Long-term safety of spinal cord stimulation systems in a prospective, global registry of patients with chronic pain.

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration: NCT01719055 (ClinicalTrials.gov).

Atypical opioids and their effect on respiratory drive.

Opioids are an important tool in the treatment of pain, but opioid overdose has become a serious health issue. Most opioid-related deaths are caused by respiratory depression, and the risk of respiratory depression is compounded because of the risks of abuse and diversion, which makes the need for safer opioids even more urgent. However, the atypical opioids (buprenorphine, tramadol, and tapentadol), with mechanisms of action not purely driven by µ-opioid receptor agonism, may be safer than conventional opioids, eg, morphine, oxycodone, and fentanyl. The purpose of this narrative review is to describe the clinical and experimental evidence regarding opioid-induced respiratory depression in the context of the mechanisms of action of the atypical opioids. Among the atypical opioids, tramadol has an advantage of being a Schedule IV drug, and thus having a relatively low abuse potential-but its effects, including its effect on respiratory drive, are dependent on cytochrome P450 2D6 metabolizer status. Tapentadol appears to affect respiratory drive, but this has not been well investigated. Buprenorphine is a Schedule III drug, thus having less abuse potential than the majority of opioids. Experimentally, a ceiling effect on the respiratory depression has been reported with intravenous buprenorphine. In addition, experimental hypercapnic stress in healthy volunteers demonstrated no respiratory depression following the administration of a single dose of the buccal film formulation of buprenorphine when compared with placebo. Overall, the data suggest that atypical opioids may be a safer option than conventional opioids for the treatment of pain.

The Use of Contrast Agents in Interventional Pain Procedures: A Multispecialty and Multisociety Practice Advisory on Nephrogenic Systemic Fibrosis, Gadolinium Deposition in the Brain, Encephalopathy After Unintentional Intrathecal Gadolinium Injection, and Hypersensitivity Reactions.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

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.

Safety and tolerability of ALO-02 (oxycodone hydrochloride and sequestered naltrexone hydrochloride) extended-release capsules in older patients: a pooled analysis of two clinical trials.

Objective: To assess the impact of age on the safety and tolerability of ALO-02, an abuse-deterrent opioid formulation consisting of oxycodone hydrochloride and sequestered naltrexone hydrochloride, in patients with chronic pain.Methods: Data from two clinical studies in patients with chronic low back pain or chronic non-cancer pain were analyzed. Patients aged ≥18 years who required continuous around-the-clock opioid analgesia for an extended period were grouped into ≥65 years and <65 years age groups. Treatment-emergent adverse events (TEAEs), use of concomitant medications, clinical laboratory measurements, and occurrences of opioid withdrawal using reported adverse events (AEs) and Clinical Opiate Withdrawal Scale (COWS) scores assessed safety. Data pooling was employed for the titration and maintenance phases of both studies.Results: Respectively 805 and 436 patients received ≥1 dose of ALO-02 in the titration and maintenance phases; 121 (15.0%) and 83 (14.6%) patients, respectively, were aged ≥65 years in the titration and maintenance phases. Average doses of ALO-02 were lower in the older patients in both phases. Incidences of TEAEs were comparable between age groups in both phases and generally lower in the maintenance phase. Concomitant medications were taken more often by patients aged ≥65 years. Incidences of potentially clinically significant laboratory results were low in both phases with no clinically important differences between age groups. There were few reports of opioid withdrawal events as assessed by reported AEs and COWS scores. One patient aged ≥65 years experienced an AE of opioid withdrawal.Conclusions: The safety and tolerability of ALO-02 is similar in those aged ≥65 years and those aged <65 years with chronic pain.ClinicalTrials.gov identifiers: NCT01571362, NCT01428583.

Effects of naltrexone exposure observed in two phase three studies with ALO-02, an extended-release oxycodone surrounding sequestered naltrexone.

OBJECTIVE: To evaluate the clinical effects of naltrexone following ALO-02 administration. DESIGN: Two phase three studies: an open-label, single-arm safety study, and a double-blind, placebo-controlled, randomized withdrawal, efficacy study (ClinicalTrials.gov identifiers: NCT01428583, NCT01571362). SETTING: Seventy US research centers. PATIENTS: Eight hundred and five patients with moderate-to-severe chronic noncancer pain (n = 395) or moderate-to-severe chronic low back pain (n = 410). INTERVENTIONS: Oral ALO-02 capsules (daily dose 20-160 mg oxycodone): openlabel titration followed by double-blind fixed dose ALO-02 or placebo (12 weeks) for the efficacy study; and open-label administration (≤12 months) for the safety study. MAIN OUTCOME MEASURES: Brief Pain Inventory-Short Form (BPI-sf), withdrawal-related adverse events, Clinical Opiate Withdrawal Scale (COWS), and naltrexone plasma concentrations. RESULTS: ALO-02 was received for = 30 days by 592 patients (73.5 percent), = 90 days by 348 patients (43.2 percent), and ≤361 days by 105 patients (13.0 percent). Maximum COWS scores were below the cutoff for mild withdrawal for the majority of patients: 86.6 percent of patients in the safety study, and for the efficacy study, 96.8 percent during titration and 95.0 percent during double-blind treatment. The frequency of quantifiable naltrexone plasma concentrations was similar between studies (18-23 percent of samples), and the levels were low, generally not exceeding 200 pg/mL. There was no apparent relationship between naltrexone plasma concentrations and COWS scores (total or change from baseline), or change from baseline in BPI-sf scores in the efficacy (R2 = 0.0184, 0.0224, and 0.0173, respectively) or safety studies (R2 = 0.0010, 0.0000, and 0.0122, respectively). CONCLUSIONS: Naltrexone plasma concentrations were low, not correlated with COWS or BPI-sf scores, and considered clinically insignificant.

Percutaneous 60-day peripheral nerve stimulation implant provides sustained relief of chronic pain following amputation: 12-month follow-up of a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Peripheral nerve stimulation (PNS) has historically been used to treat chronic pain, but generally requires implantation of a permanent system for sustained relief. A recent study found that a 60-day PNS treatment decreases post-amputation pain, and the current work investigates longer-term outcomes out to 12 months in the same cohort. METHODS: As previously reported, 28 traumatic lower extremity amputees with residual and/or phantom limb pain were randomized to receive 8 weeks of PNS (group 1) or 4 weeks of placebo followed by a crossover 4 weeks of PNS (group 2). Percutaneous leads were implanted under ultrasound guidance targeting the femoral and sciatic nerves. During follow-up, changes in average pain and pain interference were assessed using the Brief Pain Inventory-Short Form and comparing with baseline. RESULTS: Significantly more participants in group 1 reported ≥50% reductions in average weekly pain at 12 months (67%, 6/9) compared with group 2 at the end of the placebo period (0%, 0/14, p=0.001). Similarly, 56% (5/9) of participants in group 1 reported ≥50% reductions in pain interference at 12 months, compared with 2/13 (15%, p=0.074) in group 2 at crossover. Reductions in depression were also statistically significantly greater at 12 months in group 1 compared with group 2 at crossover. CONCLUSIONS: This work suggests that percutaneous PNS delivered over a 60-day period may provide significant carry-over effects including pain relief, potentially avoiding the need for a permanently implanted system while enabling improved function in patients with chronic pain. TRIAL REGISTRATION NUMBER: NCT01996254.

Unique aspects of clinical trials of invasive therapies for chronic pain.

Nearly all who review the literature conclude that the role of invasive procedures to treat chronic pain is poorly characterized because of the lack of "definitive" studies. The overt nature of invasive treatments, along with the risks, technical skills, and costs involved create challenges to study them. However, these challenges do not completely preclude evaluating invasive procedure effectiveness and safety using well-designed methods. This article reviews the challenges of studying outcomes of invasive therapies to treat pain and discuss possible solutions. Although the following discussion can apply to most invasive therapies to treat chronic pain, it is beyond the scope of the article to individually cover every invasive therapy used. Therefore, most of the examples focus on injection therapies to treat spine pain, spinal cord stimulation, and intrathecal drug therapies.

Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Pain Following Amputation.

INTRODUCTION: Chronic pain and reduced function are significant problems for Military Service members and Veterans following amputation. Peripheral nerve stimulation (PNS) is a promising therapy, but PNS systems have traditionally been limited by invasiveness and complications. Recently, a novel percutaneous PNS system was developed to reduce the risk of complications and enable delivery of stimulation without surgery. MATERIALS AND METHODS: Percutaneous PNS was evaluated to determine if stimulation provides relief from residual and phantom limb pain following lower-extremity amputation. PNS leads were implanted percutaneously to deliver stimulation to the femoral and/or sciatic nerves. Patients received stimulation for up to 60 days followed by withdrawal of the leads. RESULTS: A review of recent studies and clinical reports found that a majority of patients (18/24, 75%) reported substantial (≥50%) clinically relevant relief of chronic post-amputation pain following up to 60 days of percutaneous PNS. Reductions in pain were frequently associated with reductions in disability and pain interference. CONCLUSIONS: Percutaneous PNS can durably reduce pain, thereby enabling improvements in quality of life, function, and rehabilitation in individuals with residual or phantom limb pain following amputation. Percutaneous PNS may have additional benefit for Military Service members and Veterans with post-surgical or post-traumatic pain.

Safety of oral methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain.

PURPOSE: Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study. METHODS: Adults (n=803) with chronic noncancer pain for ≥2 months and confirmed OIC while receiving opioid doses ≥50 mg morphine equivalent per day for ≥14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores. RESULTS: TEAEs occurred at a similar incidence in the methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than methylnaltrexone 450 mg (6.20% vs 4.27% of study days, P=0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal. CONCLUSION: Oral methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal.

Mitigation of IV Abuse Through the Use of Abuse-Deterrent Opioid Formulations: An Overview of Current Technologies.

Providers who treat patients with chronic pain face a dual challenge: providing adequate access to opioid therapies for appropriate pain management while adopting strategies to minimize the risk for abuse. Commonly prescribed opioids have substantial abuse potential when administered intravenously, and extended-release (ER)/long-acting (LA) opioids may be targeted for IV abuse because of the higher per-dose medication level. The consequences of IV opioid abuse are severe and increase the risks for adverse outcomes, including mortality due to acute health events, serious infections, and deep vein thrombosis, to name a few. To reduce the potential for abuse of prescription opioids by both recreational and experienced drug abusers, abuse-deterrent formulations (ADFs) of opioid medications employ either physical/chemical barriers or agonist-antagonist combinations. Here we review the development and use of opioid ADFs as a harm-reduction strategy, and their potential for mitigating IV opioid abuse. The approved ER/LA opioids with ADF labeling in the United States include formulations of oxycodone, hydrocodone, and morphine. Findings from in vitro laboratory tests of abuse deterrence for opioid ADFs are described herein, as are data from human abuse potential studies for IV abuse of those ADF products, for which such studies are feasible (ie, abuse-deterrent agonist-antagonist formulations). The available ADF opioids may decrease both the attractiveness and the feasibility of IV abuse. The adoption of ADF opioids represents one tactic for providing access to needed medication for patients with chronic pain, while potentially reducing the risk for opioid abuse, in a comprehensive effort to combat the opioid epidemic.

Pharmacokinetics of Fentanyl Sublingual Spray in Opioid-Naïve Participants: Results of a Phase 1, Multiple Ascending Dose Study.

BACKGROUND AND OBJECTIVES: Fentanyl sublingual spray may be a viable alternative to intravenous (IV) opioids for the treatment of acute pain. As patients with acute pain may include those who have limited prior exposure to opioids, this phase 1, open-label, randomized, multiple ascending-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple doses of fentanyl sublingual spray in opioid-naïve participants. This article primarily reports the pharmacokinetics results. METHODS: Study drugs were administered in four dosing cohorts: every 0.5, 1, 2, or 4 h for a maximum of three doses per cohort. Eight fasted individuals per cohort were randomized to either fentanyl sublingual spray (100, 200, or 400 µg) or fentanyl citrate IV 50 µg (6:2 ratio). Blood samples were collected pre-dose through 24 h post first dose. RESULTS: A total of 98 healthy adults were enrolled and 96 completed the study. Mean plasma fentanyl concentrations increased with increasing doses of fentanyl sublingual spray administered every 0.5-4 h. With multiple doses, systemic exposure increased relative to the first dose; shorter dosing intervals resulted in higher concentrations. Analysis of dose proportionality suggested that systemic exposure increased in a linear but slightly greater than dose-proportional manner. Accumulation between the first and last doses of fentanyl sublingual spray was more pronounced with shorter dosing intervals. CONCLUSION: Dose-dependent fentanyl pharmacokinetics following multiple doses of fentanyl sublingual spray were well characterized in an opioid-naïve population. CLINICALTRIALS. GOV IDENTIFIER: NCT02641340.

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.

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a multiple ascending dose study in opioid-naïve healthy volunteers.

OBJECTIVE: Fentanyl sublingual spray, with its rapid onset for pain relief, may be efficacious in the management of acute or post-operative pain. Because patients in these settings may be opioid-naïve, the study was conducted to determine the safety, tolerability, and pharmacokinetics of multiple dose administration of fentanyl sublingual spray in an opioid-naïve population. METHODS: Fentanyl sublingual spray (100 mcg, 200 mcg, and 400 mcg) and fentanyl citrate intravenous (IV; 50 mcg) were administered every 0.5, 1.0, 2.0, and 4.0 h for up to three doses per cohort in opioid-naïve subjects (ClinicalTrials.gov identifier: NCT02641340). Eight subjects in each cohort were randomly assigned (six subjects received fentanyl sublingual spray; two subjects received fentanyl citrate IV). Pharmacokinetic and safety-related pharmacodynamic assessments were performed through 24 h post-first dose. Safety assessments were collected through Day 7. RESULTS: Ninety-six opioid-naïve subjects, aged 20-55 years, with a body mass index of 18.7-31.5 kg/m2, participated in the study. Multiple doses of fentanyl sublingual spray (100, 200, and 400 mcg) were generally well tolerated. Hypoxia, observed in the 200-mcg and 400-mcg dose groups, increased with increasing doses and higher dosing frequency, but was readily managed by nasal cannula oxygenation. Overall, nausea increased with increasing doses, and ∼52.6% (10 out of 19) cases of nausea that occurred at the highest dose of 400 mcg were treated with concomitant medication. Overall, the reported adverse events were consistent with the known safety profile of fentanyl. CONCLUSION: Fentanyl sublingual spray (100 mcg, 200 mg, and 400 mcg) administered every 0.5, 1, 2, and 4 h was generally well tolerated in an opioid-naïve population. The results suggest that doses of 200 mcg or lower may be safe for use in an opioid-naïve population.

Totally Implantable IV Treprostinil Therapy in Pulmonary Hypertension Assessment of the Implantation Procedure.

BACKGROUND: Prostacyclins improve symptoms and survival in pulmonary arterial hypertension (PAH). In response to risks associated with external delivery systems, an implantable IV infusion system was developed. A multicenter, prospective, single-arm, clinical trial (DelIVery for PAH) was conducted to evaluate this system for treprostinil in PAH. This analysis describes the findings related to the implant procedure. METHODS: Patients (N = 64) with PAH (World Health Organization group 1) receiving stable IV treprostinil were enrolled. Patients were transitioned to a temporary peripheral IV infusion catheter prior to the procedure. System implantation was performed at 10 centers under general anesthesia or deep IV sedation by clinicians from various specialties. Central venous access was via the cephalic, subclavian, jugular, or axillary vein. Using an introducer and fluoroscopic guidance, the distal tip of the infusion catheter was placed at the superior caval-atrial junction. The catheter was tunneled from the venous access site to an abdominal subcutaneous pocket, where the pump was placed. RESULTS: Of the 64 patients enrolled, four exited prior to implantation. All 60 implant procedures were successful. At baseline, all patients were receiving treprostinil via an external pump at a mean dose of 71.4 ± 27.8 ng/kg/min (range: 22-142 ng/kg/min). The implant averaged 102 ± 32 min (range: 47-184 min). Clinically significant implant procedure-related complications included one pneumothorax, two infections, and one episode of atrial fibrillation. There were three postimplantation catheter dislocations in two patients. Common implant-related events that were not complications included implant site pain (83%) and bruising (17%). CONCLUSIONS: The procedure for inserting a fully implantable system for treprostinil was successfully performed, with few complications. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.

Lubiprostone for Opioid-Induced Constipation Does Not Interfere with Opioid Analgesia in Patients with Chronic Noncancer Pain.

OBJECTIVE: To determine whether lubiprostone 24 µg twice daily (BID), administered to relieve opioid-induced constipation (OIC), affects opioid analgesia in patients with chronic noncancer pain. METHODS: Data were pooled from 3 randomized, double-blind, placebo-controlled trials of lubiprostone in adults with chronic noncancer pain receiving stable opioid analgesia and who had documented OIC. In each study, lubiprostone 24 µg BID or placebo was administered for 12 weeks for relief of OIC using a common protocol. The Brief Pain Inventory short form (BPI-SF) was administered, and opioid use (expressed as morphine-equivalent daily dose [MEDD]) was recorded at baseline and months 1, 2, and 3. The BPI-SF provided patient scores for pain severity, the worst pain experienced in the past 24 hours, and pain interference with daily life. RESULTS: The pooled patient population (N = 1300) was predominately female (62.5%) and white (82.1%), with a mean age of 50.5 years. The MEDD was 97.5 mg (range, 5 to 3656 mg) in patients receiving placebo and 112.5 mg (range, 4 to 7605 mg) in patients treated with lubiprostone. Lubiprostone 24 µg BID treatment did not appear to affect opioid use or pain scores; changes from baseline were not significantly different with placebo vs. lubiprostone 24 µg BID at months 1, 2, and 3 for MEDD (P ≥ 0.435) and for BPI-SF scores for pain interference, pain severity, and worst pain (P ≥ 0.402). DISCUSSION: Lubiprostone 24 µg BID administered for relief of OIC in patients with chronic noncancer pain does not interfere with opioid analgesia.

Opioid-Induced Constipation Survey in Patients with Chronic Noncancer Pain.

Chronic pain patients relying on chronic opioid therapy are often challenged with opioid-induced constipation (OIC), a difficult condition to treat that has a significant psychosocial impact on those who are affected (Bruner et al., J Pain Res, 8, 2015, 289). Unlike other side effects of opioids, OIC does not resolve over time during chronic opioid use, and treatments used for functional constipation often fail to provide adequate symptom relief (Nelson and Camilleri, Therap Adv Gastroenterol, 8, 2015, 206). Estimates of the prevalence of OIC vary. It has been reported that 15% to 90% of opioid users are affected by OIC (Gaertner et al., J Clin Gastroenterol, 49, 2015, 9; Wan et al., Am Health Drug Benefits, 8, 2015, 93; Coyne et al., Clinicoecon Outcomes Res, 6, 2014, 269). In addition, a recent rise in opioid prescriptions by nonpain specialists has contributed to the increase in opioid-related side effects, such as OIC (Nelson and Camilleri, Therap Adv Gastroenterol, 8, 2015, 206; Tuteja et al., Neurogastroenterol Motil, 22, 2010, 424). We conducted a survey on OIC through PainPathways magazine in fall of 2014 and in spring of 2015. Survey results showed the prevalence of depression and the modification of opioid dosage were higher than previously thought. Additionally, we found that discussions with healthcare workers regarding OIC do not take place regularly. Our results re-emphasize the need for a consensus on OIC-specific diagnostic criteria, evidence-based treatment strategies, outcome metrics, and education about OIC for both prescribers and patients to improve clinical outcome as well as patient satisfaction.

Past, Present, and Future of Informed Consent in Pain and Genomics Research: Challenges Facing Global Medical Community.

In recent decades, there has been a revision of the role of institutional review boards with the intention of protecting human subjects from harm and exploitation in research. Informed consent aims to protect the subject by explaining all of the benefits and risks associated with a specific research project. To date, there has not been a review published analyzing issues of informed consent in research in the field of genetic/Omics in subjects with chronic pain, and the current review aims to fill that gap in the ethical aspects of such investigation. Despite the extensive discussion on ethical challenges unique to the field of genetic/Omics, this is the first attempt at addressing ethical challenges regarding Informed Consent Forms for pain research as the primary focus. We see this contribution as an important one, for while ethical issues are too often ignored in pain research in general, the numerous arising ethical issues that are unique to pain genetic/Omics suggest that researchers in the field need to pay even greater attention to the rights of subjects/patients. This article presents the work of the Ethic Committee of the Pain-Omics Group (www.painomics.eu), a consortium of 11 centers that is running the Pain-Omics project funded by the European Community in the 7th Framework Program theme (HEALTH.2013.2.2.1-5-Understanding and controlling pain). The Ethic Committee is composed of 1 member of each group of the consortium as well as key opinion leaders in the field of ethics and pain more generally.

Fentanyl sublingual spray for breakthrough cancer pain in patients receiving transdermal fentanyl.

AIM: To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). METHODS: Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 µg). RESULTS: Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse event included nausea (9%) and peripheral edema (9%). CONCLUSION: FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850.