An evidence-based review of neuromodulation for the treatment and management of refractory angina.

Angina pectoris is defined as substernal chest pain that is typically exacerbated by exertion, stress, or other exposures. There are various methods of treatment for angina. Lifestyle modification and pharmacological management are considered as conservative treatments. If these medications do not result in the resolution of pain, more invasive approaches are an option, like coronary revascularization. Refractory angina (RA) is differentiated from acute or chronic angina based on the persistence of symptoms despite conventional therapies. Overall, the prevalence of RA is estimated to be 5%-15% in patients with coronary artery disease, which can account for up to 1,500,000 current cases and 100,000 new cases in the United States per year. Spinal cord stimulation treatment is a viable option for patients who are suffering from RA pain and are either not candidates for revascularization surgery or are currently not being well managed on more traditional treatments. Many studies show a positive result.

Systematic Review and Neural Network Analysis to Define Predictive Variables in Implantable Motor Cortex Stimulation to Treat Chronic Intractable Pain.

Implantable motor cortex stimulation (iMCS) has been performed for >25 years to treat various intractable pain syndromes. Its effectiveness is highly variable and, although various studies revealed predictive variables, none of these were found repeatedly. This study uses neural network analysis (NNA) to identify predictive factors of iMCS treatment for intractable pain. A systematic review provided a database of patient data on an individual level of patients who underwent iMCS to treat refractory pain between 1991 and 2017. Responders were defined as patients with a pain relief of >40% as measured by a numerical rating scale (NRS) score. NNA was carried out to predict the outcome of iMCS and to identify predictive factors that impacted the outcome of iMCS. The outcome prediction value of the NNA was expressed as the mean accuracy, sensitivity, and specificity. The NNA furthermore provided the mean weight of predictive variables, which shows the impact of the predictive variable on the prediction. The mean weight was converted into the mean relative influence (M), a value that varies between 0 and 100%. A total of 358 patients were included (202 males [56.4%]; mean age, 54.2 ±13.3 years), 201 of whom were responders to iMCS. NNA had a mean accuracy of 66.3% and a sensitivity and specificity of 69.8% and 69.4%, respectively. NNA further identified 6 predictive variables that had a relatively high M: 1) the sex of the patient (M = 19.7%); 2) the origin of the lesion (M = 15.1%); 3) the preoperative numerical rating scale score (M = 9.2%); 4) preoperative use of repetitive transcranial magnetic stimulation (M = 7.3%); 5) preoperative intake of opioids (M = 7.1%); and 6) the follow-up period (M = 13.1%). The results from the present study show that these 6 predictive variables influence the outcome of iMCS and that, based on these variables, a fair prediction model can be built to predict outcome after iMCS surgery. PERSPECTIVE: The presented NNA analyzed the functioning of computational models and modeled nonlinear statistical data. Based on this NNA, 6 predictive variables were identified that are suggested to be of importance in the improvement of future iMCS to treat chronic pain.

Dietary Intake of Polyunsaturated Fatty Acids and Pain in Spite of Inflammatory Control Among Methotrexate-Treated Early Rheumatoid Arthritis Patients.

OBJECTIVE: To investigate potential associations between dietary intake of polyunsaturated fatty acids (FAs) and pain patterns in early rheumatoid arthritis (RA) patients after 3 months of methotrexate (MTX) treatment. METHODS: We included 591 early RA patients with MTX monotherapy from a population-based prospective case-control study, the Epidemiological Investigation of Rheumatoid Arthritis. Dietary data on polyunsaturated FAs (food frequency questionnaires) were linked with data on unacceptable pain (visual analog scale [VAS] >40 mm), noninflammatory/refractory pain (VAS >40 mm and C-reactive protein [CRP] level <10 mg/liter), and inflammatory pain (VAS >40 mm and CRP level >10 mg/liter) after 3 months. Statistical analysis included logistic regression. RESULTS: After 3 months of MTX treatment, 125 patients (21.2%) had unacceptable pain, of which 92 patients had refractory pain, and 33 patients had inflammatory pain. Omega-3 FA intake was inversely associated with unacceptable pain and refractory pain (odds ratio [OR] 0.57 [95% confidence interval (95% CI) 0.35-0.95] and OR 0.47 [95% CI 0.26-0.84], respectively). The omega-6:omega-3 FA ratio, but not omega-6 FA alone, was directly associated with unacceptable pain and refractory pain (OR 1.70 [95% CI 1.03-2.82] and OR 2.33 [95% CI 1.28-4.24], respectively). Furthermore, polyunsaturated FAs were not associated with either inflammatory pain or CRP level and erythrocyte sedimentation rate at followup. Omega-3 FA supplementation was not associated with any pain patterns. CONCLUSION: Omega-3 FA was inversely associated with, and the omega-6:omega-3 FA ratio was directly associated with, unacceptable and refractory pain, but not with inflammatory pain or systemic inflammation. The inverse association between omega-3 FA and refractory pain may have a role in pain suppression in RA.

Trigeminal branch stimulation for the treatment of intractable craniofacial pain.

OBJECT Trigeminal branch stimulation has been used in the treatment of craniofacial pain syndromes. The risks and benefits of such an approach have not been clearly delineated in large studies, however. The authors report their experience in treating craniofacial pain with trigeminal branch stimulation and share the lessons they have learned after 93 consecutive electrode placements. METHODS A retrospective review of all patients who underwent trigeminal branch electrode placement by the senior author (C.J.W.) for the treatment of craniofacial pain was performed. RESULTS Thirty-five patients underwent implantation of a total of 93 trial and permanent electrodes between 2006 and 2013. Fifteen patients who experienced improved pain control after trial stimulation underwent implantation of permanent stimulators and were followed for an average of 15 months. At last follow-up 73% of patients had improvement in pain control, whereas only 27% of patients had no pain improvement. No serious complications were seen during the course of this study. CONCLUSIONS Trigeminal branch stimulation is a safe and effective treatment for a subset of patients with intractable craniofacial pain.

Cancer pain and current theory for pain control.

This article discusses current trends in managing cancer pain, with specific regard to opioid transmission, descending pathway inhabitation, and ways to facilitate the endogenous antinociceptive chemicals in the human body. Various techniques for opioid and nonopioid control of potential pain situations of patients with cancer are discussed. The benefits of using pharmacogenetics to assess the appropriate medications are addressed. Finally, specific treatment of abdominal cancer pain using radiofrequency lesioning is discussed.

Percutaneous treatment of symptomatic aneurysmal bone cyst of L5 by percutaneous injection of osteoconductive material (Cerament).

We present a case report of a 33-year-old woman with back pain for several months which was resistant to medical treatment. Thoracolumbar MRI and multidetector CT showed an aneurysmal bone cyst intersecting the body and pedicles of L5. Minimally invasive treatment was performed with percutaneous injection of osteoconductive cement (Cerament) to induce sclerosis and bone remodeling of the bone cyst lesion with an analgesic effect. Before treatment, spinal angiography was performed to exclude arterial afferents. No bone biopsy was done. Under general anesthesia and fluoroscopic guidance, a first vertebroplasty was performed by a bilateral transpedicular approach using the osteoconductive cement followed 2 months later by a second treatment with CT-fluoro-guided direct injection of Cerament. No complications occurred during the procedure. At 4 and 6 months follow-up the MRI/CT showed sclerotic bone remodeling of the walls of the aneurysmal cyst with clinical improvement.

Treatment of cancer pain.

In patients with active cancer, the management of chronic pain is an essential element in a comprehensive strategy for palliative care. This strategy emphasises multidimensional assessment and the coordinated use of treatments that together mitigate suffering and provide support to the patient and family. This review describes this framework, an approach to pain assessment, and widely accepted techniques to optimise the safety and effectiveness of opioid drugs and other treatments. The advances of recent decades suggest a future that includes increased evidence-based targeting of specific analgesic interventions within an individualised plan of care that is appropriate throughout the course of illness.

Peripheral nerve stimulation of the thoracic paravertebral plexus for chronic neuropathic pain.

Persistent post surgical pain is reported in 70% of patients following thoracotomy and mastectomy. This pain is often neuropathic in nature and occasionally it is refractory to traditional medical and interventional management. Neurostimulation of peripheral nerves can be a highly effective clinical modality for the management of neuropathic pain. The placement of a percutaneously sited electrode in the thoracic paravertebral plexus offers a new and novel mode of managing refractory thoracic neuropathic pain. We present 2 cases that demonstrate the effectiveness of this intervention in the long-term management of this clinical dilemma. The first case presented is that of a 61-year-old female, with unilateral neuropathic pain for 6 years following mastectomy refractory to traditional interventions. Targeted field stimulation of the thoracic paravertebral plexus resulted in significant improvement for 12 years. The second case is that of a 65-year-old male, with Type II diabetes with neuropathic thoracic pain for 6 years following multiple rib fractures (T4-T7) who responded positively to neurostimulation of the thoracic paravertebral plexus. Both of these cases demonstrate a relative reduction in pain intensity (> 80%), the elimination of oral analgesics, and improved functionality directly related to the novel use of this intervention. Effective and reproducible pain relief is achieved by specifically using a low frequency (10 Hz) and low amplitude (2 mA) stimulation technique. Equally important is that these cases highlight the increased risk of inadvertent pleural puncture with the development of a pneumothorax that can be associated with this intervention. Possible clinical, investigative and equipment modifications that need to be considered are discussed. The limitations include only 2 case reports, considered as the lowest level of evidence available in the era of evidence-based medicine, and lack of utilization of multiple other modalities of treatments utilized in managing neuropathic pain. In conclusion, these cases demonstrate the effectiveness of peripheral nerve stimulation of the thoracic paravertebral plexus in the long-term management of refractory neuropathic pain. They also serve to underline the importance of clinical awareness in order to improve patient safety.

Subcutaneous occipital region stimulation for intractable headache syndromes.

Subcutaneous occipital nerve region stimulation is becoming an important part of the overall treatment regimen for a number of chronic headache syndromes refractory to nonsurgical, medical management. A combination of improved device technology and methodology, further understanding about appropriate indications and achievement of on-label FDA status should support continued use and success of this neuromodulation modality.

Peripheral subcutaneous stimulation for intractable abdominal pain.

Peripheral subcutaneous stimulation has been utilized for a variety of painful conditions affecting the abdominal wall, including sequelae of hernia repair, painful surgical scars, ilio-inguinal neuritis. It has also occasionally been shown to be effective in patients with intractable abdominal visceral pain. Since this is a very recent modality, no large series or prospective studies exist. The results, however, are promising and certainly warrant further investigation.

Motor cortex stimulation for trigeminal neuropathic or deafferentation pain: an institutional case series experience.

BACKGROUND: Trigeminal neuropathy is a rare, devastating condition that can be intractable and resistant to treatment. When medical treatment fails, invasive options are limited. Motor cortex stimulation (MCS) is a relatively recent technique introduced to treat central neuropathic pain. The use of MCS to treat trigeminal neuropathic or deafferentation pain is not widespread and clinical data in the medical literature that demonstrate efficacy are limited. METHOD: We retrospectively reviewed patients with trigeminal neuropathic or trigeminal deafferentation pain who were treated at the Oregon Health & Science University between 2001 and 2008 by 1 neurosurgeon using MCS. RESULTS: Eight of 11 patients (3 male, 8 female) underwent successful permanent implantation of an MCS system. All 8 patients reported initial satisfactory pain control. Three failed to experience continued pain control (6 months of follow-up). Five continued to experience long-term pain control (mean follow-up, 33 months). Average programming sessions were 2.2/year (all 8 patients) and 1.55/year (5 patients who sustained long-term pain control). Patients with anesthesia dolorosa or trigeminal deafferentation pain who had previously undergone ablative trigeminal procedures responded poorly to MCS. We encountered no perioperative complications. CONCLUSION: MCS is a safe and potentially effective therapy in certain patients with trigeminal neuropathy.

The abuse potential of the synthetic cannabinoid nabilone.

AIM: Nabilone is a synthetic cannabinoid prescription drug approved in Canada since 1981 to treat chemotherapy-induced nausea and vomiting. In recent years, off-label use of nabilone for chronic pain management has increased, and physicians have begun to express concerns about nabilone becoming a drug of abuse. This study evaluates the evidence for abuse of nabilone, which is currently ill-defined. STUDY DESIGN: Scientific literature, popular press and internet databases were searched extensively for evidence of nabilone abuse. Focused interviews with medical professionals and law enforcement agencies across Canada were also conducted. FINDINGS: The scientific literature and popular press reviews found very little reference to nabilone abuse. Nabilone is perceived to produce more undesirable side effects, to have a longer onset of action and to be more expensive than smoked cannabis. The internet review revealed rare and isolated instances of recreational use of nabilone. The database review yielded little evidence of nabilone abuse, although nabilone seizures and thefts have occurred in Canada in the past few years, especially in Ontario. Most law enforcement officers reported no instances of nabilone abuse or diversion, and the drug has no known street value. Medical professionals reported that nabilone is not perceived to be a matter of concern with respect to its abuse potential. CONCLUSIONS: Reports of nabilone abuse are extremely rare. However, follow-up of patients using nabilone for therapeutic purposes is prudent and should include assessment of tolerance and dependence. Prospective studies are also needed to definitively address the issue of nabilone abuse.

Intracranial neurostimulation for pain control: a review.

Intracranial neurostimulation for pain relief is most frequently delivered by stimulating the motor cortex, the sensory thalamus, or the periaqueductal and periventricular gray matter. The stimulation of these sites through MCS (motor cortex stimulation) and DBS (deep brain stimulation) has proven effective for treating a number of neuropathic and nociceptive pain states that are not responsive or amenable to other therapies or types of neurostimulation. Prospective randomized clinical trials to confirm the efficacy of these intracranial therapies have not been published. Intracranial neurostimulation is somewhat different than other forms of neurostimulation in that its current primary application is for the treatment of medically intractable movement disorders. However, the increasing use of intracranial neurostimulation for the treatment of chronic pain, especially for pain not responsive to other neuromodulation techniques, reflects the efficacy and relative safety of these intracranial procedures. First employed in 1954, intracranial neurostimulation represents one of the earliest uses of neurostimulation to treat chronic pain that is refractory to medical therapy. Currently, 2 kinds of intracranial neurostimulation are commonly used to control pain: motor cortex stimulation and deep brain stimulation. MCS has shown particular promise in the treatment of trigeminal neuropathic pain and central pain syndromes such as thalamic pain syndrome. DBS may be employed for a number of nociceptive and neuropathic pain states, including cluster headaches, chronic low back pain, failed back surgery syndrome, peripheral neuropathic pain, facial deafferentation pain, and pain that is secondary to brachial plexus avulsion. The unique lack of stimulation-induced perceptual experience with MCS makes MCS uniquely suited for blinded studies of its effectiveness. This article will review the scientific rationale, indications, surgical techniques, and outcomes of intracranial neuromodulation procedures for the treatment of chronic pain.

Tonic pain abolishes cortical habituation of visual evoked potentials in healthy subjects.

UNLABELLED: We investigated changes in visual cortex excitability by analyzing visual evoked potential (VEP) habituation in healthy subjects during tonic pain evoked by the cold-pressor test (CPT). We tested VEP amplitude habituation (slope of the linear regression line for N1-P1 amplitude from the 1st to 6th block of 100 sweeps) in 19 healthy volunteers during 4 experimental conditions: baseline; no-pain (hand held in warm water, 25 degrees C); pain (hand held in cold water, 2-4 degrees C); and the after-effects of tonic pain. During baseline and no-pain sessions, VEPs habituated normally across the 6 consecutive blocks (mean slope -.28 and -.18%), whereas during pain and its after-effects they failed to decrease (0%, and -.11%). Tonic pain induced by the CPT abolishes normal VEP habituation and the lack of habituation persists after the CPT is stopped. Tonic pain probably abolishes VEP habituation by acting on brainstem neural structures which modulate thalamo-cortical activation thereby changing visual cortex excitability. PERSPECTIVE: This study shows that tonic pain alters visual cortex excitability, a brain region unrelated to pain processing. These changes probably reflect defensive strategies against pain. Extending the study from healthy volunteers to patients with migraine between attacks would offer the opportunity to investigate visual cortical excitability under conditions when baseline habituation is absent.

Feasibility study of Transcutaneous Electrical Nerve Stimulation (TENS) for cancer bone pain.

UNLABELLED: This multicenter study assessed the feasibility of conducting a phase III trial of transcutaneous electrical nerve stimulation (TENS) in patients with cancer bone pain recruited from palliative care services. Eligible patients received active and placebo TENS for 1 hour at site of pain in a randomized crossover design; median interval between applications 3 days. Responses assessed at 30 and 60 minutes included numerical and verbal ratings of pain at rest and on movement, and pain relief. Recruitment, tolerability, adverse events, and effectiveness of blinding were also evaluated. Twenty-four patients were randomised and 19 completed both applications. The intervention was well tolerated. Five patients withdrew: 3 due to deteriorating performance status, and 2 due to increased pain (1 each following active and placebo TENS). Confidence interval estimation around the differences in outcomes between active and placebo TENS suggests that TENS has the potential to decrease pain on movement more than pain on rest. Nine patients did not consider that a placebo was used; the remaining 10 correctly identified placebo TENS. Feasibility studies are important in palliative care prior to undertaking clinical trials. Our findings suggest that further work is required on recruitment strategies and refining the control arm before evaluating TENS in cancer bone pain. PERSPECTIVE: Cancer bone pain is common and severe, and partly mediated by hyperexcitability. Animal studies suggest that Transcutaneous Electrical Nerve Stimulation can reduce hyperalgesia. This study examined the feasibility of evaluating TENS in patients with cancer bone pain in order to optimize methods before a phase III trial.

A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain.

The midbrain periaqueductal grey (PAG) is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp), one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

Validity of electrical stimulus magnitude matching in chronic pain.

OBJECTIVE: To examine the validity of the PainMatcher in chronic pain. DESIGN: Comparison of parallel pain estimates from visual analogue scales with electrical stimulus magnitude matching. PATIENTS: Thirty-one patients with chronic musculoskeletal pain. METHODS: Twice a day ongoing pain was rated on a standard 100-mm visual analogue scale, and thereafter magnitude matching was performed using a PainMatcher. The sensory threshold to electrical stimulation was tested twice on separate occasions. RESULTS: In 438 observations visual analogue scale ranged from 3 to 95 (median 41) mm, and PainMatcher magnitudes from 2.67 to 27.67 (median 6.67; mean 7.78) steps. There was little correlation between visual analogue scale and magnitude data (r = 0.29; p < 0.0001). The mean sensory threshold was 3.67 steps, indicating that the PainMatcher, on average, stimulated at 2.1 times the perception threshold at matching point. CONCLUSION: Electrical magnitude matching of chronic pain intensity elicited limited activation of nerve fibres at 2.0-2.2 times sensory threshold, indicating that the induced pain was evoked by coarse nociceptive Adelta fibres. While the visual analogue scale estimates covered the whole range of the instrument, the PainMatcher readings utilized only a small part of the instrument range and, importantly, had little or no relation to the visual analogue scale estimates. The validity of the PainMatcher procedure is doubtful.

[Spinal cord stimulation at the level of the conus medullaris : treatment option for therapy-resistant postoperative neuralgia of the pudendal nerve]. / "Spinal cord stimulation" in Höhe des Conus medullaris : Behandlungsoption bei therapierefraktärer postoperativer Neuralgie des N. pudendus.

Injuries of the pudendal nerve, due to a perineal tear during delivery for example, can cause significant and debilitating neurological deficits. Aconuresis and anal incontinence, as well as sensory loss of the outer genitals or even impotency in men are the well known consequences. In addition some patients suffer from a severe neuropathic pain syndrome which is resistant to conservative treatment options. Epidural spinal cord stimulation at the level of the terminal cone of the spinal cord may be a new and successful therapeutic concept in otherwise untreatable cases.