Controversies in intrathecal drug delivery for cancer pain.

Pain and suffering related to cancer are challenging issues that continue to deserve consideration for treatment optimization. Advances in analgesic management and control of the underlying cancer have improved symptom management, yet many patients still suffer from uncontrolled pain. Intrathecal drug delivery has an established role in the management of refractory cancer pain, but there are significant knowledge gaps in our understanding and application of this therapy. This review addresses several areas of controversy, including the importance of intrathecal catheter tip location, the necessity of an intrathecal trial and the role of intrathecal ziconotide and local anesthetics. In each area, the evidence is discussed, with an emphasis on presenting practical clinical guidance and highlighting deficiencies in our knowledge that are worthy of future investigation.

Long term results of Dorsal Root Entry Zone (DREZ) lesions for the treatment of intractable pain: A systematic review of the literature on 1242 cases.

BACKGROUND: Different Dorsal root entry zone (DREZ) lesion techniques have been reported as effective treatment for intractable painful conditions, though with contradictory results. Overall, good results were reported especially in specific conditions, such as pain due to brachial plexus avulsion, spinal cord injuries and oncological pain management. However, data on long term results in different clinical conditions are still missing. OBJECTIVE: This study aims to systematically review the pertinent literature to evaluate indications, clinical outcomes, and complications of DREZ lesion (DREZotomy), in chronic pain management. METHODS: A systematic literature review was conducted according to the PRISMA statement. Papers on DREZotomy for chronic pain in cancer, brachial plexus avulsion, spinal cord injury, post herpetic neuralgia, and phantom limb pain were considered for eligibility. For each category we further identified two sub-group according to the length of follow up: medium term and long term follow up (more than 3 years) respectively. RESULTS: 46 papers, and 1242 patients, were included in the present investigation. When considering long term results DREZotomy provided favorable clinical outcomes in brachial plexus avulsion and spinal cord injury, in 60.8% and 55.8% of the cases respectively. Conversely, the success rate was 35.3% in phantom limb pain and 28.2% in post herpetic neuralgia. A poor clinical outcome was reported in over than 25% of the patients suffering from phantom limb pain, post herpetic neuralgia and spinal cord injury. The mean complications rate was 23.58%. While BPA and SCI patients presented stable improvement over time, good outcomes among PHN and PLP groups dropped by - 46.2%; and - 14.7% at long term follow up respectively. CONCLUSION: DREZotomy seems to be an effective treatment for chronic pain conditions, especially for brachial plexus avulsion, spinal cord injury and intractable cancer/post-radiation pain. According to the low level of evidence of the pertinent literature, further studies are strongly recommended, to better define potential benefits and limitations of this technique.

Association of Refractory Pain in the Acute Phase After Subarachnoid Hemorrhage With Continued Outpatient Opioid Use.

OBJECTIVE: Little is known about the prevalence of continued opioid use following aneurysmal subarachnoid hemorrhage (aSAH) despite guidelines recommending their use during the acute phase of disease. We sought to determine prevalence of opioid use following aSAH and test the hypothesis that acute pain and higher inpatient opioid dose increased outpatient opioid use. METHODS: We reviewed consecutively admitted patients with aSAH from November 2015 through September 2019. We retrospectively collected pain scores and daily doses of analgesics. Pain burden was calculated as area under the pain-time curve. Univariate and multivariable regression models determined risk factors for continued opioid use at discharge and outpatient follow-up. RESULTS: We identified 234 patients with aSAH with outpatient follow-up. Continued opioid use was common at discharge (55% of patients) and follow-up (47% of patients, median 63 [interquartile range 49-96] days from admission). Pain burden, craniotomy, and racial or ethnic minority status were associated with discharge opioid prescription in multivariable analysis. At outpatient follow-up, pain burden (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.5-2.4), depression (OR 3.1, 95% CI 1.1-8.8), and racial or ethnic minority status (OR 2.1, 95% CI 1.1-4.0) were independently associated with continued opioid use; inpatient opioid dose was not. CONCLUSION: Continued opioid use following aSAH is prevalent and related to refractory pain during acute illness, but not inpatient opioid dose. More efficacious analgesic strategies are needed to reduce continued opioid use in patients following aSAH. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that continued opioid use following aSAH is associated with refractory pain during acute illness but not hospital opioid exposure.

Association between Lifetime History of Traumatic Brain Injury, Prescription Opioid Use, and Persistent Pain: A Nationally Representative Study.

Pain is common among adults with traumatic brain injury (TBI), yet little data exist regarding prevalence of opioid use in this population. The objective of this retrospective cohort study was to evaluate the association between lifetime TBI exposure, opioid use, and pain in a nationally representative sample of 1022 adults aged 50+ who participated in the Health and Retirement Study (HRS). Our primary exposure was lifetime TBI history measured via the Ohio State University TBI Identification Method. We evaluated three alternate TBI exposures (years since most recent TBI, age at first TBI, and number of lifetime TBIs) in sensitivity analyses. We evaluated two outcomes: recent opioid medication use, and moderate-to-severe pain measured over two HRS waves. We classified three pain groups (persistent, intermittent, and no pain). Prevalences of opioid use among individuals with and without TBI were 19.7% and 13.6%, respectively. After adjustment for age, sex, and race, individuals with TBI had a 52% increased risk for opioid use compared with individuals without TBI (relative risk = 1.52, 95% confidence interval: 1.11, 2.04). Individuals with recent TBI (1-10 years ago), first TBI after age 40+, and 2+ lifetime TBIs had greatest risk for opioid use. Compared with individuals without TBI, individuals with TBI had 4.9-times increased odds for persistent versus no pain, and 1.9-times increased odds of intermittent versus no pain. Persistent pain among adults with lifetime TBI is elevated compared with the general population, which may contribute to increased opioid use among persons with TBI, particularly those with recent injuries or multiple lifetime TBIs.

Management of refractory pain in Stiff-Person syndrome.

Stiff-Person syndrome (SPS) is a rare autoimmune neurological disorder characterised by episodic painful muscle rigidity and violent spasms. A significant trigger for the painful spasms experienced by patients is pain itself, making optimal pain management and avoidance a necessity. While first-line and second-line therapies for spasm prevention and termination are known, there is a paucity of evidence to guide pain management. We report the case of a 26-year-old woman with SPS referred for excruciating muscle cramping and rigidity with pain lasting beyond the episodes themselves. We report the novel use of ketamine and intravenous magnesium sulfate which may provide analgesia, spasm avoidance and early termination of exacerbations in SPS.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Neuroablative Procedures for Patients With Cancer Pain.

BACKGROUND: Managing cancer pain once it is refractory to conventional treatment continues to challenge caregivers committed to serving those who are suffering from a malignancy. Although neuromodulation has a role in the treatment of cancer pain for some patients, these therapies may not be suitable for all patients. Therefore, neuroablative procedures, which were once a mainstay in treating intractable cancer pain, are again on the rise. This guideline serves as a systematic review of the literature of the outcomes following neuroablative procedures. OBJECTIVE: To establish clinical practice guidelines for the use of neuroablative procedures to treat patients with cancer pain. METHODS: A systematic review of neuroablative procedures used to treat patients with cancer pain from 1980 to April 2019 was performed using the United States National Library of Medicine PubMed database, EMBASE, and Cochrane CENTRAL. After inclusion criteria were established, full text articles that met the inclusion criteria were reviewed by 2 members of the task force and the quality of the evidence was graded. RESULTS: In total, 14 646 relevant abstracts were identified by the literature search, from which 189 met initial screening criteria. After full text review, 58 of the 189 articles were included and subdivided into 4 different clinical scenarios. These include unilateral somatic nociceptive/neuropathic body cancer pain, craniofacial cancer pain, midline subdiaphragmatic visceral cancer pain, and disseminated cancer pain. Class II and III evidence was available for these 4 clinical scenarios. Level III recommendations were developed for the use of neuroablative procedures to treat patients with cancer pain. CONCLUSION: Neuroablative procedures may be an option for treating patients with refractory cancer pain. Serious adverse events were reported in some studies, but were relatively uncommon. Improved imaging, refinements in technique and the availability of new lesioning modalities may minimize the risks of neuroablation even further.The full guidelines can be accessed at https://www.cns.org/guidelines/browse-guidelines-detail/guidelines-on-neuroablative-procedures-patients-wi.

Interventional Cryoneurolysis: An Illustrative Approach.

The application of advanced imaging guidance and the interventional radiology skill set has expanded the breadth of nerve and nerve plexus targets in the body for potential cryoneurolysis. Advancement of the basic science supporting cryoneurolysis has further solidified proceduralists' confidence and ability to select and manage patients clinically. As these procedures continue to evolve, a structured approach to the wide variety of indications is necessary.

Extended pulsed radiofrequency as a part of multimodal pain management in a refractory case of Bernhardt-Roth syndrome.

Bernhardt-Roth syndrome (BRS) is a neurological condition characterised by pain, burning or numbness in anterolateral thigh due to entrapment of the lateral femoral cutaneous nerve (LFCN). The possible aetiologies can be mechanical, iatrogenic, neuropathic or idiopathic. After consent for possible publication, we are discussing a case of pain management in a 38-year-old patient with BRS secondary to diabetes. The coherent history, uncontrolled glycaemic status and reduced nerve conduction velocity for LFCN helped reach the diagnosis. Initial treatment with pharmacotherapy, steroid LFCN block and conventional pulsed radiofrequency (PRF) provided moderate temporary pain relief. Extended PRF over 8 min provided significant analgesia without any complications. Physical therapy, adequate glycaemic control and extended PRF provided complete pain relief and improved function over 6 months of follow-up duration. Hence, a cautious multifaceted approach targeting the basic aetiology with extended PRF helped achieve significant analgesia in our refractory case of BRS.

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.

Tailoring of neurosurgical ablative procedures in the management of refractory cancer pain.

INTRODUCTION: Neurosurgical ablative procedures can offer immediate and effective pain relief for patients suffering from refractory cancer pain. However, choosing the appropriate procedure for each patient may not be straightforward and warrants an interdisciplinary approach. The purpose of the current study was to evaluate the outcome of patients with cancer who were carefully selected for neurosurgical intervention by a dedicated interdisciplinary team composed of a palliative physician and nurse practitioner, a pain specialist and a neurosurgeon. METHODS: A retrospective review was carried out on all patients who underwent neurosurgical ablative procedures in our institute between March 2015 and September 2019. All patients had advanced metastatic cancer with unfavorable prognosis and suffered from intractable oncological pain. Each treatment plan was devised to address the patients' specific pain syndromes. RESULTS: A total of 204 patients were examined by our service during the study period. Sixty-four patients with localized pain and nineteen patients with diffuse pain syndromes were selected for neurosurgical interventions, either targeted disconnection of the spinothalamic tract or stereotactic cingulotomy. Substantial pain relief was reported by both groups immediately (cordotomy: Numerical Rating Scale (NRS) 9 ≥1, p=0.001, cingulotomy: NRS 9 ≥2, p=0.001) and maintained along the next 3-month follow-up visits. CONCLUSIONS: An interdisciplinary collaboration designated to provide neurosurgical ablative procedures among carefully selected patients could culminate in substantial relief of intractable cancer pain. TRIAL REGISTRATION NUMBER: IR0354-17.

Percutaneous CT-Guided Cryoablation of the Celiac Plexus: A Retrospective Cohort Comparison with Ethanol.

PURPOSE: To retrospectively analyze and compare the incidence of diarrhea in patients who underwent cryoablation of the celiac plexus for intractable abdominal pain versus ethanol therapy over a 5-year period. MATERIALS AND METHODS: From June 2014 to August 2019, 83 patients were identified who underwent neurolysis of the celiac plexus for management of intractable abdominal pain by using either cryoablation (n = 39 [59% female; age range, 36-79 years old [average, 60 ± 11 years old]) or alcohol (n = 44 [48% female; age range, 29-76 years old [average, 60 ± 12 years old]). Pain scores and reports of procedure-related complications or side effects, with special attention to diarrhea and/or other gastrointestinal symptoms, were collected from follow-up visits at 1 week, 1 month, and 3 months post-intervention and were compared between groups. RESULTS: The mean time of follow-up was 17.7 days. Four patients who underwent cryoablation developed gastrointestinal symptoms consisting of 2 cases of nausea and vomiting and 2 cases of diarrhea (5.1%). Twelve patients who underwent ethanol ablation developed gastrointestinal symptoms, including 1 case of nausea, 3 cases of vomiting, and 9 cases of diarrhea (20.5%). There was a significantly higher incidence of both diarrhea (chi-squared likelihood ratio, P = .03) and overall gastrointestinal symptoms (chi-squared likelihood ratio, P = .04) in the ethanol group than in the cryoablation group. CONCLUSIONS: Cryoablation of the celiac plexus may provide a new treatment option for intractable abdominal pain, and it appears to have a lower incidence of diarrhea and fewer gastrointestinal side effects than ablation using ethanol.

European headache federation consensus on the definition of resistant and refractory migraine : Developed with the endorsement of the European Migraine & Headache Alliance (EMHA).

INTRODUCTION: Despite advances in the management of headache disorders, some patients with migraine do not experience adequate pain relief with acute and preventive treatments. It is the aim of the present document to provide a definition of those migraines which are difficult-to-treat, to create awareness of existence of this group of patients, to help Healthcare Authorities in understanding the implications, and to create a basis to develop a better pathophysiological understanding and to support further therapeutic advances. MAIN BODY: Definitions were established with a consensus process using the Delphi method. Patients with migraine with or without aura or with chronic migraine can be defined as having resistant migraine and refractory migraine according to previous preventative failures. Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement; definition can be based on review of medical charts. Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months. Drug failure may include lack of efficacy or lack of tolerability. Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy at the recommended dose and taken early during the attack; failure of at least two different triptans is required. CONCLUSIONS: We hope, that the updated EHF definition will be able to solve the conflicts that have limited the use of definitions which have been put forward in the past. Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved. This new definition has also the aim to increase the understanding of the impact of the migraine as a disease with all of its social, legal and healthcare implications. It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.

Cryoneurolysis in Patients with Dorsal Neuropathic Pain Secondary to Tumor Invasion.

PURPOSE: To evaluate the safety and efficacy of cryoneurolysis (CNL) in patients with refractory thoracic neuropathic pain related to tumor invasion. MATERIALS AND METHODS: Between January 2013 and May 2017, this single-center and retrospective study reviewed 27 computed tomography-guided CNLs performed on 26 patients for refractory thoracic neuropathic pain related to tumor invasion. Patients with cognitive impairment were excluded. Pain levels were recorded on a visual analog scale (VAS) before the procedure, on days 1, 7, 14, 28 and at each subsequent follow-up appointment. CNL was clinically successful if the postprocedural VAS decreased by 3 points or more. To determine the duration of clinical success, the end of pain relief was defined as either an increased VAS of 2 or more points, the introduction of a new analgesic treatment, a death with controlled pain, or for lost to follow-up patients, the latest follow-up appointment date with controlled pain. RESULTS: Technical success rate was 96.7% and clinical success rate was 100%. Mean preprocedural pain score was 6.4 ± 1.7 and decreased to 2.4 ± 2.4 at day 1; 1.8 ± 1.7 at day 7 (P < .001); 3.3 ± 2.5 at day 14; 3.4 ± 2.6 at day 28 (P < .05). The median duration of pain relief was 45 days (range 14-70). Two minor complications occurred. CONCLUSIONS: Cryoneurolysis is a safe procedure that significantly decreased pain scores in patients with thoracic neuropathic pain related to tumor invasion, with a median duration of clinical success of 45 days.

Deep Brain Stimulation for Pain in the Modern Era: A Systematic Review.

BACKGROUND: Deep brain stimulation (DBS) has been considered for patients with intractable pain syndromes since the 1950s. Although there is substantial experience reported in the literature, the indications are contested, especially in the United States where it remains off-label. Historically, the sensory-discriminative pain pathways were targeted. More recently, modulation of the affective sphere of pain has emerged as a plausible alternative. OBJECTIVE: To systematically review the literature from studies that used contemporary DBS technology. Our aim is to summarize the current evidence of this therapy. METHODS: A systematic search was conducted in the MEDLINE, EMBASE, and Cochrane libraries through July 2017 to review all studies using the current DBS technology primarily for pain treatment. Study characteristics including patient demographics, surgical technique, outcomes, and complications were collected. RESULTS: Twenty-two articles were included in this review. In total, 228 patients were implanted with a definitive DBS system for pain. The most common targets used were periaqueductal/periventricular gray matter region, ventral posterior lateral/posterior medial thalamus, or both. Poststroke pain, phantom limb pain, and brachial plexus injury were the most common specific indications for DBS. Outcomes varied between studies and across chronic pain diagnoses. Two different groups of investigators targeting the affective sphere of pain have demonstrated improvements in quality of life measures without significant reductions in pain scores. CONCLUSION: DBS outcomes for chronic pain are heterogeneous thus far. Future studies may focus on specific pain diagnosis rather than multiple syndromes and consider randomized placebo-controlled designs. DBS targeting the affective sphere of pain seems promising and deserves further investigation.

Validity and reliability of Turkish version of the Brief Pain Inventory-Short Form for patients with chronic nonmalignant pain.

OBJECTIVES: The aim of this study was to evaluate the validity and reliability of the Turkish version of the Brief Pain Inventory-Short Form for patients with chronic nonmalignant pain. METHODS: An analytical design was used. A total of 192 patients were included in the study. A demographic questionnaire and the Brief Pain Inventory-Short Form were used to collect data. Content validity was assessed by experts and construct validity was tested using exploratory factor analysis. Reliability analyses estimated the internal consistency and test-retest reliability. Cronbach's alpha and the item-total correlations were calculated for the subscales to examine internal consistency. RESULTS: Exploratory factor analysis yielded 2 factors: pain severity and pain interference, which accounted for 68.81% of the total variance. The coefficient alpha of both subscales demonstrated good internal consistency. The item-total correlations of the scale ranged between 0.56 and 0.87. The test-retest reliability was r=0.774 for pain severity and r=0.808 for pain interference (p=0.001). CONCLUSION: The Turkish version of the Brief Pain Inventory-Short Form is a valid and reliable instrument to assess chronic nonmalignant pain.

Measuring sensory and pain thresholds by Semmes-Weinstein monofilaments in patients with leg ulcers: a pilot study.

OBJECTIVE: Pain is a common and disabling symptom in patients with leg ulcers. Clinical quantification of pain mostly depends on subjective pain reports, which do not reveal underlying mechanisms. The aim of this pilot study is to identify mechanisms underlying the pain in patients with leg ulcers by documenting alterations in pain processing using quantitative sensory testing. METHODS: In nine ulcer patients the mechanical sensory thresholds and the mechanical pain thresholds were determined by Semmes-Weinstein monofilaments (SWM) at three different sites: on the contralateral (unaffected) leg, on the skin of the affected leg 10cm from the ulcer margin, and on the affected leg, close (1-2cm) to the ulcer margin. Besides the mechanical sensory thresholds and mechanical pain thresholds, pain at the site of the ulcer, using an 11-point numeric rating scale (NRS), was documented. RESULTS: Mechanical sensory thresholds were increased in all subjects. Almost half (44%) of patients consistently showed allodynia at the unaffected site. The lowering of mechanical pain thresholds correlated with higher scores on the NRS. CONCLUSION: All patients showed diminished touch and/or protective sensation, which might have contributed to ulcer development via (partial) loss of protective function. The allodynia at the unaffected site suggests the presence of central sensitisation of pain processing.

Inpatient Management of Migraine.

Migraine is a frequently disabling neurologic condition which can be complicated by medication overuse headache and comorbid medical disorders, including obesity, anxiety and depression. Although most migraine management takes place in outpatient clinics, inpatient treatment is indicated for migraine refractory to multiple outpatient treatments, with intractable nausea or vomiting, need for detoxification from medication overuse (such as opioids and barbiturates), and significant medical and psychiatric disease. The goals of inpatient treatment include breaking the current cycle of headache pain, reducing the frequency and/or severity of future attacks, monitored detoxification of overused medications, and reducing disability and improving quality of life.

Endoscopic Ultrasound-guided Celiac Plexus Neurolysis to Alleviate Intractable Pain Caused by Advanced Pancreatic Cancer.

This study aimed to analyze the clinical safety and effectiveness of endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in alleviating intractable abdominal pain caused by advanced pancreatic cancer. A total of 58 patients with inoperable pancreatic cancer who underwent EUS-CPN from May 2015 to December 2017 were enrolled. Pain levels before and after EUS-CPN were assessed and compared using the Visual Analogue Scale. The preoperative Visual Analogue Scale score was 8.2±2.3, which decreased significantly to 3.6±1.5 at 2 days after EUS-CPN and to 2.2±0.8 after 1 month. The response rate was 79.3%. No patient experienced serious complications; 14 patients experienced mild, transient side effects (self-limiting diarrhea, reflex hypotension, and worsening of abdominal pain) that resolved within 48 hours. For pancreatic cancer patients, EUS-CPN can effectively control pain with minimal adverse effects.

A Delphi consensus statement of the Neuropathic Pain Special Interest Group of the Italian Neurological Society on pharmacoresistant neuropathic pain.

To improve patient care and help clinical research, the Neuropathic Pain Special Interest Group of the Italian Neurological Society appointed a task force to elaborate a consensus statement on pharmacoresistant neuropathic pain. The task force included 19 experts in neuropathic pain. These experts participated in a Delphi survey consisting of three consecutive rounds of questions and a face-to-face meeting, designed to achieve a consensus definition of pharmacoresistant neuropathic pain. In the three rounds of questions, the participants identified and described the main distinguishing features of pharmacoresistance. In the face-to-face meeting the participants discussed the clinical features determining pharmacoresistance. They finally agreed that neuropathic pain is pharmacoresistant when "the patient does not reach the 50% reduction of pain or an improvement of at least 2 points in the Patient Global Impression of Change, having used all drug classes indicated as first, second, or third line in the most recent and widely agreed international guidelines, for at least 1 month after titration to the highest tolerable dose." Our consensus statement might be useful for identifying eligible patients for invasive treatments, and selecting patients in pharmacological trials, thus improving patient care and helping clinical research.