The Polyanalgesic Consensus Conference (PACC)®: Intrathecal Drug Delivery Guidance on Safety and Therapy Optimization When Treating Chronic Noncancer Pain.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians and scientists based on expertise with international representation to establish evidence-based guidance on intrathecal drug delivery in treating chronic pain. This Polyanalgesic Consensus Conference (PACC)® project, created more than two decades ago, intends to provide evidence-based guidance for important safety and efficacy issues surrounding intrathecal drug delivery and its impact on the practice of neuromodulation. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when PACC® last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence is scant. RESULTS: The PACC® examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The PACC® recommends best practices regarding intrathecal drug delivery to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate.

Noninvasive Electrical Stimulation for the Treatment of Chronic Ocular Pain and Photophobia.

INTRODUCTION: "Dry eye" or "keratoconjunctivitis sicca" is a multifactorial disease estimated to have a worldwide prevalence of 5-33%. Conventional therapies targeting the ocular surface with artificial tears, anti-inflammatories, punctal closure, eyelid hygiene, and antibiotics do not provide relief in all patients, especially those with neuropathic-like ocular complaints (wind hyperalgesia and photophobia). We anticipated that ocular transcutaneous electrical nerve stimulation (TENS) would alleviate symptoms of ocular pain, photophobia, and dryness in these latter individuals. METHODS: All individuals who received electrical stimulation between May 10, 2016 and April 6, 2017 for the treatment of chronic ocular pain at the oculofacial pain clinic of the Miami Veterans Administration Hospital were included in this retrospective review. All patients had symptoms of dryness along with other neuropathic-like symptoms (e.g., photophobia) and minimal signs of tear dysfunction. Ocular pain intensity, symptoms of dryness, and light sensitivity were compared pre-treatment and five min post-treatment via a two-tailed paired Student's t-test. RESULTS: The use of TENS significantly reduced the mean pain intensity in both the right and left eyes five min after treatment compared to prior to treatment (p < 0.05, paired t-test). The use of TENS significantly decreased light sensitivity in both eyes (p < 0.05). The findings for symptoms of dryness, however, were equivocal with a significant decrease in the left eye but not the right (p < 0.05, paired t-test). DISCUSSION: Our data indicate that TENS may similarly provide analgesia in patients with dry eye symptoms as it does for many other chronic pain conditions. Furthermore, the noted effect on symptoms of photophobia and dryness suggest that all may be linked by similar trigeminal-thalamic-cortical pathways. Prospective studies with electrical stimulation of dry eye are needed to further elucidate its benefit and mechanism of action.

Evidence that Dry Eye Represents a Chronic Overlapping Pain Condition.

Abstract: Recent data suggest that corneal somatosensory dysfunction may be the underlying cause of severe dry eye symptoms in the absence of ocular surface pathology seen in a subset of patients diagnosed with "dry eye syndrome." This subset of patients tends to demonstrate a unique constellation of symptoms that are persistent, more severe, and generally respond poorly to current dry eye therapies targeting inadequate or dysfunctional tears. A growing body of literature suggests that symptoms in these patients may be better characterized as neuropathic ocular pain rather than dry eye. In these patients, dry eye symptoms are often associated with numerous comorbid pain conditions and evidence of central pain processing abnormalities, where eye pain is just one of multiple overlapping peripheral manifestations. In this review, we discuss the concept and potential mechanisms of chronic overlapping pain conditions as well as evidence for considering neuropathic ocular pain as one of these overlapping pain conditions.

The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines.

INTRODUCTION: Pain treatment is best performed when a patient-centric, safety-based philosophy is used to determine an algorithmic process to guide care. Since 2007, the International Neuromodulation Society has organized a group of experts to evaluate evidence and create a Polyanalgesic Consensus Conference (PACC) to guide practice. METHODS: The current PACC update was designed to address the deficiencies and innovations emerging since the previous PACC publication of 2012. An extensive literature search identified publications between January 15, 2007 and November 22, 2015 and authors contributed additional relevant sources. After reviewing the literature, the panel convened to determine evidence levels and degrees of recommendations for intrathecal therapy. This meeting served as the basis for consensus development, which was ranked as strong, moderate or weak. Algorithms were developed for intrathecal medication choices to treat nociceptive and neuropathic pain for patients with cancer, terminal illness, and noncancer pain, with either localized or diffuse pain. RESULTS: The PACC has developed an algorithmic process for several aspects of intrathecal drug delivery to promote safe and efficacious evidence-based care. Consensus opinion, based on expertise, was used to fill gaps in evidence. Thirty-one consensus points emerged from the panel considerations. CONCLUSION: New algorithms and guidance have been established to improve care with the use of intrathecal drug delivery.

Chronic dry eye symptoms after LASIK: parallels and lessons to be learned from other persistent post-operative pain disorders.

Laser in-situ keratomileusis (LASIK) is a commonly performed surgical procedure used to correct refractive error. LASIK surgery involves cutting a corneal flap and ablating the stroma underneath, with known damage to corneal nerves. Despite this, the epidemiology of persistent pain and other long-term outcomes after LASIK surgery are not well understood. Available data suggest that approximately 20-55% of patients report persistent eye symptoms (generally regarded as at least 6 months post-operation) after LASIK surgery. While it was initially believed that these symptoms were caused by ocular surface dryness, and referred to as "dry eye," it is now increasingly understood that corneal nerve damage produced by LASIK surgery resembles the pathologic neuroplasticity associated with other forms of persistent post-operative pain. In susceptible patients, these neuropathological changes, including peripheral sensitization, central sensitization, and altered descending modulation, may underlie certain persistent dry eye symptoms after LASIK surgery. This review will focus on the known epidemiology of symptoms after LASIK and discuss mechanisms of persistent post-op pain due to nerve injury that may be relevant to these patients. Potential preventative and treatment options based on approaches used for other forms of persistent post-op pain and their application to LASIK patients are also discussed. Finally, the concept of genetic susceptibility to post-LASIK ocular surface pain is presented.

Comparison of FDA-Approved Electrical Neuromodulation Techniques for Focal Neuropathic Pain: A Narrative Review of DRG, HF10, and Burst Neuromodulation.

BACKGROUND: Evidence suggests that dorsal root ganglion stimulation (DRGS) is a more effective treatment for focal neuropathic pain (FNP) compared with tonic, paresthesia-based dorsal column spinal cord stimulation (SCS). However, new advancements in waveforms for dorsal column SCS have not been thoroughly studied or compared with DRGS for the treatment of FNP. OBJECTIVES: The purpose of this review was to examine the evidence for these novel technologies; to highlight the lack of high-quality evidence for the use of neuromodulation to treat FNP syndromes other than complex regional pain syndrome I or II of the lower extremity; to emphasize the absence of comparison studies between DRGS, burst SCS, and high-frequency SCS; and to underscore that consideration of all neuromodulation systems is more patient-centric than a one-size-fits-all approach. STUDY DESIGN: This is a review article summarizing case reports, case series, retrospective studies, prospective studies, and review articles. SETTING: The University of Miami, Florida. METHODS: A literature search was conducted from February to March 2020 using the PubMed and EMBASE databases and keywords related to DRGS, burst SCS, HF10 (high-frequency of 10 kHz), and FNP syndromes. All English-based literature from 2010 reporting clinical data in human patients were included. RESULTS: Data for the treatment of FNP using burst SCS and HF10 SCS are limited (n = 11 for burst SCS and n = 11 for HF10 SCS). The majority of these studies were small, single-center, nonrandomized, noncontrolled, retrospective case series and case reports with short follow-up duration. To date, there are only 2 randomized controlled trials for burst and HF10 for the treatment of FNP. LIMITATIONS: No studies were available comparing DRGS to HF10 or burst for the treatment of FNP. Data for the treatment of FNP using HF10 and burst stimulation were limited to a small sample size reported in mostly case reports and case series. CONCLUSIONS: FNP is a complex disease, and familiarity with all available systems allows the greatest chance of success.

Spinal bromodomain-containing protein 4 contributes to neuropathic pain induced by HIV glycoprotein 120 with morphine in rats.

The symptoms of HIV-sensory neuropathy are dominated by neuropathic pain. Recent data show that repeated use of opiates enhances the chronic pain states in HIV patients. Limited attention has so far been devoted to exploring the exact pathogenesis of HIV painful disorder and opiate abuse in vivo, for which there is no effective treatment. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal domain protein (BET) family and functions as a chromatin 'reader' that binds acetylated lysines in histones in brain neurons to mediate the transcriptional regulation underlying learning and memory. Here, we established a neuropathic pain model of interaction of intrathecal HIV envelope glycoprotein 120 (gp120) and chronic morphine in rats. The combination of gp120 and morphine (gp120/M, for 5 days) induced persistent mechanical allodynia compared with either gp120 or morphine alone. Mechanical allodynia reached the lowest values at day 10 from gp120/M application, beginning to recover from day 21. In the model, gp120/M induced overexpression of Brd4 mRNA and protein at day 10 using RT-qPCR and western blots, respectively. Immunohistochemical studies showed that Brd4 at day 10 was expressed in the neurons of spinal cord dorsal horn. BET inhibitor I-BET762 dose-dependently increased the mechanical threshold in the gp120/M pain state. The present study provides preclinical evidence for treating HIV neuropathic pain with opioids using the BET inhibitor.

Neuropathic Ocular Pain due to Dry Eye is Associated with Multiple Comorbid Chronic Pain Syndromes.

UNLABELLED: Recent data show that dry eye (DE) susceptibility and other chronic pain syndromes (CPS) such as chronic widespread pain, irritable bowel syndrome, and pelvic pain, might share common heritable factors. Previously, we showed that DE patients described more severe symptoms and tended to report features of neuropathic ocular pain (NOP). We hypothesized that patients with a greater number of CPS would have a different DE phenotype compared with those with fewer CPS. We recruited a cohort of 154 DE patients from the Miami Veterans Affairs Hospital and defined high and low CPS groups using cluster analysis. In addition to worse nonocular pain complaints and higher post-traumatic stress disorder and depression scores (P < .01), we found that the high CPS group reported more severe neuropathic type DE symptoms compared with the low CPS group, including worse ocular pain assessed via 3 different pain scales (P < .05), with similar objective corneal DE signs. To our knowledge, this was the first study to show that DE patients who manifest a greater number of comorbid CPS reported more severe DE symptoms and features of NOP. These findings provided further evidence that NOP might represent a central pain disorder, and that shared mechanistic factors might underlie vulnerability to some forms of DE and other comorbid CPS. PERSPECTIVE: DE patients reported more frequent CPS (high CPS group) and reported worse DE symptoms and ocular and nonocular pain scores. The high CPS group reported symptoms of NOP that share causal genetic factors with comorbid CPS. These results imply that an NOP evaluation and treatment should be considered for DE patients.

A minimally invasive surgical technique for the treatment of posttraumatic trigeminal neuropathic pain with peripheral nerve stimulation.

BACKGROUND: Facial pain occurring after traumatic injury of the facial branches of the trigeminal nerve is a medical condition that is often very difficult to treat. Patients are quite disabled by their symptoms and most therapies are ineffective in relieving this pain. Peripheral nerve stimulation has been used as a treatment to provide pain relief for this type of intractable atypical facial pain. OBJECTIVE: To describe a minimally invasive peripheral nerve stimulation surgical technique for treating posttraumatic trigeminal neuralgia. STUDY DESIGN: Case report based on a patient seen in a university setting with posttraumatic trigeminal neuropathic pain who underwent a minimally invasive technique for the placement of a peripheral nerve stimulator. SETTING: University-based outpatient clinic. METHODS: A patient with a clinical picture suggestive of trigeminal neuropathic pain secondary to trauma involving the V1 and V2 branches of the trigeminal nerve was selected. Conservative management was attempted with no improvement before peripheral nerve stimulation was tried with a minimally invasive surgical technique. We recorded the patient's subjective assessment of pain and daily function before and after the procedure. RESULTS: Following the procedure, the patient's pain score decreased approximately 50% and the patient reported a better quality of life with improvement in daily function as well as a more positive outlook on her condition. There were no complications after the procedure and the patient reported no complaints with the device. LIMITATIONS: Case report. CONCLUSIONS: This surgical technique for placing peripheral nerve stimulators allows for a minimally invasive approach for the treatment of intractable posttraumatic trigeminal neuralgia with potentially less risk of facial nerve damage. This case confirms the need for further studies to be done in the future to prove the safety and effectiveness of this technique.