesiology 11 2018, Vol.129, 1015-1024. doi:10.1097/ALN.0000000000002417

Abstract Editor’s Perspective:
What We Already Know about This Topic:



Ketamine is an N-methyl-d-aspartate antagonist with growing use in the management of chronic pain


Descending pain modulatory circuits are key modulators of chronic pain What This Article Tells Us That Is New:


The infusion of ketamine resulted in meaningful pain relief in about 50% of patients with chronic neuropathic pain

The magnitude of temporal summation of pain and the dynamic engagement of the descending pain modulatory circuit predicted treatment efficacy and point to mechanisms by which ketamine can relieve pain Background: Ketamine is an N-methyl-d-aspartate receptor antagonist that reduces temporal summation of pain and modulates antinociception. Ketamine infusions can produce significant relief of neuropathic pain, but the treatment is resource intensive and can be associated with adverse effects. Thus, it is crucial to select patients who might benefit from this treatment. The authors tested the hypothesis that patients with enhanced temporal summation of pain and the capacity to modulate pain via the descending antinociceptive brain pathway are predisposed to obtain pain relief from ketamine.


Methods: Patients with refractory neuropathic pain (n = 30) and healthy controls underwent quantitative sensory testing and resting-state functional magnetic resonance imaging and then completed validated questionnaires. Patients then received outpatient intravenous ketamine (0.5 to 2 mg · kg−1 · h−1; mean dose 1.1 mg · kg−1 · h−1) for 6 h/day for 5 consecutive days. Pain was assessed 1 month later. Treatment response was defined as greater than or equal to 30% pain relief (i.e., reduction in pain scores). We determined the relationship between our primary outcome measure of pain relief with pretreatment temporal summation of pain and with brain imaging measures of dynamic functional connectivity between the default mode network and the descending antinociceptive brain pathway.
Results: Approximately 50% of patients achieved pain relief (mean ± SD; Responders, 61 ± 35%; Nonresponders, 7 ± 14%). Pretreatment temporal summation was associated with the effect of ketamine (ρ = −0.52, P = 0.003) and was significantly higher in Responders (median [25th, 75th] = 200 [100, 345]) compared with Nonresponders (44 [9, 92]; P = 0.001). Pretreatment dynamic connectivity was also associated with the clinical effect of ketamine (ρ = 0.51, P = 0.004) and was significantly higher in Responders (mean ± SD, 0.55 ± 0.05) compared with Nonresponders (0.51 ± 0.03; P = 0.006). Finally, the dynamic engagement of the descending antinociceptive system significantly mediated the relationship between pretreatment pain facilitation and pain relief (95% CI, 0.005 to 0.065).
Conclusions: These findings suggest that brain and behavioral measures have the potential to prognosticate and develop ketamine-based personalized pain therapy.

Visual Abstract:





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NEUROPATHIC pain is a highly prevalent and often refractory chronic pain condition that is associated with substantial disability and deterioration in quality of life.1 Accumulating evidence suggests that intravenous infusion of ketamine can result in significant relief of refractory neuropathic pain, when the dose is individually titrated to minimize adverse effects and maximize long-term analgesia.2–5 However, approximately 50% of patients will not respond to this therapy. The factors that contribute to the analgesic effectiveness in some, but not in other patients, are unknown. Here we investigated whether there are noninvasive quantitative sensory testing or measures of brain function that point to aberrant pain mechanisms underlying refractory neuropathic pain that may have prognostic value regarding ketamine treatment.

One mechanism responsible for refractory neuropathic pain is an upregulation of N-methyl-d-aspartate (NMDA) receptor activity, which leads to central sensitization and elevated temporal summation.6,7 Ketamine produces analgesic effects primarily through inhibition of the NMDA receptor.8,9 Thus, patients with NMDA-mediated central sensitization are likely to maximally benefit from treatment with ketamine. Temporal summation of pain is a sensory phenomenon that is known to reflect NMDA-mediated brain and spinal cord “wind-up” of nociceptive neurons.10,11 The severity of temporal summation of pain is measured by administering repetitive brief painful stimuli at approximately 0.33 Hz to evoke a successive increase in perceived pain.10,12–15 Temporal summation of pain is heightened in some patients with chronic pain, indicating enhanced sensitization, and it is inhibited by NMDA blockers or antagonists.11,13,14 Therefore, pretreatment measures of temporal summation of pain could be useful in identifying patients who have enhanced NMDA-related central sensitization and thus are likely to benefit from intravenous ketamine.

We recently demonstrated that intersubject variability in temporal summation of pain is associated with variability in the functionality of an individual’s ascending nociceptive and descending pain-modulatory pathways.16 Therefore, we propose that treatment response to ketamine also depends on an individual’s capacity to modulate pain via antinociceptive pathways.

Pain modulation is inherently dynamic, and there are individual differences in one’s ability to disengage attention from pain.17,18 Compelling evidence suggests that neural fluctuations between networks, measured by dynamic functional connectivity between the default mode network (implicated in the intrinsic attention to pain19 ) and the descending antinociceptive pathway (implicated in endogenous analgesia), underlie this perceptual decoupling.18 Specifically, greater dynamic functional connectivity between these two systems was associated with a greater ability to disengage attention from pain.18 In patients with ongoing neuropathic pain, the capacity for this cognitive modulation involving interactions between the default mode network and descending antinociceptive pathway may be useful as predictive indicators and point to mechanisms by which ketamine relieves pain.

Thus, the aim of this study was to identify factors that predict the effect of ketamine treatment for neuropathic pain. Toward this aim, we tested the hypotheses that patients with (1) high temporal summation of pain and (2) enhanced fluctuations between networks and pathways that underlie the ability to disengage attention from pain will achieve sustained pain relief from treatment with ketamine.

Materials and Methods


Participants

Participants included 30 patients with refractory moderate-to-severe neuropathic pain (17 women, 13 men; mean age ± SD, 43.4 ± 13.8 yr) and 30 age- and sex-matched healthy controls (17 women, 13 men; mean age ± SD, 41.9 ± 12.6 yr). Data were collected between April 2015 and November 2017. Patients with neuropathic pain were recruited from the pain clinic at Toronto Western Hospital (Toronto, Ontario, Canada), and healthy controls were recruited from the community. All participants provided informed written consent to procedures approved by the University Health Network Research Ethics Board in accordance with the Declaration of Helsinki. The study is registered at ClinicalTrials.gov (NCT02373449). The inclusion criteria for patients were as follows: (1) sustained (3 months or longer) refractory neuropathic pain as diagnosed on the basis of history, examination, and relevant investigations, as well as a score of more than 4 on the Douleur Neuropathique 4 questionnaire20 ; (2) moderate-to-severe average daily pain (numerical rating scale for pain score of 4 of 10 or higher); and (3) insufficient analgesia from trials lasting 6 weeks or longer of at least three different pharmacologic groups of medications for neuropathic pain (e.g., anticonvulsants, tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors). The Douleur Neuropathique 4 was used as additional criteria to indicate the presence of neuropathic pain in our study. This instrument has a sensitivity of 83% and a specificity of 90% for detecting neuropathic pain.21,22 Exclusion criteria included the following: (1) ketamine or lidocaine intravenous infusion within 6 months preceding study enrollment; (2) contraindications to ketamine (e.g., allergy, raised intracranial pressure, severe coronary artery disease, uncontrolled hypertension or hyperthyroidism); (3) ongoing litigations issues related to the patient’s pain that may affect reporting of pain and quality of life; (4) unstable medical or psychiatric conditions (anxiety with panic attacks, depression with suicidal ideation, psychosis, and schizophrenia); (5) contraindications for magnetic resonance imaging; and (6) inability to comply with the study protocol. The exclusion criteria for the health control participants were as follows: (1) history of neurologic disease or psychiatric or pain disorder and (2) contraindications for magnetic resonance imaging. All participants underwent behavioral testing and magnetic resonance imaging (details in “Psychophysical Assessment” and “Neuroimaging Acquisition” sections). Patients were then treated with intravenous ketamine infusion over 5 consecutive days (details in “Ketamine Infusion” section) followed by oral ketamine (0.5 mg · kg−1 three times daily for 6 weeks). Patients underwent a second test session 1 month after treatment.

Ketamine Infusion

Ketamine treatment consisted of an intravenous infusion for 6 h/day over 5 consecutive days. The target therapeutic range was 0.5 to 2.0 mg · kg−1 · h−1 (mean dose 1.1 mg · kg−1 · h−1).The dose was adjusted in each patient to achieve maximal pain relief while minimizing adverse effects to a tolerable level. Intravenous midazolam (0.03 mg · kg−1), ondansetron (0.1 mg · kg−1 to a maximum dose of 8 mg), and dexamethasone (0.1 mg · kg−1 to a maximum dose of 8 mg) were administered to mitigate the common adverse effects of ketamine (e.g., nausea, vomiting, increased heart rate). Further doses of midazolam (1 to 2 mg) were administered to treat psychoactive adverse effects of ketamine (e.g., hallucinations, agitation).

Questionnaires


All participants completed the Hospital Anxiety and Depression Scale (subscores above 8 are considered clinically relevant),23 the Pain Catastrophizing Scale,24 and the Resilience Scale.25 Patients also completed the Brief Pain Inventory (each item on a 0 to 10 scale),26,27 and pain relief was calculated as a percentage of change from posttreatment compared with pretreatment rating of “pain now.” Patients who achieved 30% or greater reduction in numerical rating scale pain scores at 1 month after the infusion were classified as treatment Responders, and those unable to achieve this outcome were classified as treatment Nonresponders. Pain and psychologic data were compared between controls, Responders, and Nonresponders using a one-way ANOVA and post hoc Tukey pairwise comparisons.

Psychophysical Assessment

All participants underwent a psychophysical assessment that included quantitative sensory tests. Thermal stimuli were delivered to the test sites by a computer-controlled Peltier device (Q-sense, 3- × 3-cm thermode, Medoc Ltd., Israel). Temperatures were adjusted until the stimulus-evoked pain intensity was rated as 50 of 100, and this temperature was then used to assess temporal summation of pain. The temporal summation of pain protocol consisted of 10 thermal stimuli manually applied to the skin of the volar forearm every 3 s (i.e., 0.33 Hz; stimulus duration = 2 s). Participants were instructed to rate their pain immediately after each stimuli. Temporal summation of pain was calculated as a percentage of change of the peak pain rating from the pain evoked by the first stimulus.

Neuroimaging Acquisition

All study participants underwent a magnetic resonance imaging (3T GE) neuroimaging session to acquire a high-resolution T1-weighted anatomical scan (1 × 1 × 1-mm3 voxels, matrix = 256 × 256, 180 axial slices, repetition time = 7.8 s, echo time = 3 ms, inversion time = 450 ms) and a T2*-weighted resting-state functional magnetic resonance imaging scan (3.125 × 3.125 × 4-mm3 voxels, matrix = 64 × 64, 36 axial slices, repetition time = 2 s, echo time = 30 ms, flip angle = 85°, 277 volumes, total scan time = 9 min, 14 s). For the resting-state scan, participants were instructed to “close your eyes; do not try to think about anything in particular; do not fall asleep.”

Preprocessing of Resting-state Functional Magnetic Resonance Imaging Data

We performed all preprocessing of the resting-state functional magnetic resonance imaging data using the FEAT (functional magnetic resonance imaging expert analysis tool) toolbox in Oxford Centre of Functional Magnetic Resonance Imaging of the Brain's (FMRIB's) Software Library (FSL).28 The first four volumes of the resting-state functional magnetic resonance imaging scan were removed, nonbrain tissues were removed using the Brain Extract Tool, and motion correction was performed using Motion Correction FMRIB's Linear Image Registration Tool (MCFLIRT). Linear registration between each participant’s resting-state functional magnetic resonance imaging data to their skull-stripped (opti–Brain Extract Tool29 ), high-resolution anatomical image was followed by nonlinear registration to MNI152-2 mm space using FMRIB’s Non-linear Image Registration Tool (FNIRT). Scanner-related and physiologic noise was removed by means of applying aCompCor30,31 as described previously.18 Finally, spatial smoothing was applied using a 4-mm full-width at half-maximum kernel, and temporal filtering was performed in FSL to retain the signal between 0.01 to 0.1 Hz.

Dynamic Functional Connectivity


To examine whether dynamics in brain function were associated with the clinical effect of treatment, we calculated dynamic functional connectivity between the components of the dynamic pain connectome as follows. (1) We generated regions of interest from key regions of the default mode network and the descending antinociceptive pathway. The default mode network included 6-mm seeds in the posterior cingulate cortex (x = −2, y = −46, z = 28) and the medial prefrontal cortex (x = 4, y = 54, z = 2), whereas the descending antinociceptive pathway included a 6-mm seed in the periaqueductal grey (x = 0, y = −32, z = −10) and a 2-mm seed in the rostral ventral medulla (x = 0, y = −34, z = −50). (2) A nonlinear transformation of each seed region from standard space to each subject’s magnetic resonance imaging space was performed, and the average time series from seeds within each network or pathway were extracted. (3) Dynamic functional connectivity was measured by calculating the dynamic conditional correlation method as described previously.32,33 (4) The SD of each dynamic conditional correlation across the time series was computed and utilized as the summary metric of dynamic functional connectivity.33 High dynamic functional connectivity values indicate that the connectivity between seeds (or networks) greatly fluctuates in and out of synchrony, reflecting flexible brain communication between the brain regions.

Statistical Analyses

This is the primary analysis of these data, and all statistical tests were computed to test a priori hypotheses. The primary outcome variable of interest for this study was pain relief. No statistical power calculation was conducted before the study, and the sample size was based on the available data. All hypotheses were tested using two-tailed testing procedures. With the exception of one Douleur Neuropathique 4 score from one patient that was missing, there were no other missing data or outliers excluded from the analysis. Temporal summation of pain was compared between controls and neuropathic pain patients and between Responders and Nonresponders using a Kruskal–Wallis test and Mann–Whitney U post hoc pairwise comparisons. The relationship between pretreatment temporal summation of pain and pain relief was determined using a Spearman’s correlation. We then determined between-group (controls vs. patients) and subgroup (Responders vs. Nonresponders) differences in dynamic functional connectivity using a one-way ANOVA (parametric assumptions were met as determined by examination of histograms and tests of normality via the Shapiro–Wilk test) and post hoc Tukey pairwise comparisons. Furthermore, correlation analyses were conducted to determine the association between dynamic functional connectivity values and the percentage of pain relief. Finally, to determine whether the relationship between temporal summation of pain and pain relief was mediated by dynamic functional connectivity, a mediation analysis was performed using the PROCESS toolbox in SPSS (SPSS Inc., USA).34,35 The significance of the mediation analyses was evaluated using a bootstrap estimation approach with 1,000 samples. We determined the outcome of our mediation analysis to be significant if the CI does include 0.

Results

Pain and Clinical Characteristics of Patients with Neuropathic Pain

The demographic and clinical characteristics of the patients and corresponding healthy control information are presented in table 1. All patients had a history, signs, and symptoms consistent with the definition of neuropathic pain as “pain arising as a direct consequence of lesion or disease affecting the central and or peripheral somatosensory system” (https://www.iasp-pain.org/GlobalYear/NeuropathicPain; accessed April 5, 2018).36 Etiologies for neuropathic pain in our study included traumatic injury (n = 23), postherpetic neuralgia (n = 2), vasculitis (n = 1), stroke (n = 1), spinal injury (n = 1), scleroderma (n = 1), or syringomyelia (n = 1). All patients also had features of sensory gain and or sensory loss (allodynia, hyperalgesia, hypoesthesia) as established by physical examination. Pain was localized to the arm or hand (n = 14), foot or leg (n = 11), abdominal or thoracic wall (n = 4), or on one side of the body (n = 1). The duration of pain ranged from 6 to 240 months (mean, 66 ± 55 months). Approximately 50% of patients (14 of 30) responded to treatment intravenous ketamine infusion (Responders, 61 ± 35%; Nonresponders, 7 ± 14%). There were no significant differences in age (P = 0.668) or sex between controls and patients. However, one-way ANOVAs indicated that there were pre-ketamine treatment group Responder versus Nonresponder versus control differences in anxiety (F[2,57] = 21.72, P < 0.001), depression (F[2,57] = 74.35, P < 0.001), pain catastrophizing (F[2,57] = 13.49, P < 0.001), and resilience (F[2,57] = 11.73, P < 0.001). Pairwise comparison tests revealed that compared with controls before treatment, Responders had significantly higher anxiety (P < 0.001), depression scores (P < 0.001), and pain catastrophizing scores (P = 0.001) and significantly lower resilience scores (P = 0.003). Compared with controls, Nonresponders also had significantly higher anxiety (P < 0.001), depression scores (P < 0.001), and pain catastrophizing scores (P < 0.001) and significantly lower resilience scores (P < 0.001). However, the Responders and Nonresponders did not differ in any of the measures assessed. Specifically, there were no significant differences between Responders and Nonresponders for pretreatment measures of clinical pain (Douleur Neuropathique 4, P = 0.179; numerical pain rating, P = 0.059) or psychiatric or psychologic variables (depression, P = 0.675; anxiety, P = 0.905; pain catastrophizing, P = 0.635; or resilience, P = 0.585; descriptive statistics in table 1).

Table 1.

Pretreatment Psychologic and Pain Measures




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Pretreatment Temporal Summation Is Associated with the Clinical Treatment Effect


The pretreatment temporal summation of pain group scores and individual correlations against pain relief are shown in figure 1A. The group analysis clearly indicates significant differences in pretreatment temporal summation of pain scores between Responders (median [25th, 75th]) = 200 [100, 345]), Nonresponders (44 [9, 92]), and healthy controls (13 [0, 100]), χ2 (2, N = 60) = 12.51, P = 0.002. Follow-up pairwise comparisons indicated that pretreatment temporal summation of pain was significantly higher in responders compared with controls (U = 87.00, P = 0.002) and compared with Nonresponders (U = 38.00, P = 0.001) but did not differ between Nonresponders and healthy controls (U = 206.00, P = 0.420). At the individual patient level, we found a strong correlation between pretreatment temporal summation of pain with the subsequent percentage of pain relief after ketamine treatment (Spearman’s ρ = 0.52, P = 0.003).

Fig. 1.

Pretreatment temporal summation of pain (median [25th, 75th]; (A) and mean dynamic functional connectivity (mean ± SD) between the default mode network and the descending antinociceptive pathway (B) was significantly enhanced in Responders compared with Nonresponders and controls and significantly predicted percentage of pain relief after ketamine treatment. Significant differences (*P < 0.05) are indicated by horizontal bars or P values. Black indicates healthy controls, red indicates Nonresponders, and green indicates Responders. HC, healthy controls; Non-R, Nonresponders; Res, Responders.





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Pretreatment Default Mode Network–descending Antinociceptive Dynamic Functional Connectivity Is Associated with Treatment Effect

The pretreatment dynamic functional connectivity between the default mode network and the descending antinociception pathway is shown in figure 1B at the group level. We identified clear group differences in the default mode network–descending antinociceptive dynamic functional connectivity between Responders (mean ± SD, 0.55 ± 0.05) compared with Nonresponders (0.51 ± 0.03) and healthy controls (0.52 ± 0.04; F[2, 57] = 5.4, P = 0.007). Furthermore, pairwise comparisons indicated that pretreatment dynamic functional connectivity was significantly higher in Responders compared with controls (P = 0.039) and compared with Nonresponders (P = 0.006), but there was no significant difference between Nonresponders and healthy controls (P = 0.450). As shown in figure 1B, at the individual level, pretreatment default mode network–descending antinociceptive dynamic functional connectivity was significantly correlated with percentage of pain relief (ρ= 0.51, P = 0.004).

Relationship between Temporal Summation of Pain and Pain Relief Is Mediated by Default Mode Network–descending Antinociceptive Dynamic Functional Connectivity

We used a mediation analysis to test the hypothesis that the dynamic engagement of the descending antinociceptive system mediates the relationship between pretreatment pain facilitation and pain relief. The outcome of this mediation analysis is shown in figure 2. The analysis indicated that pain relief was significantly predicted by temporal summation of pain (P = 0.035) and also by the dynamic functional connectivity between the default mode network and descending antinociception pathway (P = 0.014). Furthermore, temporal summation of pain was significantly related to the dynamic functional connectivity between the default mode network and descending antinociception pathway dynamic functional connectivity (P = 0.043). However, when both temporal summation of pain and the dynamic engagement of the descending antinociceptive system variables were included in the model, temporal summation of pain was no longer a significant predictor of pain relief (P = 0.178). A bootstrap estimation, in which our data were compared with an empirically derived distribution generated based on resampling, indicated a significant full mediation (95% CI from bootstrap analysis, 0.005 to 0.065).

Fig. 2.

The relationship between temporal summation of pain (TSP) and pain relief is mediated by default mode network–descending antinociceptive pathway dynamic functional connectivity (DMN-Des dFC). These variables were entered as predictors into a model with pain relief as the outcome variable. The direct path and indirect effect are shown. *P < 0.05. mPFC, medial prefrontal cortex; PAG, periaqueductal grey; PCC, posterior cingulate cortex; RVM, rostral ventral medulla.






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Discussion

This study provides novel insight into brain and behavioral factors that are prognostic indicators of the effect of ketamine infusion for the treatment of neuropathic pain. Our key findings were that (1) the effect of ketamine for pain relief in patients with refractory neuropathic pain was associated with pretreatment temporal summation of pain and by pretreatment engagement of the descending antinociceptive pathway, as measured by default mode network–descending antinociceptive pathway dynamic functional connectivity, and (2) the dynamic engagement of the descending antinociceptive system significantly mediates the relationship between pretreatment pain facilitation and pain relief. By understanding factors that promote or constrain responsiveness to ketamine treatment, we can better develop and target therapeutic approaches with the purpose of alleviating pain in patients with neuropathic pain.

Approximately 50% of patients in our study had a reduction in numerical rating scale pain scores of 30% or greater at 1 month after intravenous ketamine infusion. This rate of response is consistent with previous findings and suggests that in some patients, neuropathic pain is related to NMDA receptor–independent mechanisms.37 Furthermore, patients who were in the Responder and Nonresponder subgroups did not differ on clinical pain or psychologic measures in the pretreatment phase or on pretreatment clinical pain measures. This again suggests that patients with neuropathic pain can have identical pain characteristics and psychologic profiles and yet have completely different underlying pain mechanisms (i.e., central sensitization, changes in descending antinociceptive activity),38 which may account for why some patients respond or do not respond to treatment with ketamine. Thus, the first part of our study was to examine whether we could use quantitative sensory tests to probe underlying pain mechanisms associated with NMDA-related central sensitization11 and determine who would respond to ketamine.

Our main psychophysical finding is that pretreatment temporal summation of pain measured in neuropathic pain patients is associated with the clinical effect of intravenous ketamine. Temporal summation of pain is a sensory phenomenon that is known to reflect NMDA-mediated enhancement of nociceptive signaling.10,11 Thus, our results support our hypothesis that patients who have enhanced temporal summation of pain benefit from treatment with an NMDA antagonist. This study builds on previous work using quantitative sensory testing to profile individual patient pain modulation patterns and predict treatment outcomes. For example, Yarnitsky et al.39 have demonstrated that patients with painful diabetic neuropathy who have lower pain inhibitory capacity, as assessed by less efficient conditioned pain modulation, are most likely to benefit from treatment with duloxetine. Because duloxetine is a serotonin-noradrenalin reuptake inhibitory that acts to enhance the pain inhibitory system and not sensitization, it is unsurprising that pretreatment temporal summation of pain did not predict the efficacy of duloxetine.39 This provides further evidence that quantitative sensory tests such as temporal summation of pain and conditioned pain modulation reflect distinct underlying pain mechanisms. These measures therefore can provide some indication of dysfunctional mechanisms of pain modulation in patients, which could subsequently guide targeted therapeutic approaches according to this dysfunction.40,41

The development of predictive measures of the effect of ketamine has a practical importance because the treatment is not currently widely available because it requires significant resources for drug administration, titration, and patient monitoring. The treatment could become more widely available if overall costs could be reduced by treating only those patients most likely to respond. Personalized pain medicine has the potential to substantially reduce healthcare-related costs that result from series of unsuccessful therapies and may improve disease management, enabling faster return to normal daily functioning. However, measures used for treatment prognostics must be standardized, reliable, and easily adaptable for clinical assessment purposes. Although quantitative sensory testing has been extensively used in clinical research, it is not largely used in clinical practice.39 However, a lot of work is currently underway, building a repertoire of evidence toward the clinical feasibility and use of these measures.42 The results of the current study provide the foundation for future studies to continue to examine the clinical utility of temporal summation of pain to predict treatment response in individual patients with neuropathic pain.

The second part of our study used neuroimaging to identify abnormalities in brain function that provide insight into the mechanisms underlying dysfunctional pain modulation and neuropathic pain. Our analysis of dynamic functional connectivity between the default mode network and descending antinociceptive pathway identified clear group differences between Responders compared with Nonresponders and healthy controls. Specifically, pretreatment dynamic functional connectivity was significantly higher in Responders compared with controls and compared with Nonresponders, but there was no significant difference between Nonresponders and healthy controls. Previous work has demonstrated that fluctuations in connectivity (i.e., as measured by dynamic functional connectivity) between the default mode network–descending antinociceptive pathway reflects an individual’s capability to orient attention away from pain.18 Thus, greater pretreatment dynamics between these regions may reflect a greater capacity of patients with neuropathic pain to decouple attention and perception. Furthermore, at the individual level, pretreatment default mode network–descending antinociceptive pathway dynamic functional connectivity was significantly correlated with the magnitude of pain relief. Cognitive modulations of pain, such as manipulation of attention, are believed to involve endogenous analgesic activity within the descending antinociceptive system.43 Thus, our findings may reflect an adaptive mechanism by which neuropathic pain patients with high pretreatment default mode network–descending antinociceptive pathway dynamic functional connectivity have high attention–perception decoupling yet fail to adequately modulate their chronic pain. In support of this, previous work in patients with chronic lower back pain has demonstrated that default mode network–descending antinociceptive pathway functional connectivity is associated with the ability to modulate pain.44 Thus, we propose that the capacity to engage these brain systems predicts treatment effect of ketamine infusions in patients with neuropathic pain.

Finally, we used a mediation analysis to test the hypothesis that the dynamic engagement of the descending antinociceptive system mediates the relationship between pretreatment pain facilitation and pain relief. We found a significant mediation indicating that dynamics within the default mode network–descending antinociceptive pathway systems plays an important mechanistic role linking temporal summation of pain and pain relief. Default mode network–descending antinociceptive pathway dynamic functional connectivity has been linked to the ability to let the mind wander away from pain, a cognitive modulation that likely involves engaging endogenous antinociceptive processes.18 Therefore, patients with high pain facilitation who also activate/engage the descending antinociceptive system, perhaps indicative of low intrinsic attention to pain, will experience the greatest pain relief with ketamine treatment. Previous studies have demonstrated that in healthy controls, ketamine suppresses temporal summation of pain11 and also alters resting-state brain networks, including cross-network connectivity with the default mode network.45 Furthermore, although temporal summation of pain paradigms may evoke enhancement of the dorsal horn signal trafficking (wind-up) through the ascending nociceptive pathway, it is also known that wind-up engages endogenous inhibitory mechanisms.46 It is the dynamic balance between excitatory and inhibitory mechanisms that determines the level of neuron excitability and spinal pain transmission.46,47 We have demonstrated that variability in temporal summation of pain scores reflects intersubject variability in the balance of functional connectivity between the ascending nociceptive and descending modulatory pathways.16 Therefore, we propose that treatment response to ketamine also depends on an individual’s capacity to modulate pain via their antinociceptive pathways. In addition to their predictive value, future studies are required to determine how ketamine changes these brain and behavioral measures posttreatment in patients with neuropathic pain.

Although numerous laboratory studies have used heat pain temporal summation of pain paradigms and demonstrated changes in central sensitivity in chronic pain patients, the clinical utility of these measures is still limited by the lack of standardized protocols and interpretation. Similarly, although functional magnetic resonance imaging measures have provided great insights into the mechanisms underlying pain perception in humans, these measures require complex statistical analyses to derive that are not readily implemented. The sample size of our study does not allow us to make definitive conclusions regarding the impact of higher intensity of neuropathic pain or depression on the likelihood of analgesic benefit. The small sample size also limited our ability to explore relationships between analgesic response to ketamine and the etiology of neuropathic pain. The results of this study may also not be applicable to patients with pain in whom neuropathic mechanisms are contributory but not the major cause of ongoing pain (e.g., low back pain and osteoarthritis). Furthermore, the new consensus guidelines describe that the optimal dosage of ketamine varies by patient.48,49 However, there is evidence that higher dosages of ketamine, over longer periods of time, may be effective for chronic pain management.48

Altogether, our findings demonstrate that enhanced temporal summation of pain and the dynamic engagement of the descending antinociceptive system are important predictive markers (at the subgroup level and in individuals) of the effect of ketamine treatment and point to mechanisms by which ketamine can relieve refractory neuropathic pain (fig. 3). This study is an important step toward a personalized approach to pain therapy based on individual brain and personality characteristics. Development of a prediction tool using this model could also optimize use of other expensive and resource-intensive therapies to treat neuropathic pain (e.g., spinal cord stimulation).

Fig. 3.

Summary figure depicts the main findings that patients who had enhanced levels of temporal summation of pain (TSP) and who had greater default mode network–descending antinociceptive pathway dynamic functional connectivity (DMN-DeS dFC) were more likely to respond to treatment with ketamine. mPFC, medial prefrontal cortex; PAG, periaqueductal grey; PCC, posterior cingulate cortex; RVM, rostral ventral medulla.





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Acknowledgments

The authors thank Aaron Kucyi, Ph.D. (Krembil Research Institute, Toronto, Canada) for his help developing the analysis pipeline, Eugen Hlasny, M.R.T. (M.R.) and Keith Ta, M.R.T. (M.R.) (both Toronto Western Hospital, Toronto, Canada) for expert technical assistance in magnetic resonance imaging acquisition, Marie-Andree Coulombe, Ph.D. (Krembil Research Institute, Toronto, Canada) for contributions to set up the study design, and Jamal Kara, B.Sc. and Sabeeh Alvi, H.B.Sc., C.C.R.P. (both Toronto Western Hospital, Toronto, Canada) for study assistance.

Research Support


Supported by the Academic Health Science Centre Alternative Funding Plan Innovation Fund (Toronto Western Hospital, Toronto, Canada). R.L.B. was supported by a post-doctoral fellowship from the Canadian Institutes of Health Research (Ottawa, Canada).

Competing Interests

The authors declare no competing interests.

References (see source link below)

http://anesthesiology.pubs.asahq.org/article.aspx?articleid=2702159

Monday, 22 October 2018

Is Ketamine A Viable Alternative For Opioids In Treating Chronic Pain? Part One


Today's short post from news-medical.net (see link below) is the first of two posts (see tomorrow) about Ketamine as an effective analgesic for chronic pain. This article doesn't mention neuropathic pain at all but tomorrow's post goes into great detail concerning prescribing Ketamine for chronic nerve pain. Today's post provides back up information about ketamine being reintroduced into the list of analgesics that may be considered alternatives for opioids. Ketamine has had a bad rap over the years, mainly due to recreational drug use and abuse but has been prescribed by doctors more or less, 'off-label' for both chronic after surgery pain and pain caused by injury. Many neuropathy patients have also benefited from ketamine prescriptions, just as they have from methadone, that has an equally bad press but very few doctors will issue ketamine without a great deal of knowledge and experience. Today's article and that from tomorrow, explain just why ketamine is a viable alternative to opioids and standard chronic pain relief drugs. Well worth a read but in combination with tomorrow's article too.


Ketamine can be considered as alternative to opioids for short-term pain control in ED
Reviewed by Alina Shrourou, BSc Oct 15 2018

 Download PDF Copy

Intravenous, low-dose ketamine (LDK) is as effective as intravenous morphine in the control of acute pain in adults in the emergency department (ED). That is the finding of a study to be published in the October 2018 issue of Academic Emergency Medicine (AEM), a journal of the Society for Academic Emergency Medicine (SAEM). The results indicate that ketamine can be considered as an alternative to opioids for ED short-term pain control.

The lead author of the study is Nicholas Karlow, MPHS, a medical student at the Washington University School of Medicine in St. Louis, Missouri. The findings of the study are discussed in the featured

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The systematic review and meta-analysis by Karlow, et al. maintains that there is a role for opioids in the treatment of pain in the ED, but suggest that as physicians continue to face pressure to reduce opioid use, it is important to establish that alternatives such as ketamine are comparable in providing patients with appropriate analgesia in a similar time frame.

The study further suggests that for patients with opioid use disorders or substance use disorders that require a potent analgesic in the emergency department, ketamine may be a favorable option compared to an opioid.

Moving forward, the authors suggest that observational studies assessing adverse events should use similar outcome measures and time frames, and that researchers should explore patient and physician satisfaction with ketamine analgesia and side effects compared to other opioid alternatives for acute pain.

"Karlow and colleagues provide persuasive evidence that emergency physicians can reasonably expect sub-dissociative ketamine to be as effective as morphine for patients with acute abdominal or musculoskeletal pain. Minor ketamine adverse effects will likely prevent this therapy from becoming routinely first line, but low dose ketamine represents a good alternative choice for selected patients," commented Steven M. Green, MD, professor of emergency medicine and residency director at Loma Linda University, California.

Dr. Green's principal research interest has been on procedural sedation and analgesia, with numerous studies of ketamine dating back to 1990 and more recent works relating to sedation's optimal practice, politics, and future. He is a deputy editor at Annals of Emergency Medicine journal.

Source:

http://saem.org/

https://www.news-medical.net/news/20181015/Ketamine-can-be-considered-as-alternative-to-opioids-for-short-term-pain-control-in-ED.aspx

Sunday, 21 October 2018

Neuropathy: Addressing Multiple Causes And Multiple Treatments, Is Essential For Effective Outcomes

Today's post from neuropathydr.com (see link below) is another helpful post for neuropathy patients faced with confusing symptoms and more than one extra medical condition. It puts your mind at ease when searching for reasons why this, that and the other part of your body displays painful and seemingly irrational symptoms. The point is that neuropathy itself is complex enough (more than 100 sorts and more than 100 causes alone!) but squaring your neuropathy symptoms with symptoms from other concurrent medical problems is sometimes so confusing that you literally don't know which way to turn. Add to that the fact that many drugs prescribed for neuropathic pain have side effects of their own and there's little wonder that patients become severely depressed. The author of this article quite rightly puts forward the case for holistic treatment which covers your whole medical spectrum. This requires that doctors take the time to look at everything medically wrong with you and then apply appropriate treatments that are not just confined to nerve pain. Just like patients, doctors are used to prescribing one treatment, specifically linked to the disease that's giving you the most problems at that time. That just effectively pushes the other things aside and never gets to the root of the problem which requires a multi-treatment approach. The problem is that doctors just don't have the time to develop individual plans for each of their patients when in fact that is exactly what they need to do. You may need to really work on your doctor-patient relationship and develop a personal 'click' which persuades your doctor that your case is worth looking at far more deeply than is currently the case. Systems don't help patients - people do but that may require your doctor to step out of the system to provide the best possible help for you.

Multiple Underlying Causes
by admin | Sep 10, 2018 


Perhaps the most frustrating, but real issue surrounding patients who suffer from peripheral neuropathy and many types of chronic pain is that more often than not, there are often multiple underlying causes.

As you know, life is an accumulation of experiences—sometimes, unfortunately, including trauma and illnesses.

All of these things have consequences, some of which will not show up for many years. You probably also know that things that are very easy to ignore at 25 now become impossible to ignore at 65 and beyond.

One of the issues that concerns me while treating many neuropathy patients is when clinicians and patients focus exclusively on trying to find the “one” cause of their pain, burning, tingling numbness or other neuropathy symptoms.

The reason for this is quite simple. Most commonly, patients develop peripheral neuropathy as the result of multiple underlying causes.

For example, a common scenario is an overweight smoker who had a history of back surgery. Perhaps they are overweight or pre-diabetic, or have used some medications (commonly statins) known to cause neuropathy. These are some of the many multiple underlying causes we find in patient histories every day.

The reality is, all these things are risk factors for the development of chronic pain, and often peripheral neuropathy.

So, unless all these multiple underlying causes are addressed, the patient is unlikely to significantly improve.

Worse yet is when doctors and other caregivers are not familiar with this all-too-common scenario.

We honestly believe this is the reason why so many patients receive symptomatic prescriptions, yet no constructive advice on how to manage, let alone possibly beat, their peripheral neuropathy.

So the best advice we can give you is to try and understand everything that may be contributing to your current situation.

Also understand how very important it is NOT to delay proper treatment. The longer the delay, the more difficult peripheral neuropathy and chronic pain becomes to manage.

We find this is also why the biggest neuropathy treatment successes come when implementation of EARLY effective pain & neuropathy treatment, including neurostimulation (NDGen(R)), manual and massage therapy, laser (LLLT/LED) therapy, can have a profound impact on our patients’ outcomes, no matter what the multiple underlying cause(s) might turn out to be.

Learn so much more about treatment options, products and service at https://NeuropathyDR.com

https://neuropathydr.com/multiple-underlying-causes/

Saturday, 20 October 2018

Small Fibre Neuropathy - A Rose By Any Other Name - Same S**t - Same Treatment

Today's post from journals.sagepub.com (see link below) tells you all you need to know (from a medical standpoint) about small fibre neuropathy. Now if you've been diagnosed with SFN, then you will (or should) have undergone a whole series of neurological tests to establish that diagnosis. If you haven't had those tests and have still received an SFN diagnosis, then you can reasonably assume that your doctor is making an educated guess. The problem is that irrespective of the detailed diagnosis, the symptoms are much the same as for other common forms of neuropathy (with a few exemptions) and the treatments too! However, if your doctor has taken the trouble to subject you to extensive testing then small fibre neuropathy is what you've got. Basically, small fiber neuropathy occurs when the small fibers of the peripheral nervous system (outside the brain and the spinal cord) are damaged. Small fibers in the skin relay sensory information about pain and temperature and the symptoms will be recognisable to all patients with a neuropathy diagnosis. The point I'm making is that an SFN diagnosis is just a more detailed neuropathic diagnosis, not much more. Practically speaking, you're still at the same starting point regarding treatment, as other people with neuropathy and once you have it, the cause is pretty much irrelevant too. You need to concentrate on learning to manage your neuropathy with the current tools available and for that, you can reference almost any other article about neuropathy treatment. That all said, this article does provide you with an enormous amount of useful information that may help you learn to live with the condition better.



Small Fiber Neuropathy: Disease Classification Beyond Pain and Burning
Todd D Levine, First Published April 18, 2018 Review Article


Abstract


Small fiber neuropathy (SFN) has a poorly understood pathology, but patients would benefit from determination of clinical phenotypes that allows for better diagnosis and treatment planning. I propose that patients should be classified dependent on whether there is sodium channel dysfunction, classic neurologic symptoms only, widespread neuropathic pain, or autonomic symptoms. Patients with SFN can then be considered in light of their clinical phenotype, allowing for focus on subsets of patients who might have diagnosable conditions or be more prone to responding to a particular type of therapy that may not be efficacious in the broader patient population with SFN. There are several therapies currently available that can address the symptoms of SFN; however, to develop novel therapeutic strategies, it will be imperative to classify patients to understand and target the underlying pathology.


Introduction

Since the 19th century work of Ramón y Cajal and French neurologist Charcot, neurologists have focused on localization with the long-standing belief that only by understanding if a disease process affects the brain, spinal cord, nerve, and/or muscle, can the clinician begin to determine the cause of the specific pathology. In the peripheral nervous system, we now understand that some diseases can affect all types of nerves, but others can be confined to just the myelin or just the axon. Likewise, a disease can affect just large fiber neurons or small fiber neurons. Even within diseases that affect purely small fibers, we now understand that this can present as purely sensory disruption such as pain, purely autonomic dysfunction, or in some patients a combination of both sensory and autonomic. Being able to parse patients into different subsets of neuropathies allows for a better understanding of the pathophysiology and potential treatments. One disease that would benefit from a more specific determination of clinical phenotypes to allow for a more precise diagnosis and potential improvement in patient condition is small fiber neuropathy (SFN).

Small fiber neuropathy is the result of damage to peripheral nerves,1 including those that are small and myelinated (Aδ), as well as those that are unmyelinated (unmyelinated C fibers).2 In SFN, small somatic and autonomic fibers can be affected.1 Normally, these fibers control thermal and pain perception and control autonomic and enteric functions. For this reason, patients with SFN can present with either autonomic or somatic symptoms, or both. Symptoms are potentially numerous and can include allodynia, burning, lower thermal sensation, hyperesthesia, paresthesia, numbness in the lower extremities with potential to affect limbs and trunk, restless leg syndrome, dry eyes and mouth, abnormal sweating, bladder control issues, gastric issues, skin discoloration, and cardiac symptoms.3 Cardiac symptoms include syncope, palpitations, and orthostatic hypotension. Even without diffuse autonomic dysfunction, a percentage of patients with postural orthostatic tachycardia syndrome (POTS) can have SFN.

Small fiber neuropathy has a poorly understood pathology. It can be a result of a variety of diseases, including diabetes mellitus, autoimmune disorders such as Sjögren or sarcoidosis, paraproteinemia, and paraneoplastic syndrome, with diabetes mellitus being the most common cause of SFN (Table 1).1,3 Hereditary amyloid neuropathy also results in damage to small nerve fibers.4 Amyloid neuropathies can be multisystemic or relegated to the cardiac system or only neuropathy.5,6 There can be some presentation of neuropathy and cardiac symptoms without being widespread. Familial amyloid neuropathies include those caused by mutations in transthyretin (TTR) amyloidosis, apoprotein A1, and gelsolin.4




Table 1. Common causes of neuropathy and the corresponding confirmatory testing.




Table 1. Common causes of neuropathy and the corresponding confirmatory testing.
View larger version


Considerations for diagnosis and treatment of small fiber neuropathies

As shown in Figure 1, patients with SFN can present with a wide variety of symptoms, both somatic and autonomic. Although there may sometimes be significant overlap between these symptoms, patients with SFN can be thought of in terms of their clinical phenotypes as a way of focusing on smaller subsets of patients who might have diagnosable conditions or respond to specific medications that do not treat all patients with SFN. In that vein, I suggest using the term small fiber sodium channel dysfunction (SFSCD) as a way of referring to patients who have symptoms of paroxysmal neuropathic pain characteristic of mutations in sodium channel proteins such as NaV1.7, 1.8, or 1.9. These patients may previously have been labeled as having erythromelalgia or other paroxysmal pain disorders. These patients may differ from other patients with SFN as they may have genetically proven mutations in their sodium channels and physiologically proven nerve hyperexcitability without having a reduced intraepidermal nerve fiber density. While current sodium channel–blocking agents are not always effective, novel sodium channel blocking drugs could be revolutionary for this subset of patients, although not helpful to patients with other causes of painful SFN.7,8





Figure 1. Small fiber neuropathy symptom clusters and neuropathy classifications.

In addition to patients with sodium channel–mediated SFN are patients with SFN who have classic neuropathic symptoms such as burning, tingling, stabbing, and numbness. These patients can be classified into the group small fiber–mediated painful neuropathy (SFMPN). These patients will have reduced intraepidermal nerve fiber density on skin biopsy in addition to the classic neuropathic symptoms. Another group of patients who have recently been shown to have objective evidence for damage to their small fibers are patients who have more widespread pain, experiencing muscle cramps and muscle pain, and in many cases, these patients have been confused as having fibromyalgia. I propose labeling the group of these patients who have evidence for objective loss of small nerve fibers as having small fiber–mediated widespread pain (SFMWP). These patients often have symptoms such as headache, fatigue, irritable bowel syndrome, cognitive dysfunction, and sleep disturbances. In an extreme form of these disorders, patients have objective evidence for autonomic dysfunction: abnormal gastric emptying studies with nausea and vomiting, abnormal tilt table tests, and abnormal quantitative sudomotor autonomic reflex testing. These patients should be labeled as having small fiber–mediated autonomic dysfunction (SFMAD), as their clinical phenotype is often overshadowed by gastrointestinal symptoms, heart rate dysregulation, temperature sensitivities, fatigue, and irritable bowel syndrome.

It is clear to see in Figure 1 that there are a variety of symptoms that overlap between these different categories of SFNs. This would be expected as in these cases, the localization of the pathophysiology is the small nerve fibers. Patients who experience small fiber hyperexcitability in SFSCD may not be the same type of patients who experience small fiber medaited autonomic dysfunction (SFMAD) and thus it may be inappropriate to approach their diagnostic algorithm and treatment in the same way.


Diagnosis


To properly place a patient into the subcategories of SFN, ie, SFSCD, SFMPN, SFMWP, SFMAD, it is essential to take a comprehensive history of all the patient’s symptoms. Patients may need skin biopsies, autonomic reflex screens, gastric emptying studies, etc, to know how many of their symptoms can be objectively defined. Once a patient is diagnosed as having a small fiber–mediated disorder, a thorough investigation to look for potential causes of the neuropathy is required. It is important to note that this article examines only those patients with pure SFN, defined as normal neurologic examinations and normal nerve conduction studies. Table 1 lists common causes of neuropathy and the corresponding tests to rule those causes out. A detailed patient history should be taken to determine whether there is family history of neuropathies, human immunodeficiency virus risk factors, hepatitis C infection, history of exposure to neurotoxins, and chemotherapeutics. Furthermore, laboratory testing including blood counts, metabolic enzymes, lipids, erythrocyte sedimentation rate, thyroid hormones, antinuclear antibodies, angiotensin-converting enzyme level, immunofixation testing, vitamin B12, and a glucose tolerance test should be administered. In some cases, special laboratory testing may be necessary depending on the specific medical history of the patient. In severe cases, more aggressive evaluation can include lumbar puncture, fat pad, and rectal biopsies, as well as sural nerve biopsies.


Treatments

In the case of SFN that can be attributed to a particular underlying cause, the underlying cause should be addressed to modify the SFN (ie, glucose control, exercise for dysglycemia-associated SFN).3 Pain management and other symptomatic therapies are crucial components of the treatment regimen for patients with neuropathy, as pain may be ameliorated by up to 50%, although elimination of pain is not usually achieved.9,10 Limited evidence for specific therapies in the treatment of neuropathic pain syndromes exist; however, there are some treatment options that can be effective in treating a variety of types of SFN.

Two therapies recommended for neuropathic pain include tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Tricyclic antidepressants have a high level of evidence that support their use in treating neuropathy. They have been suggested to be a first-line therapeutic for the treatment of chronic neuropathic pain.10 Use of these drugs potentially requires a process of dose escalation and proper timing of the dose to mitigate sedating or stimulating side effects.10 Typically, the doses used for patients with chronic neuropathic pain are less than those used to exert antidepressant effects. Serotonin-norepinephrine reuptake inhibitors are also used to reduce pain associated with neuropathy; their efficacy derives from their ability to potentiate nociceptive inhibitory pathways. The dosing for SNRIs to be effective at reducing pain is typically higher than the doses used for antidepressant purposes.10 Although this class of drug may be effective for pain reduction, the side effect profile associated with antidepressants may limit their usefulness in certain patients and/or prevent proper dose escalation.11

Anticonvulsant medications are also frequently used in patients with neuropathic pain. Gabapentin blocks the flux of calcium through calcium channels in the central nervous system, whereas pregabalin reduces the calcium influx in both peripheral and central neurons.10 Both γ-aminobutyric acid analogues are considered first-line therapeutics.10

Recently, the use of opioids has become controversial. The Centers for Disease Control and Prevention, as well as the Food and Drug Administration, has issued guidelines regarding the use of opioids in an effort to combat the growing public health problem that is opioid abuse and misuse.12,13 However, it is possible to use opioids, which typically target the µ-opioid receptor, to ameliorate pain associated with neuropathy, although use of opioids in those with SFMAD may be problematic, as exogenous opioids target the enteric nervous system and worsen gastrointestinal function.14 Because opioids can be abused and misused and may not be efficacious in patients with SFNs, it is imperative that novel therapeutics are developed that more specifically target the pathophysiology of SFNs. Currently, opioids should be considered as a treatment option only in patients who have resistance to other nonopioid mechanisms of treatment and there are very specific guidelines regarding how to use these drugs.10,12,13 In addition, related drugs such as µ-opioid receptor agonist norepinephrine reuptake inhibitors not only act at the µ-opioid receptor but also act to prevent norepinephrine reuptake.

Topical treatments may also be used to alleviate pain. Patches that contain drugs such as lidocaine can act locally to inhibit sodium channels and therefore nerve conduction. Capsaicin patches can also be used; however, capsaicin targets the vanilloid TRPV1 receptor; it leads to deterioration of nerve fibers in the skin which can regenerate within 3 months, therefore providing temporary relief. Both pain patches can be used alone or in combination with other therapeutics.10 Novel treatments under study include targeting transient receptor potential channels, angiotensin II type 2 receptor (ATR2) antagonism, intrathecal delivery of medications to reduce systemic exposure, and use of erythropoietin (EPO).

In the case of immune-mediated SFNs, there are different approaches to treatment that have shown preliminary efficacy in addressing SFN. One retrospective study of patients with sarcoidosis-associated SFN demonstrated that use of intravenous immunoglobulin G, anti-tumor necrosis factor, or a combination thereof resulted in improvement of symptoms.15 There is currently one clinical trial exploring the utility of IVIg in patients with idiopathic SFN (clinicaltrials.gov: NCT02637700). ARA 290 is a small molecule that is in development to address sarcoidosis-related SFN and it has had early positive results. It is a small peptide derived from EPO that targets the innate repair receptor complex.16,17 Preclinical data indicate that ARA 290 is capable of supporting the growth of intraepidermal nerve fibers, and preliminary clinical reports indicate that ARA 290 can induce small nerve fiber growth and provide relief from neuropathy symptoms.18,19

Inherited amyloid polyneuropathies can be treated; however, the treatments can range from conventional neuropathy drugs to surgical intervention. For example, a first-line treatment for individuals with familial amyloid polyneuropathy (FAP) due to the Val30Met mutation is liver transplantation. Removal of the source of the mutant protein and replacement with a liver donation effectively allow for a 95% reduction in variant protein from the blood and ultimately has an impact on disease progression.4,20 In severe cases, liver transplant may be accompanied by a heart transplant due to cardiomyopathy.20 Neither of these approaches, however, address the production of amyloid proteins in other tissues such as the eyes or central nervous system.20 Although transplantation is an accepted treatment for FAP, the outcomes for patients have been poor.

Novel approaches to addressing the mutated protein have been explored. One such tactic is the use of tafamidis.21 It is capable of selectively binding to TTR to stabilize and prevent dissociation and aggregation to amyloid deposits.22 Tafamidis is typically indicated for use in symptomatic TTR-FAP with proven amyloid deposits.22 In clinical trials, it has been shown to reduce worsening of nerve function.23 Diflunisal is a nonsteroidal anti-inflammatory drug (NSAID) that can also bind to TTR and stabilize the tetramer.24,25 A phase 1 study initially indicated that the generic NSAID was able to stabilize circulating TTR, reducing available substrate for amyloid formation.25 A 2-year study of the use of diflunisal in patients with this disease has shown that it can inhibit disease progression.26 A regimen of doxycycline and tauroursodeoxycholic acid has been explored in a phase 2 study that indicated that the combination can stabilize disease.27

Another approach to reduce the amyloid-forming ability of mutated TTR is to prevent its production in the first place. Short synthetic oligonucleotides (ASOs) directed against TTR messenger RNA have been explored as a method of protein reduction. Current clinical data regarding the use of ASOs are primarily from healthy volunteers, but there are ongoing trials to assess the ability of ASOs to control disease progression.20 Small-interfering RNAs (RNAi) have been brought to phase 2 trials, designed as a lipid nanoparticle delivering RNAi directed against a 3ʹ untranslated region of both mutant and wild-type TTR. A single dose of ALN-TTR02 reduced TTR production28; phase 2 data indicate that ALN-TTR02 dose dependently reduces circulating TTR protein.29 Monoclonal antibodies have been produced that are designed to target serum amyloid P component, although this is a common component of amyloid deposits, not unique to TTR. There are currently ongoing clinical trials with amyloid depleting antibodies; a phase 1 study has been initiated in patients with systemic amyloidosis to determine the efficacy in clearing serum amyloid. It is currently unclear whether this will affect disease progression in patients with TTR amyloidosis or lead to improved nerve function.20


Conclusions

To improve patient outcomes for those who have dysfunction of small nerve fibers and autonomic nerve fibers, it is imperative to be able to parse them into different subgroups. We have proposed and made an argument that patients should be classified as follows:


SFSCD, those with sodium channel dysfunction


Patients with normal nerve density but known abnormalities of their voltage gated sodium channels causing nociceptive dysfunction without loss of intraepidermal nerve fiber density.


SFMPN, those with classic neurologic symptoms


Patients with normal electromyography (EMG)/nerve conduction velocity (NCV) and neurologic examinations who have reduced intraepidermal nerve fiber density and neuropathic pain as their predominant complaint.


SFMWP, those with widespread neuropathic pain


Patients with normal EMG/NCV and neurologic examinations who have reduced intraepidermal nerve fiber density who have muscle pain, achy pain as opposed to neuropathic pain as their predominant complaint.


SFMAD, those with autonomic symptoms


Patients who have autonomic dysfunction as their predominant complaint, such as POTS, autonomic instability, and gastroparesis.

Patients should be classified by the type of SFN they experience to improve management of disease and patient outcomes. Distinction between patients who have autonomic dysfunction in addition to the painful neuropathy induced by small fiber dysfunction is critical to proper treatment and disease management. For example, individuals diagnosed with SFMPN may be likely to respond to anticonvulsants and channel blocking drugs, whereas those with SFMWP may be more likely to respond to TCAs and SNRIs. Until patients are classified into the appropriate groups and treatment algorithms adjusted to accommodate the various characteristics of the pathology, will it be possible to address issues related to the lack of efficacy of some therapeutics in individuals having SFN.

Not only is patient management affected by the appropriate classification of a patient’s disease but also future work to develop novel therapeutics and approaches may be hindered if the root causes of each disease are not uncovered. Pursuit of novel therapeutic strategies and agents may stem from grouping patients together more appropriately and studying the similarities and differences and systemic effects experienced.30 Ultimately, classifying patients more specifically by the symptomology with which they present may lead to understanding the underlying mechanism of the development of neuropathy, particularly in determining what causes widespread neuropathy as compared with amyloid neuropathy that primarily affects particular systems.


Acknowledgements


The author would likes to acknowledge medical writing assistance provided by AXON Communications.


Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests:
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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 http://journals.sagepub.com/doi/10.1177/1179573518771703