Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain.

BACKGROUND: Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood. METHODS: A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types. RESULTS: We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at ∼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia. CONCLUSIONS: These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.

Repetitive neonatal procedural pain affects stress-induced plasma corticosterone increase in young adult females but not in male rats.

Exposure to repetitive painful procedures in the neonatal intensive care unit results in long-lasting effects, especially visible after a "second hit" in adulthood. As the nociceptive system and the hypothalamic-pituitary-adrenal (HPA) axis interact and are vulnerable in early life, repetitive painful procedures in neonates may affect later-life HPA axis reactivity. The first aim of the present study was to investigate the effects of repetitive neonatal procedural pain on plasma corticosterone levels after mild acute stress (MAS) in young adult rats. Second, the study examined if MAS acts as a "second hit" and affects mechanical sensitivity. Fifty-two rats were either needle pricked four times a day, disturbed, or left undisturbed during the first neonatal week. At 8 weeks, the animals were subjected to MAS, and plasma was collected before (t0), after MAS (t20), and at recovery (t60). Corticosterone levels were analyzed using an enzyme-linked immunosorbent assay, and mechanical sensitivity was assessed with von Frey filaments. Results demonstrate that repetitive neonatal procedural pain reduces stress-induced plasma corticosterone increase after MAS only in young adult females and not in males. Furthermore, MAS does not affect mechanical sensitivity in young adult rats. Altogether, the results suggest an age- and sex-dependent effect of repetitive neonatal procedural pain on HPA axis reprogramming.

Genome-wide association study suggests a critical contribution of the adaptive immune system to chronic post-surgical pain.

Chronic post-surgical pain affects a large proportion of people undergoing surgery, delaying recovery time and worsening quality of life. Although many environmental variables have been established as risk factors, less is known about genetic risk. To uncover genetic risk factors we performed genome-wide association studies in post-surgical cohorts of five surgery types- hysterectomy, mastectomy, abdominal, hernia, and knee- totaling 1350 individuals. Genetic associations between post-surgical chronic pain levels on a numeric rating scale (NRS) and additive genetic effects at common SNPs were evaluated. We observed genome-wide significant hits in almost all cohorts that displayed significance at the SNP, gene, and pathway levels. The cohorts were then combined via a GWAS meta-analysis framework for further analyses. Using partitioned heritability, we found that loci at genes specifically expressed in the immune system carried enriched heritability, especially genes related to B and T cells. The relevance of B cells in particular was then demonstrated in mouse postoperative pain assays. Taken altogether, our results suggest a role for the adaptive immune system in chronic post-surgical pain.

Spinal Cord Stimulation Paradigms and Pain Relief: A Preclinical Systematic Review on Modulation of the Central Inflammatory Response in Neuropathic Pain.

OBJECTIVES: Spinal cord stimulation (SCS) is a last-resort treatment for patients with chronic neuropathic pain. The mechanism underlying SCS and pain relief is not yet fully understood. Because the inflammatory balance between pro- and anti-inflammatory molecules in the spinal nociceptive network is pivotal in the development and maintenance of neuropathic pain, the working mechanism of SCS is suggested to be related to the modulation of this balance. The aim of this systematic review is to summarize and understand the effects of different SCS paradigms on the central inflammatory balance in the spinal cord. MATERIALS AND METHODS: A systematic literature search was conducted using MEDLINE, Embase, and PubMed. All articles studying the effects of SCS on inflammatory or glial markers in neuropathic pain models were included. A quality assessment was performed on predetermined entities of bias. RESULTS: A total of 11 articles were eligible for this systematic review. In general, induction of neuropathic pain in rats results in a proinflammatory state and at the same time an increased activity/expression of microglial and astroglial cells in the spinal cord dorsal horn. Conventional SCS seems to further enhance this proinflammatory state and increase the messenger RNA expression of microglial markers, but it also results in a decrease in microglial protein marker levels. High-frequency and especially differential targeted multiplexed SCS can not only restore the balance between pro- and anti-inflammatory molecules but also minimize the overexpression/activation of glial cells. Quality assessment and risk of bias analysis of the studies included make it clear that the results of these preclinical studies must be interpreted with caution. CONCLUSIONS: In summary, the preclinical findings tend to indicate that there is a distinct SCS paradigm-related effect in the modulation of the central inflammatory balance of the spinal dorsal horn.

The development of descending serotonergic modulation of the spinal nociceptive network: a life span perspective.

The nociceptive network, responsible for transmission of nociceptive signals that generate the pain experience, is not fully developed at birth. Descending serotonergic modulation of spinal nociception, an important part of the pain network, undergoes substantial postnatal maturation and is suggested to be involved in the altered pain response observed in human newborns. This review summarizes preclinical data of the development of descending serotonergic modulation of the spinal nociceptive network across the life span, providing a comprehensive background to understand human newborn pain experience and treatment. Sprouting of descending serotonergic axons, originating from the rostroventral medulla, as well as changes in receptor function and expression take place in the first postnatal weeks of rodents, corresponding to human neonates in early infancy. Descending serotonergic modulation switches from facilitation in early life to bimodal control in adulthood, masking an already functional 5-HT inhibitory system at early ages. Specifically the 5-HT3 and 5-HT7 receptors seem distinctly important for pain facilitation at neonatal and early infancy, while the 5-HT1a, 5-HT1b, and 5-HT2 receptors mediate inhibitory effects at all ages. Analgesic therapy that considers the neurodevelopmental phase is likely to result in a more targeted treatment of neonatal pain and may improve both short- and long-term effects. IMPACT: The descending serotonergic system undergoes anatomical changes from birth to early infancy, as its sprouts and descending projections increase and the dorsal horn innervation pattern changes. Descending serotonergic modulation from the rostral ventral medulla switches from facilitation in early life via the 5-HT3 and 5-HT7 receptors to bimodal control in adulthood. A functional inhibitory serotonergic system mainly via 5-HT1a, 5-HT1b, and 5-HT2a receptors at the spinal level exists already at the neonatal phase but is masked by descending facilitation.

Dopamine-neurotransmission and nociception in zebrafish: An anti-nociceptive role of dopamine receptor drd2a.

Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic variations within DA neurotransmission have been associated with altered pain sensitivity and development of chronic pain syndromes. The variant rs6277 in dopamine receptor 2 a (drd2a) has been associated with a decreased D2 receptor availability and increased nociception. The aim of this study is to further characterize the role of DA neurotransmission in nociception and the anti-nociceptive function of drd2a. The phenotype caused by rs6277 was modelled in zebrafish larvae using morpholino's and the effect on nociception was tested using a validated behavioural assay. The anti-nociceptive role of drd2a was tested using pharmacological intervention of D2 agonist Quinpirole. The experiments demonstrate that a decrease in drd2a expression results in a pro-nociceptive behavioural phenotype (P = 0.016) after a heat stimulus. Furthermore, agonism of drd2a with agonist Quinpirole (0.2 µM) results in dose-dependent anti-nociception (P = 0.035) after a heat stimulus. From these results it is concluded that the dopamine receptor drd2a is involved in anti-nociceptive behaviour in zebrafish. The model allows further screening and testing of genetic variation and treatment involved in nociception.

Conventional Dorsal Root Ganglion Stimulation in an Experimental Model of Painful Diabetic Peripheral Neuropathy: A Quantitative Immunocytochemical Analysis of Intracellular γ-Aminobutyric Acid in Dorsal Root Ganglion Neurons.

BACKGROUND AND OBJECTIVE: The sensory cell somata in the DRG contain all equipment necessary for extensive GABAergic signaling and are able to release GABA upon depolarization. With this study, we hypothesize that pain relief induced by conventional dorsal root ganglion stimulation (Con-DRGS) in animals with experimental painful diabetic peripheral neuropathy is related to the release of GABA from DRG neurons. With use of quantitative immunocytochemistry, we hypothesize DRGS to result in a decreased intensity of intracellular GABA-immunostaining in DRG somata. MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 31) were injected with streptozotocin (STZ) in order to induce Diabetes Mellitus. Animals that developed neuropathic pain after four weeks (Von Frey) were implanted with a unilateral DRGS device at L4 (n = 14). Animals were then stimulated for 30 min with Con-DRGS (20 Hz, pulse width = 0.2 msec, amplitude = 67% of motor threshold, n = 8) or Sham-DRGS (n = 6), while pain behavior (von Frey) was measured. DRGs were then collected and immunostained for GABA, and a relation to size of sensory cell soma diameter (small: 12-26 µm, assumed to be C-fiber related sensory neurons; medium: 26-40 µm, assumed to be Aδ related sensory neurons; and large: 40-54 µm, assumed to be Aß related sensory neurons) was made. RESULTS: DRGS treated animals showed significant reductions in STZ-induced mechanical hypersensitivity. No significant differences in GABA immunostaining intensity per sensory neuron cell soma type (small-, medium-, or large-sized) were noted in DRGs of stimulated (Con-DRGS) animals versus Sham animals. No differences in GABA immunostaining intensity per sensory cell soma type in ipsi- as compared to contralateral DRGs were observed. CONCLUSION: Con-DRGS does not affect the average intracellular GABA immunofluorescence staining intensity in DRG sensory neurons of those animals which showed significant pain reduction. Similarly, no soma size related changes in intracellular GABA immunofluorescence were observed following Con-DRGS.

Personalized Medicine: Recent Progress in Cancer Therapy.

Personalized medicine (PM) or precision medicine in oncology is an emerging approach for tumor treatment and prevention that takes into account inter- and intra-tumor variability in genes, tumor (immune) environment, and lifestyle and morbidities of each person diagnosed with cancer [...].

Effect of Anesthesia on Microelectrode Recordings During Deep Brain Stimulation Surgery: A Narrative Review.

Deep brain stimulation (DBS) is an effective surgical treatment for patients with various neurological and psychiatric disorders. Clinical improvements rely on careful patient selection and accurate electrode placement. A common method for target localization is intraoperative microelectrode recording (MER). To facilitate MER, DBS surgery is traditionally performed under local or regional anesthesia. However, sedation or general anesthesia is sometimes needed for patients who are unable to tolerate the procedure fully awake because of severe motor symptoms, psychological distress, pain, or other forms of discomfort. The effect of anesthetic drugs on MER is controversial but likely depends on the type and dose of a particular anesthetic agent, underlying disease, and surgical target. In this narrative review, we provide an overview of the current literature on the anesthetic drugs most often used for sedation and anesthesia during DBS surgery, with a focus on their effects on MERs.

Qualitative review on N-methyl-D-aspartate receptor expression in rat spinal cord during the postnatal development: Implications for central sensitization and pain.

The N-methyl-D-aspartate receptor (NMDAR) is an important mediator of central sensitization and nociception in the rat spinal dorsal horn. The NMDAR subunits and splice variants determine the properties of the receptor. Understanding the expression of NMDAR subunits in spinal cord during the neonatal development is important as it may have consequences for the process of central sensitization and nociception in later life. In this review, a systematic literature search was conducted using three databases: Medline, Embase, and PubMed. A quality assessment was performed on predetermined entities of bias. Thirteen articles were identified to be relevant. The results show that NMDAR subunits and splice variants are dynamically expressed during postnatal development in the spinal dorsal horn. During the first 2 weeks, the expression of less excitable GluN2A subunit and more sensitive GluN2B subunit increases while the expression of high excitable GluN2C subunit decreases. During the 2nd week of postnatal development GluN1 subunits with exon 21 spliced in but exon 22 spliced out are predominantly expressed, increasing phosphorylation, and transport to the membrane. The data suggest that in rats, the nociceptive system is most susceptible to central sensitization processes during the first two postnatal weeks. This may have important consequences for nociception and pain responses in later life. From this, we conclude that targeted therapy directed toward specific NMDAR subunits is a promising candidate for mechanism-based treatment of pain in neonates.

Polygenic risk scores indicates genetic overlap between peripheral pain syndromes and chronic postsurgical pain.

Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that has a substantial effect on quality of life. CPSP shows considerable clinical overlap with different chronic peripheral pain syndromes, suggesting a shared aetiology. This study aims to assess the genetic overlap between different chronic pain syndromes and CPSP, providing relevant biological context for potential chronic pain markers of CPSP. To analyse the genetic overlap between CPSP and chronic peripheral pain syndromes, recent GWAS studies were combined for polygenic risk scores (PRS) analysis, using a cohort of CPSP patients as starting point. Biological contextualisation of genetic marker, overlap between CPSP and chronic pain syndromes, was assessed through Gene Ontology (GO), using Pathway Scoring Algorithm (PASCAL) and REVIGO. PRS analyses suggest a significant genetic overlap between CPSP and 3 chronic pain disorders: chronic widespread pain (CWP, p value threshold = 0.003, R2 0.06, p = 0.003), rheumatoid arthritis (RA, p value threshold = 0.0177, R2 = 0.04, p = 0.017) and possibly sciatica (p value threshold = 0.00025, R2 = 0.03, p = 0.045). Whereas no significant genetic overlap was found with cluster headache and migraine, the outcome for osteoarthritis (OA) was inconsistent between the cohorts. This is likely related to cohort composition, as repeated random reallocation of patients' nullified CPSP/OA outcome variation between the discovery and replication cohorts. GO analyses suggested an aetiological involvement of genetic markers that control neurological signalling (specifically sodium channels) and inflammatory response. The current study reaffirms the impact of sample size, cohort composition and open data accessibility on the unbiased identification of genetic overlap across disorders. In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory response may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate.

Active Recharge Burst and Tonic Spinal Cord Stimulation Engage Different Supraspinal Mechanisms: A Functional Magnetic Resonance Imaging Study in Peripherally Injured Chronic Neuropathic Rats.

OBJECTIVES: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS. METHODS: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner. RESULTS: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas. CONCLUSIONS: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst.

Burst and Tonic Spinal Cord Stimulation in the Mechanical Conflict-Avoidance System: Cognitive-Motivational Aspects.

BACKGROUND: Clinical research suggests that a novel spinal cord stimulation (SCS) waveform, known as Burst-SCS, specifically targets cognitive-motivational aspects of pain. The objective of the present study was to assess the cognitive-motivational aspects of Tonic- and Burst SCS-induced pain relief, by means of exit latency in the mechanical conflict-avoidance system (MCAS), in a rat model of chronic neuropathic pain. METHODS: Exit latency on the MCAS operant testing setup was evaluated at various probe heights for rats (n = 26) with chronic neuropathic pain induced by a partial sciatic nerve ligation (PSNL). Von Frey paw withdrawal analysis was performed to assess mechanical hypersensitivity. In a second experiment (n = 12), the behavioral effect of Tonic SCS or biphasic Burst SCS on both Von Frey analysis and MCAS exit latency was assessed. RESULTS: Burst SCS exit latencies differed significantly from Tonic SCS exit latencies at 4 mm probe height (3.8 vs. 5.8 sec, respectively; p < 0.01) and 5 mm probe height (3.2 vs. 5.4 sec respectively; p < 0.05). This difference was not detected with reflex-based Von Frey testing (Tonic-SCS vs. Burst-SCS at 30 min stimulation: p = 0.73, and at 60 min stimulation; p = 0.42). CONCLUSIONS: Testing of MCAS exit latency allows for detection of cognitive-motivational pain relieving aspects induced by either Tonic- or Burst-SCS in treatment of chronic neuropathic rats. Our behavioral findings strongly suggest that Burst-SCS specifically affects, much more than Tonic-SCS, the processing of cognitive-motivational aspects of pain.

Burst and Tonic Spinal Cord Stimulation Both Activate Spinal GABAergic Mechanisms to Attenuate Pain in a Rat Model of Chronic Neuropathic Pain.

BACKGROUND: Experimental and clinical studies have shown that tonic spinal cord stimulation (SCS) releases gamma-aminobutyric acid (GABA) in the spinal dorsal horn. Recently, it was suggested that burst SCS does not act via spinal GABAergic mechanisms. Therefore, we studied spinal GABA release during burst and tonic SCS, both anatomically and pharmacologically, in a well-established chronic neuropathic pain model. METHODS: Animals underwent partial sciatic nerve ligation (PSNL). Quantitative immunohistochemical (IHC) analysis of intracellular GABA levels in the lumbar L4 to L6 dorsal spinal cord was performed after 60 minutes of burst, tonic, or sham SCS in rats that had undergone PSNL (n = 16). In a second pharmacological experiment, the effects of intrathecal administration of the GABAA antagonist bicuculline (5 µg) and the GABAB antagonist phaclofen (5 µg) were assessed. Paw withdrawal thresholds to von Frey filaments of rats that had undergone PSNL (n = 20) were tested during 60 minutes of burst and tonic SCS 30 minutes after intrathecal administration of the drugs. RESULTS: Quantitative IHC analysis of GABA immunoreactivity in spinal dorsal horn sections of animals that had received burst SCS (n = 5) showed significantly lower intracellular GABA levels when compared to sham SCS sections (n = 4; P = 0.0201) and tonic SCS sections (n = 7; P = 0.0077). Intrathecal application of the GABAA antagonist bicuculline (5 µg; n = 10) or the GABAB antagonist phaclofen (5 µg; n = 10) resulted in ablation of the analgesic effect for both burst SCS and tonic SCS. CONCLUSIONS: In conclusion, our anatomical and pharmacological data demonstrate that, in this well-established chronic neuropathic animal model, the analgesic effects of both burst SCS and tonic SCS are mediated via spinal GABAergic mechanisms.

Nonlinear Relation Between Burst Dorsal Root Ganglion Stimulation Amplitude and Behavioral Outcome in an Experimental Model of Painful Diabetic Peripheral Neuropathy.

BACKGROUND AND OBJECTIVE: Dorsal root ganglion stimulation (DRGS) has recently emerged as a neuromodulation modality in the treatment of chronic neuropathic pain. The objective of this study was to compare the efficacy of different Burst-DRGS amplitudes in an experimental model of painful diabetic peripheral neuropathy (PDPN). METHODS: Diabetes mellitus was induced in female Sprague-Dawley rats by intraperitoneal injection of streptozotocin (STZ, n = 28). Animals were tested for mechanical hypersensitivity (von Frey paw withdrawal test) before, and four weeks after STZ injection. PDPN rats (n = 13) were implanted with a unilateral bipolar electrode at the L5 DRG. Animals received Burst-DRGS at 0%, 10%, 33%, 50%, 66%, and 80% of motor threshold (MT) in a randomized crossover design on post-implantation days 2-7 (n = 9). Mechanical hypersensitivity was assessed before stimulation onset, 15 and 30 min during stimulation, and 15 and 30 min after stimulation. RESULTS: Burst-DRGS at amplitudes of 33%, 50%, 66%, and 80% MT resulted in significant attenuation of STZ-induced mechanical hypersensitivity at 15 and 30 min during stimulation, as well as 15 min after cessation of stimulation. No effect on mechanical hypersensitivity was observed for Burst-DRGS at 0% MT and 10% MT. Optimal pain relief and highest responder rates were achieved with Burst-DRGS at 50-66% MT, with an estimated optimum at 52% MT. CONCLUSION: Our findings indicate a nonlinear relationship between Burst-DRGS amplitude and behavioral outcome, with an estimated optimal amplitude of 52% MT. Further optimization and analysis of DRGS driven by insights into the underlying mechanisms related to the various stimulation paradigms is warranted.

Dopaminergic neurotransmission and genetic variation in chronification of post-surgical pain.

Chronic post-surgical pain (CPSP) is a debilitating condition affecting 10-50% of surgical patients. The current treatment strategy for CPSP is not optimal, and the identification of genetic variation in surgical patients might help to improve prediction and treatment of CPSP. The neurotransmitter dopamine (DA) has been associated with several chronic pain disorders. This narrative review focuses on DA neurotransmission as a potential target in the treatment of CPSP. The current knowledge on genetic variation within DA neurotransmission and its role in CPSP susceptibility are reviewed. Three genes involved in DA neurotransmission (COMT, GCH1, and DRD2) have been associated with variability in pain sensitivity, development of CPSP, and analgesic requirement. The direction of the effect of the association is sometimes inconclusive because of contradictory results, but ample evidence suggests a modulatory role of DA. Because of this modulatory role, DA is an excellent pharmacological target in the treatment of pain. Pharmacotherapy focused on DA neurotransmission has potential in both prevention (via D1-like receptors) and treatment (via D2-like receptors and DA reuptake inhibitors) of CPSP. The development of prediction models including genetic risk factors is necessary to better identify patients at risk.

Effectiveness of dorsal root ganglion stimulation and dorsal column spinal cord stimulation in a model of experimental painful diabetic polyneuropathy.

AIMS: Conventional dorsal root ganglion stimulation (DRGS) is known to achieve better pain-paresthesia overlap of difficult-to-reach areas like the feet compared to dorsal column spinal cord stimulation (SCS). As in painful diabetic polyneuropathy (PDPN) pain is mostly present in the feet, we hypothesized that DRGS is more effective in relieving pain in PDPN when compared to SCS. METHODS: Diabetes was induced in female Sprague-Dawley rats with an intraperitoneal injection of 65 mg/kg of streptozotocin (STZ; n = 48). Rats with a significant decrease in mechanical paw withdrawal response to von Frey filaments 4 weeks after injection were implanted with DRGS electrodes (n = 18). Rats were assigned to DRGS (n = 11) or sham-DRGS (n = 7). Mechanical paw withdrawal thresholds (WT, measured in grams) in response to DRGS (50 Hz, 0.18 ± 0.05 mA) were assessed with von Frey testing. The results of the experiments on these animals were compared to the results of a previous study using exactly the same model on PDPN animals selected for SCS (n = 8) (40-50 Hz, 0.19 ± 0.01 mA) and sham-SCS (n = 3). RESULTS: In the SCS group, the log10 (10 000 × 50% WT) increased from 4910 to 5211 at t = 15 minutes (P < 0.05) and 5264 at t = 30 minutes (P = 0.11). In the DRGS group, the log10 (10,000 × 50% WT) increased from 4376 to 4809 at t = 15 minutes (P < 0.01) and 5042 at t = 30 minutes (P < 0.01). Both DRGS and SCS induced a similar and complete reversal of mechanical hypersensitivity. After cessation of stimulation (t = 60), the return of the log10 (10 000 × 50% WT) response was significantly faster with DRGS than that of SCS (P < 0.05). CONCLUSIONS: We conclude that conventional DRGS is as effective as SCS in reduction of PDPN-associated mechanical hypersensitivity in STZ-induced diabetic rats. The wash-in effect of DRGS and SCS was similar, but DRGS showed a faster washout course. Long-term efficacy should be studied in future animal research.

Dorsal Root Ganglion Stimulation in Experimental Painful Diabetic Peripheral Neuropathy: Burst vs. Conventional Stimulation Paradigm.

OBJECTIVES: Painful diabetic peripheral neuropathy (PDPN) is a long-term complication of diabetes mellitus (DM). Dorsal Root Ganglion Stimulation (DRGS) has recently emerged as a neuromodulation modality in the treatment of chronic neuropathic pain. The objective of this study was to compare the effect of burst DRGS (Burst-DRGS) and conventional DRGS (Con-DRGS) in an experimental model of PDPN. MATERIALS AND METHODS: DM was induced in female Sprague-Dawley rats by intraperitoneal injection of streptozotocin (STZ, n = 48). Animals were tested for mechanical hypersensitivity (50% hind paw withdrawal threshold on Von Frey test) before, and 4 weeks after STZ injection. PDPN rats were then implanted with a unilateral bipolar lead at the L5 DRG (n = 22) and were stimulated for 30 min at days 2 and 3 postimplantation. Animals received Con-DRGS and Burst-DRGS in a randomized crossover design (n = 10), or received Sham-DRGS (n = 7) for 30 min, and were tested for mechanical hypersensitivity at baseline, 15 and 30 min during DRGS, and 15 and 30 min following DRGS. Five animals were withdrawn from the study due to electrode-related technical problems. RESULTS: Con-DRGS and Burst-DRGS normalized STZ-induced mechanical hypersensitivity at 15 and 30 min during stimulation. A significant difference in terms of mechanical hypersensitivity was observed between both of the stimulated groups and the Sham-DRGS group at 15 and 30 min during stimulation. Interestingly, Burst-DRGS showed signs of a residual effect at 15 min after cessation of stimulation, while this was not the case for Con-DRGS. CONCLUSIONS: Under the conditions tested, Con-DRGS and Burst-DRGS are equally effective in attenuating STZ-induced mechanical hypersensitivity in an animal model of PDPN. Burst-DRGS showed signs of a residual effect at 15 min after cessation of stimulation, which requires further investigation.

Treatment of Pain in Cancer: Towards Personalised Medicine.

Despite increased attention to cancer pain, pain prevalence in patients with cancer has not improved over the last decade and one third of cancer patients on anticancer therapy and half of patients with advanced disease still suffer from moderate to severe pain. In this review, we explore the possible reasons for the ongoing high prevalence of cancer pain and discuss possible future directions for improvement in personalised pain management. Among possible reasons for the lack of improvement are: Barriers for patients to discuss pain with clinicians spontaneously; pain measurement instruments are not routinely used in daily practice; limited knowledge concerning the assessment of undertreatment; changes in patients' characteristics, including the ageing of the population; lack of significant improvement in the treatment of neuropathic pain; limitations of pharmacological treatment and lack of evidence-based nonpharmacological treatment strategies. In order to improve cancer pain treatment, we recommend: (1) Physicians proactively ask about pain and measure pain using assessment instruments; (2) the development of an optimal tool measuring undertreatment; (3) educational interventions to improve health care workers' skills in pain management; (4) the development of more effective and personalised pharmacological and nonpharmacological pain treatment.