Richard Rauck

Polyanalgesic consensus conference 2007: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

Background.  Expert panels of physicians and nonphysicians in the field of intrathecal therapies convened in 2000 and 2003 to make recommendations for the rational use of intrathecal analgesics based on the preclinical and clinical literature known up to those times. An expert panel of physicians convened in 2007 to update previous recommendations and to form guidelines for the rational use of intrathecal opioid and nonopioid agents.

NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study

BACKGROUND The limitations of current treatments for postherpetic neuralgia (PHN) have led to the investigation of localised, non-systemic alternatives. NGX-4010, a high-concentration (8%) capsaicin dermal patch, was developed to treat patients with neuropathic pain. We report the results of a randomised, double blind, 12-week study of the efficacy and safety of one application of NGX-4010 in patients with PHN. METHODS In this multicentre, double-blind, parallel-group trial, 402 patients were randomly assigned to one 60-min application of NGX-4010 (640 microg/cm(2) [8% capsaicin]) or a low-concentration capsaicin control patch (3.2 microg/cm(2) [0.04% capsaicin]). Patients were aged 18-90 years, had had postherpetic neuralgia for at least 6 months, and had an average baseline numeric pain rating scale (NPRS) score of 3 to 9. The primary efficacy endpoint was percentage change in NPRS score from baseline to weeks two to eight. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00115310. FINDINGS Patients who were randomly assigned to NGX-4010 (n=206) had a significantly greater reduction in pain during weeks two to eight than did patients who had the control patch (n=196). The mean changes in NPRS score were -29.6%vs -19.9% (difference -9.7%, 95% CI -15.47 to -3.95; p=0.001). 87 (42%) patients who received NGX-4010 and 63 (32%) controls had a 30% or greater reduction in mean NPRS score (odds ratio [OR] 1.56, 95% CI 1.03 to 2.37; p=0.03). The patients who had NGX-4010 had significant improvements in pain during weeks two to 12 (mean change in NPRS score -29.9%vs -20.4%, difference -9.5, -15.39 to -3.61; p=0.002). Transient blood pressure changes associated with changes in pain level were recorded on the day of treatment, and short-lasting erythema and pain at the site of application were common, self-limited, and generally mild to moderate in the NGX-4010 group and less frequent and severe in the controls. INTERPRETATION One 60-min application of NGX-4010 provided rapid and sustained pain relief in patients with postherpetic neuralgia. No adverse events were associated with treatment except for local reactions at the site of application and those related to treatment-associated pain.

An Updated Interdisciplinary Clinical Pathway for CRPS: Report of an Expert Panel

Abstract: The goal of treatment in patients with complex regional pain syndrome (CRPS) is to improve function, relieve pain, and achieve remission. Current guidelines recommend interdisciplinary management, emphasizing 3 core treatment elements: pain management, rehabilitation, and psychological therapy. Although the best therapeutic regimen or the ideal progression through these modalities has not yet been established, increasing evidence suggests that some cases are refractory to conservative measures and require flexible application of the various treatments as well as earlier consideration of interventions such as spinal cord stimulation (SCS). While existing treatment guidelines have attempted to address the comprehensive management of CRPS, all fail to provide guidance for contingent management in response to a sudden change in the patients medical status. This paper reviews the current pathophysiology as it is known, reviews the purported treatments, and provides a modified clinical pathway (guideline) that attempts to expand the scope of previous guidelines.

Epidural Clonidine Treatment for Refractory Reflex Sympathetic Dystrophy

BackgroundIntraspinally administered α2-adrenerglc agonists may relieve pain in sympathetically maintained pain (SMP) syndromes, such as reflex sympathetic dystrophy (RSD), by spinal, peripheral, and central nervous system actions. This study examined analgesic efficacy and side effects of epidurally administered clonidine in patients with severe, refractory RSD. MethodsTwenty-six patients with severe chronic pain consistent with RSD were studied in a randomized, blinded, placebo-controlled design. Cervical or lumbar epidural catheters were inserted for patients with upper or lower extremity RSD, respectively, and patients received, in random order on three consecutive days, epidural injection of clonidine, 300 or 700 μg, or placebo. Pain (by visual analog score (VAS) and McGill Pain Questionnaire), sedation, blood pressure, and heart rate were monitored at specified Intervals for 6 h after injection. Patients who responded to clonidine, but not placebo, then entered a trial of open-label, continuous epidural infusion of clonidine (10–50 μg/h). ResultsClonidine, but not placebo, caused pain relief, sedation, and decreased blood pressure and heart rate after bolus epidural injection. The smaller clonidine dose (300 μg), produced pain relief and decreases in blood pressure and heart rate similar to those of the 700 μg dose, but with less sedation. Epidural clonidine was infused for a mean of 43 days in 19 patients at a mean rate of 32 μg/h for sustained analgesia. ConclusionsTransdermal clonidine has been demonstrated to produce analgesia in the area surrounding its application site in patients with SMP. The current study indicates that extensive analgesia may be obtained by epidural administration. Sedation and hypotension may limit bolus epidural clonidine administration for RSD. The role for chronic epidural Infusion of clonidine has not yet been established.

Evidence-Based Review of the Literature on Intrathecal Delivery of Pain Medication

Evidence-based medicine depends on the existence of controlled clinical trials that establish the safety and efficacy of specific therapeutic techniques. Many interventions in clinical practice have achieved widespread acceptance despite little evidence to support them in the scientific literature; the critical appraisal of these interventions based on accumulating experience is a goal of medicine. To clarify the current state of knowledge concerning the use of various drugs for intraspinal infusion in pain management, an expert panel conducted a thorough review of the published literature. The exhaustive review included 5 different groups of compounds, with morphine and bupivacaine yielding the most citations in the literature. The need for additional large published controlled studies was highlighted by this review, especially for promising agents that have been shown to be safe and efficacious in recent clinical studies.

Epidural clonidine analgesia for intractable cancer pain: phase I

Intrathecally administered clonidine has been reported to produce analgesia in cancer patients tolerant to intrathecal opiates. To assess the efficacy, safety, and appropriate dose of epidurally administered clonidine for the treatment of cancer pain, clonidine (range, 100-900 micrograms in 100-micrograms increments) was injected in nine patients with severe, intractable cancer pain. Clonidine produced analgesia, as measured by change in verbal pain scores, lasting more than 6 h. Clonidine also decreased blood pressure, although this effect was well tolerated and no patient met criteria for receiving iv ephedrine (greater than 30% decrease in mean arterial pressure not responsive to 500 ml iv crystalloid infusion). Clonidine decreased heart rate 10-30% and produced transient sedation. Serum glucose and cortisol and oxyhemoglobin saturation were not altered by clonidine. Clonidine was absorbed in a dose-dependent manner into the systemic circulation, although absorption and elimination kinetics were highly variable. Following study seven patients received epidural clonidine/morphine infusions at home for periods of up to 5 months with sustained analgesia. These results suggest that epidurally administered clonidine may offer effective analgesia in patients with severe, intractable cancer pain.

Clinical guidelines for intraspinal infusion: Report of an expert panel

Consensus guidelines developed by an expert panel are helpful to clinicians when there is variation in practice and lack of a firm evidence base for an intervention, such as intraspinal therapy for pain. An internet-based survey of practitioners revealed remarkable variation in practice patterns surrounding intraspinal therapy. This prompted an interdisciplinary panel with extensive clinical experience in intraspinal infusion therapy to evaluate the results of the survey, the systematic reviews of the literature pertaining to this approach, and their own clinical experience with long-term spinal infusions. The panel proposed a scheme for the selection of drugs and doses for intraspinal therapy, and suggested guidelines for administration that would increase the likelihood of a successful outcome. These expert panel guidelines were designed to provide an initial structure for clinical decision making that is based on the best available evidence and the perspectives of experienced clinicians.

Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain

Abstract Background and objectives: Breakthrough cancer pain (BTcP) represents an important clinical challenge in the care of patients with cancer. This trial evaluated the efficacy and long-term tolerability of a sublingual formulation of the fast-acting opioid fentanyl, for the treatment of BTcP in opioid-tolerant patients with cancer. Research design and methods: This was a randomized, placebo-controlled, multi-center, phase III trial, conducted in opioid-tolerant male and female patients (aged ≥17 years) with BTcP. The study was conducted at 36 centers across the USA. The study comprised a 2-week open-label titration phase, followed by a double-blind efficacy phase, during which patients received sublingual fentanyl citrate orally disintegrating tablet (sublingual fentanyl ODT) or placebo, in a random order. The primary efficacy endpoint was the sum of pain intensity difference (SPID) over 30 min post-administration. Secondary efficacy endpoints included pain intensity difference (PID) and pain relief (PR) throughout the 60-min post-dose assessment period. Following efficacy evaluation, patients entered a long-term safety phase of up to 12 months. Adverse events were recorded throughout the study. [Clinical trial registration: NCT00262678] Results: A total of 131 patients entered the titration phase, of whom 61 were included in the primary efficacy analysis. Sublingual fentanyl ODT provided significant improvements in SPID relative to placebo at 30 min (49.5 vs. 36.6, p = 0.0004) and 60 min post-administration (143.0 vs. 104.5, p = 0.0002). Furthermore, sublingual fentanyl ODT provided significant improvements in PID and PR compared to placebo, from 10 min post-dose (p = 0.0055 and p = 0.049 for PID and PR, respectively). Patient recruitment was stopped early, due to positive interim analysis results (significant at prespecified level, p ≤ 0.0414). Overall, sublingual fentanyl ODT was well-tolerated both systemically and sublingually, with 41 patients experiencing ≥1 study drug-related adverse event (AE). The most common AEs included nausea (12.2%), vomiting (5.3%) and somnolence (4.6%). One serious AE (mild affect lability) was considered possibly related to study medication. The observed pattern of AEs was consistent with that previously observed with fentanyl. Conclusions: Sublingual fentanyl ODT was efficacious and well-tolerated for the treatment of BTcP in opioid-tolerant patients with cancer. Sublingual fentanyl ODT provided significant improvements in pain intensity compared to placebo, from 10 min post-administration and throughout the 60-min post-dose assessment period. Sublingual fentanyl ODT was well tolerated over 12 months of treatment.

Polyanalgesic Consensus Conference 2012: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel: INTRATHECAL THERAPY CONSENSUS

Introduction:  The use of intrathecal (IT) infusion of analgesic medications to treat patients with chronic refractory pain has increased since its inception in the 1980s, and the need for clinical research in IT therapy is ongoing. The Polyanalgesic Consensus Conference (PACC) panel of experts convened in 2000, 2003, and 2007 to make recommendations on the rational use of IT analgesics based on preclinical and clinical literature and clinical experiences.

A 12-week, randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain

ABSTRACT Objective: Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER†) in opioid-naive patients with moderate to severe chronic low back pain (CLBP). Design and methods: Patients ≥ 18 years of age were titrated with oxymorphone ER (5- to 10‑mg increments every 12 h, every 3–7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12 h for 12 weeks. Oxymorphone immediate release was available every 4–6 h, as needed, for the first 4 days and twice daily thereafter. Results: Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4 mm at screening to 22.7 mm ( p < 0.0001). After randomization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER ( p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 ± 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 ± 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group. Conclusions: Stabilized doses of oxymorphone ER were generally safe and effective over a 12‑week double-blind treatment period in opioid-naive patients with CLBP.