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.

Diaphragm Pacing: A Safety, Appropriateness, Financial Neutrality, and Efficacy Analysis of Treating Chronic Respiratory Insufficiency.

OBJECTIVES: This study aimed to evaluate the safety and applicability of treating chronic respiratory insufficiency with diaphragm pacing relative to mechanical ventilation. MATERIALS AND METHODS: A literature review and analysis were conducted using the safety, appropriateness, financial neutrality, and efficacy principles. RESULTS: Although mechanical ventilation is clearly indicated in acute respiratory failure, diaphragm pacing improves life expectancy, increases quality of life, and reduces complications in patients with chronic respiratory insufficiency. CONCLUSION: Diaphragm pacing should be given more consideration in appropriately selected patients with chronic respiratory insufficiency.

Intrathecal Baclofen Monotherapy and Polyanalgesia for Treating Chronic Pain in Patients with Severe Spasticity.

PURPOSE OF REVIEW: Intrathecal drug delivery is a well evidenced strategy for the treatment of many chronic pain syndromes. While opioids, anesthetics, and ziconotide are the most commonly used agents, intrathecal baclofen (ITB), which is indicated to treat spasticity, is also thought to have some analgesic properties that are poorly understood. These analgesic benefits have been reported with ITB use in treating patients with central neurological disorders who suffer from severe spasticity and chronic pain. Our review aims to characterize ITB's effects on pain, function, and quality of life in patients with severe spasticity. We performed a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. The primary outcome parameters were analgesic relief and functional improvements. Secondarily, quality of life and adverse effects were also recorded. RECENT FINDINGS: After an initial survey identified 393 studies, 20 studies met final inclusion criteria. Of these, 16 utilized ITB monotherapy and 4 utilized ITB polyanalgesia. Overall, there was a paucity of high-powered studies. Mean titrated ITB doses ranged from 140 to 627.9 µg daily. Nineteen studies reported improved pain and spasticity. Seven studies reported improved functional outcomes and quality of life. Our results show that ITB may be an effective agent in treatingfor the treatment of chronic pain in patients with severe spasticity independent of its spasmolytic effects. Although this evidence was largely derived from studies lacking clearly defined outcomes of pain relief, ITB is reasonable to consider for concurrent spasticity and pain management. Well-designed studies are still needed to characterize ITB's analgesic efficacy when used in patients with severe spasticity.

Combination Intrathecal Drug Therapy Strategies for Pain Management.

BACKGROUND: Numerous combination intrathecal drug therapy (CIDT) strategies exist and are utilized for varying pain syndromes, typically when monotherapy dose escalation or medication alternation is deemed untenable or unfeasible. Unfortunately, the supportive evidence basis for the use of these strategies and specific drug combinations is generally lacking and unclear, with many medications being used for off-label indications. OBJECTIVE: In this manuscript, we provide a robust exploration and analysis of the literature to provide an evidence-based narrative for the use of CIDT strategies in regard to clinical indications, pharmacologic parameters, specific drug combinations, safety profiles, and future directions. STUDY DESIGN: Narrative review. METHODS: This was an evidence based narrative performed after extensive review of the literature. RESULTS: Variances in intrathecal pharmacokinetics and pharmacodynamics are utilized advantageously with CIDT strategies to achieve improved analgesic benefit; however, appropriate use may be limited by increased or compounded risk of adverse effects. The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors, including a lack of standardized dosing. The most evidenced CIDT strategies include polyanalgesia with morphine-ziconotide, opioid-clonidine, and morphine-bupivacaine. Notably, in addition to pain relief, morphine-bupivacaine has been shown to decrease early opioid escalation requirements. LIMITATIONS: The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors including a lack of standardized dosing. CONCLUSIONS: CIDT strategies and polyanalgesia combinations can be effective for treating various patient populations with chronic pain. The appropriate use of these strategies may be limited by increased or compounded risk of adverse effects, both of which are highly patient and scenario dependent. Therefore, practitioners should maintain a particularly low threshold of suspicion for adverse effects in patients with CIDT such that safety profiles associated with this therapy can be favorably maintained.

Effectiveness of Intrathecal Baclofen for Intractable Stiffperson Syndrome: a Case Report.

BACKGROUND: Intrathecal baclofen is considered an adjuvant therapy for patients with intractable spasms due to stiff-person syndrome. There is increasing evidence to support the use of intrathecal baclofen in the management of symptomatic stiffperson syndrome, with improvement in function. CASE REPORT: A 38-year-old woman with stiff- person syndrome initially presented to inpatient rehabilitation for intractable muscle spasms. The symptoms made her non-ambulatory and limited her tolerance to wheelchair use for mobility. The patient underwent up-titration of oral baclofen and diazepam, with concurrent intravenous immunoglobulin cycles, leading to transient symptom relief. She agreed to explore intrathecal baclofen therapy. An initial trial of a single bolus of 50 µg intrathecal baclofen resulted in a significant decrease in spontaneous spasms, enabling modified independence in transfers and ambulation. The patient was subsequently implanted with a permanent intrathecal delivery system. To date, the intrathecal baclofen had been titrated to 186 µg per day with simple continuous delivery. The patient was weaned off oral baclofen. She attained complete functional independence with ambulation without the need for assistive devices, and has had no lasting post-procedural complications to date. CONCLUSION: This case report adds to the increasing evidence of cases of refractory stiff-person syndrome managed successfully using intrathecal baclofen therapy.

Management Strategies for Spinal Cord Injury Pain Updated for the Twenty-First Century.

Traumatic spinal cord injury (SCI) often results in several life-altering impairments, including paralysis, sensory loss, and neurogenic bowel/bladder dysfunction. Some of these SCI-related conditions can be accommodated with compensatory strategies. Perhaps no SCI-associated condition is more troublesome and recalcitrant to the treating physiatrist than chronic neuropathic pain. In addition to the expected challenges in treating any chronic pain condition, treatment of SCI-related pain has the added difficulty of disruption of normal neural pathways that subserve pain transmission and attenuation. This article reviews selected treatment strategies for SCI-associated neuropathic pain.

Effectiveness and Safety of Intrathecal Ziconotide: Final Results of the Patient Registry of Intrathecal Ziconotide Management (PRIZM).

BACKGROUND AND OBJECTIVES: The Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide. METHODS: The study was a prospective, multicenter observational study of intrathecal ziconotide in US clinical practice. Patients were adults with severe chronic pain that warranted intrathecal therapy. Ziconotide was initiated as the single agent in the pump; however, other intrathecal medications were permitted. The primary efficacy outcome was ≥30% reduction in numeric pain rating scale score from baseline at week 12. A secondary outcome was patient global impression of change. Adverse events were solicited at each visit. RESULTS: The registry enrolled 93 patients. Seventy-four and 28 patients completed 12 weeks and 18 months of treatment, respectively. In the overall patient population, 17.4% had ≥30% pain reduction from baseline at week 12, with a mean reduction in pain of 10.9%. At month 18, 38.5% of patients had ≥30% pain reduction from baseline, with a mean pain reduction of 24.7%. Patient-rated improvement was reported in 67% of patients at week 12 and 71% at month 18. Almost all patients experienced adverse events, the most common of which were nausea (25.8%), confusional state (22.6%), and dizziness (20.4%). CONCLUSIONS: Final study analyses showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively. At these same time points, patient-rated improvement was reported in at least two-thirds of patients. The safety profile was consistent with that listed in the ziconotide prescribing information.

Effectiveness and Safety of Intrathecal Ziconotide: Interim Analysis of the Patient Registry of Intrathecal Ziconotide Management (PRIZM).

BACKGROUND: The Patient Registry of Intrathecal Ziconotide Management (PRIZM) evaluated long-term effectiveness, safety, and tolerability of intrathecal ziconotide treatment in clinical practice. METHODS: Patient Registry of Intrathecal Ziconotide Management was an open-label, long-term, multicenter, observational study of adult patients with severe chronic pain. This interim analysis (data through July 10, 2015) of ziconotide as the first vs. not first intrathecal agent in pump included change from baseline in the Numeric Pain Rating Scale (NPRS; primary efficacy measure) and Patient Global Impression of Change (PGIC) scores. RESULTS: Enrollment closed at 93 patients; data collection was ongoing at the time of this interim analysis. Fifty-one patients (54.8%) received ziconotide as the first agent in pump (FIP+), whereas 42 (45.2%) did not (FIP-). Mean (SD) baseline NPRS scores were 7.4 (1.9) and 7.9 (1.6) in FIP+ and FIP- patients, respectively. Mean (SEM) percentage changes in NPRS scores were -29.4% (5.5%) in FIP+ patients (n = 26) and +6.4% (7.7%) in FIP- patients (n = 17) at month 6 and -34.4% (9.1%) in FIP+ patients (n = 14) and -3.4% (10.2%) in FIP- patients (n = 9) at month 12. Improvement from baseline, measured by PGIC score, was reported in 69.2% of FIP+ (n = 26) and 35.7% of FIP- (n = 14) patients at month 6 and 85.7% of FIP+ (n = 7) and 71.4% of FIP- (n = 7) patients at month 12. The most common adverse events (≥ 10% of patients overall as of the data cut) were nausea (19.6% vs. 7.1% of FIP+ vs. FIP- patients, respectively), confusional state (9.8% vs. 11.9%), and dizziness (13.7% vs. 7.1%). CONCLUSIONS: Greater improvements in efficacy outcomes were observed when ziconotide was initiated as first-line intrathecal therapy vs. not first intrathecal agent in pump. The adverse event profile was consistent with the ziconotide prescribing information.

Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Low Back Pain: Two Clinical Case Reports of Sustained Pain Relief.

As the leading cause of disability among U.S. adults, chronic low back pain (LBP) is one of the most prevalent and challenging musculoskeletal conditions. Neuromodulation provides an opportunity to reduce or eliminate the use of opioids to treat chronic LBP, but the cost and invasiveness of existing methods have limited its broad adoption, especially earlier in the treatment continuum. The present case report details the results of a novel method of short-term percutaneous peripheral nerve stimulation (PNS) in 2 subjects with chronic LBP. At the end of the 1-month therapy, stimulation was discontinued and the leads were withdrawn. PNS produced clinically significant improvements in pain (62% average reduction in Brief Pain Inventory Question #5, average pain), and functional outcomes (73% reduction in disability, Oswestry Disability Index; 83% reduction in pain interference, Brief Pain Inventory). Both subjects reduced nonopioid analgesic use by 83%, on average, and the one subject taking opioids ceased using all opioids. The only adverse event was minor skin irritation caused by a topical dressing. The clinically significant improvements were sustained at least 4 months after start of therapy (79% average reduction in pain; both reported minimal disability; 100% reduction in opioids; 74% reduction nonopioids). The results reveal the utility of this novel, short-term approach and its potential as a minimally invasive neuromodulation therapy for use earlier in the treatment continuum to produce sustained pain relief and reduce or eliminate the need for analgesic medications, including opioids, as well as more expensive and invasive surgical or therapeutic alternatives.

Intrathecal Therapies.

Intrathecal baclofen therapy is a well-established technique for spasticity management. This article briefly reviews the pharmacology of intrathecal baclofen as well as customary approach for utilization of this targeted drug delivery concept. Following these descriptions, four unusual presentations will be described, including the need for initial trialing, patient-directed boluses during chronic intrathecal baclofen therapy, use of medications other than baclofen for intrathecal therapy in spastic patients, and intraventricular baclofen delivery. These hypothetical cases are provided in an effort to expand the use of targeted drug delivery to larger population of spastic patients.

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.

The Polyanalgesic Consensus Conference (PACC): Recommendations for Trialing of Intrathecal Drug Delivery Infusion Therapy.

INTRODUCTION: Intrathecal (IT) drug infusion is an appropriate and necessary tool in the algorithm to treat refractory cancer and noncancer pain. The decision-making steps/methodology for selecting appropriate patients for implanted targeted drug delivery systems is controversial and complicated. Therefore, a consensus on best practices for determining appropriate use of IT drug infusion may involve testing/trialing this therapy before implantation. METHODS: This current Polyanalgesic Consensus Conference (PACC) update was designed to address the deficiencies and emerging innovations since the previous PACC convened in 2012. A literature search identified publications available since the previous PACC publications in 2014, and relevant sources were contributed by the PACC members. After reviewing the literature, the panel determined the evidence levels and degrees of recommendations. The developed consensus was ranked as strong (>80%), moderate (50-79%), or weak (<49%). RESULTS: The trialing for IT drug delivery systems (IDDS) remains an area of continued controversy. The PACC recommendations for trialing are presented in 34 consensus points and cover trialing for morphine, ziconotide, and medication admixtures; starting doses and titration practices; measurements of success; trial settings and monitoring; management of systemic opioids during trialing; and the role of psychological evaluation. Finally, the PACC describes clinical scenarios in which IT trialing is required or not required. CONCLUSION: The PACC provides consensus guidance on best practices of trialing for IDDS implants. In addition, the PACC recommends that no trial may be required in certain patient populations.

The Neurostimulation Appropriateness Consensus Committee (NACC) Recommendations for Infection Prevention and Management.

INTRODUCTION: The use of neurostimulation for pain has been an established therapy for many decades and is a major tool in the arsenal to treat neuropathic pain syndromes. Level I evidence has recently been presented to substantiate the therapy, but this is balanced against the risk of complications of an interventional technique. METHODS: The Neurostimulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society convened an international panel of well published and diverse physicians to examine the best practices for infection mitigation and management in patients undergoing neurostimulation. The NACC recommendations are based on evidence scoring and peer-reviewed literature. Where evidence is lacking the panel added expert opinion to establish recommendations. RESULTS: The NACC has made recommendations to improve care by reducing infection and managing this complication when it occurs. These evidence-based recommendations should be considered best practices in the clinical implantation of neurostimulation devices. CONCLUSION: Adhering to established standards can improve patient care and reduce the morbidity and mortality of infectious complications in patients receiving neurostimulation.

The Polyanalgesic Consensus Conference (PACC): Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating Risks.

INTRODUCTION: Intrathecal therapy is an important part of the pain treatment algorithm for chronic disease states. The use of this option is a viable treatment strategy, but it is inherent for pain physicians to understand risk assessment and mitigation. In this manuscript, we explore evidence and mitigating strategies to improve safety with intrathecal therapy. METHODS: A robust literature search was performed covering January 2011 to October 9, 2016, in PubMed, Embase, MEDLINE, Biomed Central, Google Scholar, Current Contents Connect, and International Pharmaceutical Abstracts. The information was cross-referenced and compiled for evidence, analysis, and consensus review, with the intent to offer weighted recommendations and consensus statements on safety for targeted intrathecal therapy delivery. RESULTS: The Polyanalgesic Consensus Conference has made several best practice recommendations to improve care and reduce morbidity and mortality associated with intrathecal therapy through all phases of management. The United States Prevention Service Task Force evidence level and consensus strength assessments are offered for each recommendation. CONCLUSION: Intrathecal therapy is a viable and relatively safe option for the treatment of cancer- and noncancer-related pain. Continued research and expert opinion are required to improve our current pharmacokinetic and pharmacodynamic model of intrathecal drug delivery, as this will undoubtedly improve safety and efficacy.

Infection Rates of Electrical Leads Used for Percutaneous Neurostimulation of the Peripheral Nervous System.

BACKGROUND: Percutaneous neurostimulation of the peripheral nervous system involves the insertion of a wire "lead" through an introducing needle to target a nerve/plexus or a motor point within a muscle. Electrical current may then be passed from an external generator through the skin via the lead for various therapeutic goals, including providing analgesia. With extended use of percutaneous leads sometimes greater than a month, infection is a concern. It was hypothesized that the infection rate of leads with a coiled design is lower than for leads with a noncoiled cylindrical design. METHODS: The literature was retrospectively reviewed for clinical studies of percutaneous neurostimulation of the peripheral nervous system of greater than 2 days that included explicit information on adverse events. The primary endpoint was the number of infections per 1,000 indwelling days. RESULTS: Forty-three studies were identified that met inclusion criteria involving coiled (n = 21) and noncoiled (n = 25) leads (3 studies involved both). The risk of infection with noncoiled leads was estimated to be 25 times greater than with coiled leads (95% confidence interval [CI] 2 to 407, P = 0.006). The infection rates were estimated to be 0.03 (95% CI 0.01 to 0.13) infections per 1,000 indwelling days for coiled leads and 0.83 (95% CI 0.16 to 4.33) infections per 1,000 indwelling days for noncoiled leads (P = 0.006). CONCLUSIONS: Percutaneous leads used for neurostimulation of the peripheral nervous system have a much lower risk of infection with a coiled design compared with noncoiled leads: approximately 1 infection for every 30,000 vs. 1,200 indwelling days, respectively.

Can Cerebrospinal Fluid Pressure Detect Catheter Complications in Patients Who Experience Loss of Effectiveness With Intrathecal Baclofen Therapy?

OBJECTIVE: The catheter status of patients who presented with loss of intrathecal baclofen (ITB) therapy effectiveness was investigated using measurements of cerebrospinal fluid (CSF) pressure transmitted through the catheter fluid path to the pump. The aim of the study was to estimate the appropriate threshold separating catheter complications from "normal" catheter function, and to compare catheter status based on CSF pressure with the clinical diagnosis. METHODS: This was a prospective, masked nonsignificant risk, research study. Patients (N = 47) received ITB for the treatment of severe spasticity and presented with symptoms of catheter malfunction. CSF pressure data were recorded using an external sensor connected to a needle inserted into the catheter access port. An algorithm calculated the energy of the variations in CSF pressure caused by respiration and heartbeat within the intrathecal space. These data were evaluated against a threshold that separated normal from abnormal catheter function. Catheter status based on the algorithm was compared with the clinical diagnosis. RESULTS: Complete data were available for 37 patients. Mean CSF pressure energy was significantly higher (p = 0.025; student t-test) for patients diagnosed with normal catheter function vs. catheters with complications. The CSF pressure algorithm matched the clinical diagnosis in 16 of 18 patients with catheter complications (sensitivity = 89%), and 13 of 19 patients with normal catheter function (specificity = 68%). CONCLUSION: In-clinic CSF pressure data acquisition is technically feasible. Overall, catheter status based on the algorithm demonstrated concordance with the clinical diagnosis in 29 of 37 patients (78.4%).

The Application of Failure Modes and Effects Analysis Methodology to Intrathecal Drug Delivery for Pain Management.

OBJECTIVE: This study aimed to utilize failure modes and effects analysis (FMEA) to transform clinical insights into a risk mitigation plan for intrathecal (IT) drug delivery in pain management. METHODS: The FMEA methodology, which has been used for quality improvement, was adapted to assess risks (i.e., failure modes) associated with IT therapy. Ten experienced pain physicians scored 37 failure modes in the following categories: patient selection for therapy initiation (efficacy and safety concerns), patient safety during IT therapy, and product selection for IT therapy. Participants assigned severity, probability, and detection scores for each failure mode, from which a risk priority number (RPN) was calculated. Failure modes with the highest RPNs (i.e., most problematic) were discussed, and strategies were proposed to mitigate risks. RESULTS: Strategic discussions focused on 17 failure modes with the most severe outcomes, the highest probabilities of occurrence, and the most challenging detection. The topic of the highest-ranked failure mode (RPN = 144) was manufactured monotherapy versus compounded combination products. Addressing failure modes associated with appropriate patient and product selection was predicted to be clinically important for the success of IT therapy. CONCLUSIONS: The methodology of FMEA offers a systematic approach to prioritizing risks in a complex environment such as IT therapy. Unmet needs and information gaps are highlighted through the process. Risk mitigation and strategic planning to prevent and manage critical failure modes can contribute to therapeutic success.