Painful Peripheral Neuropathies of the Lower Limbs and/or Lower Extremities Treated with Spinal Cord Stimulation: A Systematic Review with Narrative Synthesis.

Introduction: Painful peripheral neuropathy (PPN) is a debilitating condition with varied etiologies. Spinal cord stimulation (SCS) is increasingly used when conservative treatments fail to provide adequate pain relief. Few published reviews have examined SCS outcomes in all forms of PPN. Methods: We conducted a systematic review of SCS in PPN. The PubMed database was searched up to February 7th, 2022, for peer-reviewed studies of SCS that enrolled PPN patients with pain symptoms in their lower limbs and/or lower extremities. We assessed the quality of randomized controlled trial (RCT) evidence using the Cochrane risk of bias tool. Data were tabulated and presented narratively. Results: Twenty eligible studies documented SCS treatment in PPN patients, including 10 kHz SCS, traditional low-frequency SCS (t-SCS), dorsal root ganglion stimulation (DRGS), and burst SCS. In total, 451 patients received a permanent implant (10 kHz SCS, n=267; t-SCS, n=147; DRGS, n=25; burst SCS, n=12). Approximately 88% of implanted patients had painful diabetic neuropathy (PDN). Overall, we found clinically meaningful pain relief (≥30%) with all SCS modalities. Among the studies, RCTs supported the use of 10 kHz SCS and t-SCS to treat PDN, with 10 kHz SCS providing a higher reduction in pain (76%) than t-SCS (38-55%). Pain relief with 10 kHz SCS and DRGS in other PPN etiologies ranged from 42-81%. In addition, 66-71% of PDN patients and 38% of nondiabetic PPN patients experienced neurological improvement with 10 kHz SCS. Conclusion: Our review found clinically meaningful pain relief in PPN patients after SCS treatment. RCT evidence supported the use of 10 kHz SCS and t-SCS in the diabetic neuropathy subpopulation, with more robust pain relief evident with 10 kHz SCS. Outcomes in other PPN etiologies were also promising for 10 kHz SCS. In addition, a majority of PDN patients experienced neurological improvement with 10 kHz SCS, as did a notable subset of nondiabetic PPN patients.

Neuromodulation in the Treatment of Painful Diabetic Neuropathy: A Review of Evidence for Spinal Cord Stimulation.

BACKGROUND: Neuropathies, the most common complication of diabetes, manifest in various forms, including entrapments, mononeuropathies or, most frequently, a distal symmetric polyneuropathy. Painful diabetic neuropathy (PDN) in the classic "stocking" distribution is a disease of increasing prevalence worldwide and a condition for which standard medical treatment only provides modest relief. Neuromodulation offers a potential alternative to pharmacotherapies given its demonstrated efficacy in other refractory chronic neuropathic pain syndromes. High-quality evidence from randomized controlled trials (RCTs) is available in these other settings for two approaches to spinal cord stimulation (SCS): (1) conventional low-frequency SCS (LF-SCS), which modulates axonal activity in the dorsal column and is paresthesia-dependent, and (2) high-frequency SCS delivered at 10 kilohertz (10 kHz SCS), which targets neurons in the superficial dorsal horn and is paresthesia-independent. METHOD: This review examines the evidence for SCS from published RCTs as well as prospective studies exploring the safety and effectiveness of treating PDN with neuromodulation. RESULTS: Two RCTs enrolling 60 and 36 participants with PDN showed treatment with LF-SCS reduced daytime pain by 45% to 55% for up to two years. An RCT testing 10 kHz SCS versus conventional medical management (CMM) in 216 participants with PDN revealed 76% mean pain relief after six months of stimulation. None of the studies revealed unexpected safety issues in the use of neuromodulation in this patient population. CONCLUSION: These well-designed RCTs address the unmet need for improved PDN therapies and provide data on the safety, effectiveness, and durability of SCS therapy.

Successful treatment of central pain in a multiple sclerosis patient with epidural stimulation of the dorsal root entry zone.

OBJECTIVE: We report a case of central pain successfully treated by epidural placement of spinal cord stimulator electrodes. Neuromodulation of primary afferent fibers and the underlying dorsal root entry zone provided effective analgesia whereas traditional lead placement over the dorsal columns on a prior occasion had not been effective. The rationale for this technique based on current understanding of the mechanisms of central pain and the risk/benefit considerations are discussed. CASE REPORT: A 52-year-old woman presented with a 2-year history of pain in the lateral hand secondary to a demyelinating episode in the C2-4 spinal cord secondary to multiple sclerosis. Medications, sympathetic blocks, and acupuncture had been ineffective. One year after an unsuccessful single-lead trial of spinal cord stimulation over the cervical dorsal columns, a dual-lead trial of spinal cord stimulation over the lateral cervical spinal cord and dorsal roots provided significant analgesia, prompting a successful permanent implant. OUTCOME MEASURES: Responses on the Brief Pain Inventory short form and quantitative thermosensory testing data were collected at two timepoints 16 days apart under two conditions: no stimulation and single-lead stimulation of cervical primary afferents and underlying spinal cord. RESULTS: The patient's questionnaire responses indicated significantly improved pain scores with lateral-lead neuromodulation that was associated with a reduction in her baseline heat hypoalgesia. CONCLUSIONS: Lateral-lead spinal cord stimulation may be effective for some central pain syndromes through a partial restoration of homeostatic small-fiber signaling. Neuroanatomical and physiological data in a larger population of patients will be required to predict the best responders to this therapeutic modality.

Organization of endogenous opioids in the rostral agranular insular cortex of the rat.

The rostral agranular insular cortex (RAIC) of rats has opioid receptors and has been implicated in the analgesic and reinforcing effects of opiates. To help in understanding the function of endogenous opioids in this structure, we sought to identify and describe the opioid peptides intrinsic to the RAIC by using immunohistochemical methods. Immunolabeling for proopiomelanocortin (POMC), the precursor to beta-endorphin, and endomorphin 1 and 2 on sectioned rat forebrain revealed limited labeling consisting of individual varicose fibers. Immunolabeling for prodynorphin and enkephalin revealed numerous immunopositive cell bodies and fibers with distribution and morphology unique to each. Prodynorphin-immunopositive cell bodies consisted of two types: large, lightly labeled, pyramidal-shaped cell bodies in lamina V and more intensely labeled, small, ovoid cell bodies scattered in other lamina. Axonal fibers immunolabeled for prodynorphin varied in size and were found in all lamina. Immunolabeling for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) was rarely found in dynorphin-containing cell bodies (6%, 10/167) but was visible within a subpopulation of axons. Enkephalin immunolabeling was detected within a single morphological subpopulation of nonpyramidal neurons located predominantly in lamina II/III, 30% (33/109) of which were also GABA immunopositive. Axons immunolabeled for enkephalin were also abundant in lamina II/III. These results suggest that dynorphin and enkephalin peptides are the predominant endogenous opioids in the RAIC and their distinct distributions suggest divergent functional roles. The localization of prodynorphin immunoreactivity to pyramidal cells suggests the possibility that this neuropeptide may be used in RAIC projection neurons, whereas enkephalin distribution was more characteristic of a role in local networks.

Rostral agranular insular cortex and pain areas of the central nervous system: a tract-tracing study in the rat.

The rostral agranular insular cortex (RAIC) has recently been identified as a site where local changes in GABA and dopamine levels, or application of opioids, can alter nociceptive thresholds in awake animals. The connections of the cortex dorsal to the rhinal fissure that includes the RAIC have been examined previously, with emphasis on visceral and gustatory functions but not nociception. Here we examined the afferent and efferent connections of the RAIC with sites implicated in nociceptive processing. Sensory information from the thalamus reaches the RAIC via the submedius and central lateral nuclei and the parvicellular part of the ventral posterior nucleus. The RAIC has extensive reciprocal cortico-cortical connections with the orbital, infralimbic, and anterior cingulate cortices and with the contralateral RAIC. The amygdala, particularly the basal complex, and the nucleus accumbens are important targets of RAIC efferent fibers. Other connections include projections to lateral hypothalamus, dorsal raphe, periaqueductal gray matter, pericerulear region, rostroventral medulla, and parabrachial nuclei. The connectivity of the RAIC suggests it is involved in multiple aspects of pain behavior. Projections to the RAIC from medial thalamic nuclei are associated with motivational/affective components of pain. RAIC projections to mesolimbic/mesocortical ventral forebrain circuits are likely to participate in the sensorimotor integration of nociceptive processing, while its brainstem projections are most likely to contribute to descending pain inhibitory control.

Mental motor imagery indexes pain: the hand laterality task.

Mental motor imagery is subserved by the same cognitive systems that underlie action. In turn, action is informed by the anticipated sensory consequences of movement, including pain. In light of these considerations, one would predict that motor imagery would provide a useful measure pain-related functional interference. We report a study in which 19 patients with chronic musculoskeletal or radiculopathic arm or shoulder pain, 24 subjects with chronic pain not involving the arm/shoulder and 41 normal controls were asked to indicate if a line drawing was a right or left hand. Previous work demonstrated that this task is performed by mental rotation of the subject's hand to match the stimulus. Relative to normal and pain control subjects, arm/shoulder pain subjects were significantly slower for stimuli that required greater amplitude rotations. For the arm/shoulder pain subjects only there was a correlation between degree of slowing and the rating of severity of pain with movement but not the non-specific pain rating. The hand laterality task may supplement the assessment of subjects with chronic arm/shoulder pain.

Development of a novel location-based assessment of sensory symptoms in cancer patients: preliminary reliability and validity assessment.

We report on the development of a novel location-based assessment of sensory symptoms in cancer (L-BASIC) instrument, and its initial estimates of reliability and validity. L-BASIC is structured so that patients provide a numeric score and an adjectival description for any sensory symptom, including both pain and neuropathic sensations, present in each of the 10 predefined body areas. Ninety-seven patients completed the baseline questionnaire; 39 completed the questionnaire on two occasions. A mean of 3.5 body parts was scored per patient. On average, 2.7 (of 11) descriptor categories were used per body part. There was good internal consistency (Cronbach's alpha=0.74) for a four-item scale that combined location-specific metrics. Temporal stability was adequate (kappa>0.50 and r>0.60 for categorical and continuous variables, respectively) among patients without observed or reported subjective change in clinical status between L-BASIC administrations. We compared our four-item scale against scores obtained from validated pain and quality-of-life (QOL) scales, and as expected, correlations were higher for pain-related items than for QOL-related items. We detected differences in L-BASIC responses among patients with cancer-related head or neck pain, chemotherapy-related neuropathy and breast cancer-related lymphedema. We conclude that L-BASIC provides internally consistent and temporally stable responses, while acknowledging that further refinement and testing of this novel instrument are necessary. We anticipate that future versions of L-BASIC will provide reliable and valid syndrome-specific measurement of defined clinical pain and symptom constructs in the cancer population, which may be of particular value in assessing treatment response in patients with such multiple complaints.