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.

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.

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.

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.

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.

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.

The Effect of a Novel form of Extended-Release Gabapentin on Pain and Sleep in Fibromyalgia Subjects: An Open-Label Pilot Study.

INTRODUCTION: We assessed the efficacy and safety of extended-release gabapentin in a 15-week, open-label, single-arm, single-center study in patients with fibromyalgia (FM). METHODS: Subjects with documented diagnosis of FM were allowed to participate in the study. We opened enrollment to those who have tried and failed gabapentinoids such as gabapentin or pregabalin due to side effects. Subjects with autoimmune conditions, and or taking opioids for management of their FM pain, were excluded from the study. Subjects were given an extended-release gabapentin starter pack and treated for total of 12 weeks. The primary study endpoint of pain relief was measured using Numeric Pain Rating System (NPRS) scores, and secondary study endpoints were measured with Fibromyalgia Impact Questionnaire (FIQ), Patient's Global Impression of Change (PGIC), and Medical Outcome Sleep questionnaires (MOS). RESULTS: A total of 34 subjects were enrolled and 29 subjects completed the starter pack (85%). Patients reported significant pain relief on NPRS by end of 4 weeks (P < 0.0001) on NPRS. Subjects also reported similar magnitude of improvements in FM and its impact on daily life by end of 4 weeks on FIQ (P < 0.0001). Survey of MOS showed our subjects reporting improved sleep quantity (on average, 1.2 hours over baseline) with gradual and statistically significant improvement in quality. Improvements in primary and secondary measurements were reflected in PGIC, with significant improvement in patient's impression of FM by week 8. LIMITATIONS: Small sample size, geographical bias, relatively short duration of treatment, and single-arm study without control group. CONCLUSIONS: Extended-release gabapentin relieved FM pain symptoms and improved quality-of-life for the FM subjects studied. Subjects reported improvements in both quantity and quality of sleep.

Intrathecal Clonidine via Lumbar Puncture Decreases Blood Pressure in Patients With Poorly Controlled Hypertension.

OBJECTIVES: Oral clonidine is used to treat hypertension but often produces sedation and severe dry mouth; intrathecal clonidine is used to treat chronic pain but may produce hypotension. This clinical feasibility study was conducted to determine if intrathecal clonidine decreases blood pressure in patients with poorly controlled hypertension. MATERIALS AND METHODS: This prospective, single-arm, open-label study was conducted in ten subjects who were taking at least three antihypertensive medications including a diuretic and had an in-office systolic blood pressure between 140 and 190 mm Hg. On the day of treatment, blood pressure was measured before and after a single lumbar intrathecal dose (150 mcg) of clonidine using an automatic oscillometric device every 10-15 min for four hours. Student's paired t-test was used for statistical comparisons. RESULTS: Maximal reductions in systolic and diastolic blood pressures averaging 63 ± 20/29 ± 13 mm Hg were observed approximately two hours after clonidine administration. Decreases in systolic pressure were strongly correlated with baseline systolic pressure. Clonidine produced a significant decrease in heart rate of 11 ± 7 beats/min. No subject required intravenous fluids or vasopressor rescue therapy, or reported spinal headache. CONCLUSIONS: This is the first clinical study in subjects with hypertension that demonstrates significant and profound acute reductions in blood pressure after a single dose of intrathecal clonidine. Future placebo-controlled, dose-escalating studies are warranted to assess the long-term effects of intrathecal clonidine infusion via an implantable drug pump in patients with treatment-resistant hypertension at risk of stroke or myocardial infarction.

Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study.

OBJECTIVE: A single-agent, extended-release formulation of hydrocodone (HC) has been developed for treatment of chronic moderate-to-severe pain. This study was designed to examine the safety and efficacy of HC extended release in opioid-experienced adults with moderate-to-severe chronic low back pain (CLBP). METHODS: This multicenter, enriched enrollment, randomized withdrawal study comprised an open-label conversion/titration phase (≤6 weeks) followed by placebo-controlled, double-blind treatment (12 weeks). During the conversion/titration phase, subjects (N = 510) converted from their current opioid and were titrated to a stabilized dose of HC extended release (20-100 mg every 12 hours). During treatment, subjects (N = 151 per group) received HC extended release or placebo; rescue medication was permitted. The primary efficacy end point was mean change in average pain intensity from baseline to day 85. Response rates (30% pain improvement) and satisfaction (Subject Global Assessment of Medication) were assessed. RESULTS: Demographic and baseline characteristics were similar between groups. Mean ± SD change in average pain intensity score from baseline to day 85 was significantly lower in the HC extended-release treatment group vs placebo (0.48 ± 1.56 vs 0.96 ± 1.55; P = 0.008). Significantly more responders were in the treatment group (68% vs 31%; P < 0.001). Mean Subject Global Assessment of Medication scores increased significantly (0.8 ± 1.3 vs 0.0 ± 1.4; P < 0.0001), indicating greater satisfaction with HC extended release. The adverse event profile was consistent with other opioids. CONCLUSIONS: Extended-release HC is well tolerated and effective, without acetaminophen-associated risks of liver toxicity, for treatment of CLBP.

Treatment of post-amputation pain with peripheral nerve stimulation.

BACKGROUND: Present treatment methods are often unsatisfactory in reducing post-amputation pain. Peripheral nerve stimulation (PNS) could reduce the pain, but it is rarely used because present methods require invasive surgical access and precise placement of the leads in close proximity (≤ 2 mm) with the nerve. METHODS: The present study investigated the feasibility of delivering PNS to patients with moderate-to-severe post-amputation pain in the lower extremity using a fine-wire lead placed percutaneously under ultrasound guidance a remote distance (0.5-3.0 cm) away from the sciatic and/or femoral nerves. RESULTS: Fourteen of the 16 subjects who completed in-clinic testing responded to stimulation, reported ≥ 75% paresthesia coverage, obtained clinically significant pain relief, and proceeded to a two-week home trial with a percutaneous PNS system. Two of the 14 responders had their leads removed early because of accidental dislodgement (N = 2), two had temporary discomfort near the lead (N = 2), and one had return of post-amputation pain despite stimulation (N = 1) and did not complete the home trial. The nine responders who completed the home trial reported reductions in their mean daily worst post-amputation pain (56 ± 26%, 56 ± 26%, N = 9), average residual limb pain (72 ± 28%, 42 ± 27%, N = 7), average phantom limb pain (81 ± 28%, 47 ± 48%, N = 7), residual limb pain interference (81 ± 27%, 53 ± 17%, N = 6), phantom limb pain interference (83 ± 31%, 56 ± 46%, N = 7), and Pain Disability Index (70 ± 38%, 55 ± 32%, N = 9) during the second week of stimulation and four weeks after the end of stimulation, respectively. All nine responders rated their change in quality of life as improved at the end of stimulation and at the end of the four-week follow-up period. Subjects reported minor decreases in the Beck Depression Inventory scores (43 ± 51%, 32 ± 57%, N = 9). Most subjects had no substantial changes other than minor decreases (N = 3) in pain medication. CONCLUSION: Achievement of significant pain relief and improvements in quality of life with a minimally invasive method of PNS holds promise for providing relief of post-amputation pain.

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).

The delayed appearance of neurological signs in intrathecal granuloma warrants imaging surveillance: a case series and review of the literature.

Intrathecal pump therapy (ITP) has become a mainstay of treatment for the chronic, refractory nonmalignant pain patient. Increasingly, ITP therapy is being instituted for the failed back pain population. Inflammatory mass or granuloma is a complication that is considered "rare" or "uncommon." In this patient population, the symptoms of granuloma can often mimic the symptoms for which the patient is being treated. The case series reported here illustrates 4 cases of inflammatory mass. One patient presented with paralysis before she was diagnosed, and the remainder of the patients were asymptomatic at the time of diagnosis. The cases presented illustrate the need for broader education of inflammatory mass among nonpain specialists. Etiology, diagnosis and treatment guidelines of inflammatory mass are reviewed. The literature reviewed highlights the number of patients who present with paralysis as well as the need for regular screening of ITP patients.

Successful dose finding with sublingual fentanyl tablet: combined results from 2 open-label titration studies.

OBJECTIVE: This analysis was conducted to determine the likelihood of identifying an effective dose of fentanyl sublingual tablet during the initial titration phase of 2 clinical trials, to characterize the actual effective dose in patients achieving successful titration, and to examine the relationship between baseline characteristics and likelihood of achieving an effective dose. METHODS: Data were derived from 2 clinical trials (Study 1, n=131; Study 2, n=139) of fentanyl sublingual tablet in patients with cancer-associated breakthrough pain (BTP). Both trials comprised a 2-week titration phase and 12-month maintenance phase. The initial dose was 100 µg, titrated to an effective dose (producing effective relief of all BTP episodes on 2 consecutive days) of 100 to 800 µg. RESULTS: A total of 270 patients entered the titration phase. Mean (SD) baseline BTP opioid dose was 25.7 (88.9) mg morphine equivalent, and mean baseline around-the-clock opioid dose was 196.5 (151.6) mg morphine equivalent. Using conservative criteria for determining effective dose, 174 patients (64.4%) were successfully titrated to an effective dose (mean [SD], 498.2 [234.8] µg). The most frequent (27.6%) effective dose was 800 µg, and more than 85% of patients required an effective dose ≥300 µg. There were no significant relationships between any baseline characteristics and titration success. CONCLUSION: Despite stringent criteria, 64.4% of patients achieved an effective dose of fentanyl sublingual tablet within the dose range of 100 to 800 µg. Baseline characteristics were not identified to be associated with the likelihood of successful titration or with the actual effective dose of fentanyl sublingual tablet.

Peripheral nerve stimulation for the treatment of postamputation pain--a case report.

Many amputees suffer from postamputation pain, which can be extremely debilitating, decrease quality of life, increase the risk of depression, and negatively affect interpersonal relationships and the ability to work. Present methods of treatment, including medications, are often unsatisfactory in reducing postamputation pain. Electrical stimulation of the nerve innervating the painful area could reduce the pain, but peripheral nerve stimulation is rarely used to treat postamputation pain because present methods require invasive surgical access and precise placement of the leads in close proximity (≤ 2 mm) with the nerve. The present study investigated a novel approach to peripheral nerve stimulation in which a lead was placed percutaneously a remote distance (> 1 cm) away from the femoral nerve in a patient with severe residual limb pain (RLP) 33 years following a below-knee amputation. Electrical stimulation generated ≥ 75% paresthesia coverage, reduced RLP by > 60%, and improved quality of life outcomes as measured by the pain interference scale of the Brief Pain Inventory-Short Form (100% reduction in pain interference), Pain Disability Index (74% reduction in disability), and the Patient Global Impression of Change (very much improved) during a 2-week home trial. There were no adverse events. The ability to generate significant paresthesia coverage and pain relief with a single lead inserted percutaneously and remotely from the target nerve holds promise for providing relief of postamputation pain.

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.

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.

What is the case for prescribing long-acting opioids over short-acting opioids for patients with chronic pain? A critical review.

INTRODUCTION: Effective pain management requires appropriate patient assessment, ongoing reassessment, and an understanding of the options available for the treatment of patients with chronic pain. Opioids have long been an important option in the management of moderate to severe chronic pain, but optimal use requires understanding the variety of choices currently available. METHODS: Literature search was carried out using PubMed. Search terms included "steady state," "pharmacokinetics," "pharmacodynamics," "chronic non-cancer pain," "sustained release opioid," "extended release opioid," "controlled release opioid," "morphine," "oxymorphone," "hydromorphone," "oxycodone," and "fentanyl." RESULTS: This search found 12 chronic pain studies that compared short- and long-acting opioids head-to-head. These were supplemented with representative studies from the chronic pain literature. DISCUSSION: The objective of this article is to review clinical data for the use of long-acting and short-acting opioids in a variety of chronic noncancer pain conditions. Although some patients with chronic pain appear to prefer short-acting opioids, many patients receiving long-acting opioid formulations show improved treatment responses and better perception of quality of life. In addition, the sustained reductions in pain seen with long-acting opioid formulations may promote patients' focus on daily activities rather than on their pain, thereby improving therapy adherence and reducing pain-related anxieties. CONCLUSION: Long-term clinical trials of these formulations are needed to allow clinicians to make informed decisions about which patient groups might benefit most from these formulations.