Long-Term Safety and Efficacy of Subcutaneous Methylnaltrexone in Patients with Opioid-Induced Constipation and Chronic Noncancer Pain: A Phase 3, Open-Label Trial.

OBJECTIVE: Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, alleviates opioid-induced constipation. Understanding its long-term safety and efficacy profile in patients with chronic noncancer pain is warranted given the persistence of opioid-induced constipation. METHODS.: In this phase 3, multicenter, open-label trial, adults with chronic noncancer pain (N = 1034) received subcutaneous methylnaltrexone 12 mg once daily for 48 weeks. RESULTS: The most common adverse events were gastrointestinal related (e.g., abdominal pain, diarrhea, nausea) and were mild to moderate in intensity. Only 15.2% of patients discontinued because of an adverse event. Serious cardiac-related adverse events occurred in nine patients. Of the seven instances of major adverse coronary events reported, three were adjudicated after external review; all instances occurred in patients with cardiovascular risk factors. Methylnaltrexone elicited a bowel movement within four hours in 34.1% of the injections throughout the 48-week treatment period. CONCLUSIONS: Change from baseline in mean weekly bowel movement rate, Bowel Movement Straining Scale score, Bristol Stool Scale score, and mean percentage of patients with complete evacuation from baseline to week 48 were significantly improved ( P < 0.001 for all). Long-term subcutaneous methylnaltrexone was well tolerated, with no new safety concerns, and provided consistent opioid-induced constipation relief in patients with chronic noncancer pain.

Injury and Liability Associated with Implantable Devices for Chronic Pain.

BACKGROUND: Due to an increase in implantable device-related anesthesia pain medicine claims, the authors investigated anesthesia liability associated with these devices. METHODS: After institutional review board approval, the authors identified 148 pain medicine device claims from 1990 or later in the Anesthesia Closed Claims Project Database. Device-related damaging events included medication administration events, infections, hematomas, retained catheter fragments, cerebrospinal fluid leaks, cord or cauda equina trauma, device placed at wrong level, stimulator incorrectly programmed, delay in recognition of granuloma formation, and other issues. RESULTS: The most common devices were implantable drug delivery systems (IDDS; 64%) and spinal cord stimulators (29%). Device-related care consisted of surgical device procedures (n = 107) and IDDS maintenance (n = 41). Severity of injury was greater in IDDS maintenance claims (56% death or severe permanent injury) than in surgical device procedures (26%, P < 0.001). Death and brain damage in IDDS maintenance claims resulted from medication administration errors (n = 13; 32%); spinal cord injury resulted from delayed recognition of granuloma formation (n = 9; 22%). The most common damaging events for surgical device procedures were infections, inadequate pain relief, cord trauma, retained catheter fragments, and subcutaneous hygroma. Care was more commonly assessed as less than appropriate (78%) and payments more common (63%) in IDDS maintenance than in surgical device procedure claims (P < 0.001). CONCLUSIONS: Half of IDDS maintenance claims were associated with death or permanent severe injury, most commonly from medication errors or failure to recognize progressive neurologic deterioration. Practitioners implanting or managing devices for chronic pain should exercise caution in these areas to minimize patient harm.

National Perioperative Outcomes for Intrathecal Pump, Spinal Cord Stimulator, and Peripheral Nerve Stimulator Procedures.

BACKGROUND: There is abundant literature on the long-term complications of intrathecal pumps (ITP), spinal cord stimulators (SCS), and peripheral nerve stimulators (PNS) used in the treatment of chronic pain. There is less information, however, on the perioperative complications of these procedures. OBJECTIVE: Exploration of the perioperative outcomes of implantable pain devices. STUDY DESIGN: Observational study. SETTING: University hospitals, community hospitals, specialty hospitals, attached surgery centers, and freestanding surgery centers METHODS: Data were obtained from the National Anesthesia Clinical Outcomes Registry (NACOR) of the Anesthesia Quality Institute (AQI). Information was collected on patient demographics, procedure information, anesthetic administered, diagnosis linked to the procedure, and perioperative outcomes. RESULTS: The search yielded 12,611 ITP, 19,276 SCS, and 15,184 PNS cases from 2010 to 2014. In this sample, the majority of procedures were performed at community hospitals, not university medical centers. The most common diagnosis cited for an ITP was an implant complication (n = 2,570), followed by spasticity, and non-malignant back pain. For SCS, the most common diagnoses were lower back pain (n = 5,515) or radiculopathy (n = 2,398). For PNS, by far the most common diagnosis related to urinary dysfunction (n = 8,745), with painful bladder syndrome a small minority (n = 133). General anesthetics were more often performed for ITP than for SCS and PNS procedures (60.6% vs. 31.8% and 32.2%, respectively). Hemodynamic instability was a common outcome (13.9% for ITP procedures); other common outcomes for all the procedures included case delays, inadequate pain control, and extended PACU stays. LIMITATIONS: Despite the large sample size in this study, not all medical centers transmit their outcome data to NACOR. Furthermore, some institutions do not report clinical outcomes for every case to NACOR, making the sample size of assessing complications smaller and potentially more biased. Finally, procedures identified in the NACOR database using CPT may be similar but not identical and therefore potentially influence outcomes. CONCLUSIONS: Databases such as NACOR can provide rich information on ITP, SCS, and PNS for physicians performing these procedures. In this sample, ITP procedures, performed on the patients with the most severe cormobidities and often-requiring general anesthesia, were the most likely to be associated with hemodynamic instability, inadequate pain control, and extended PACU stays. Complications relating to the ITP are also the most common reason for an operation. These findings underscore the importance of proper patient selection for ITP and other implantable pain devices, in particular for patients with malignant pain or multiple co-morbidities. To identify the root causes of complications, additional information is needed on the procedure performed (e.g., an implant vs a revision), the surgical technique used, and the device implanted, as well as on specific patient comorbidities. Such information will likely become more available as resources like NACOR expand and as electronic medical record systems and coding become more integrated.

Trends in Pain Medicine Liability.

BACKGROUND: The authors examined changes in the frequency of pain medicine malpractice claims and associated treatment modalities and outcomes over time. METHODS: The authors analyzed trends in pain medicine claims from 1980 to 2012 in the Anesthesia Closed Claims Project database by binary logistic regression on year of event. Pain procedures in claims from 2000 to 2012 were compared with the proportion of pain procedures reported to the National Anesthesia Clinical Outcomes Registry in 2010-2014. RESULTS: Malpractice claims for pain medicine increased from 3% of 2,966 total malpractice claims in the Anesthesia Closed Claims Project database in 1980-1989 to 18% of 2,743 anesthesia claims in 2000-2012 (odds ratio [OR], 1.088 per year; 95% CI, 1.078 to 1.098; P < 0.001). Outcomes in pain claims became more severe over time, with increases in death and permanent disabling injury (OR, 1.094 per year; P < 0.001). Nonneurolytic cervical injections increased to 27% of pain claims in 2000-2012 (OR, 1.054; P < 0.001), whereas National Anesthesia Clinical Outcomes Registry demonstrates that lumbar injections are a more common procedure. Claims associated with medication management increased to 17% of pain claims in 2000-2012 (OR, 1.116 per year; P < 0.001). CONCLUSIONS: Pain medicine claims have increased over time and have increased in severity. Claims related to cervical procedures were out of proportion to the frequency with which they are performed. These liability findings suggest that pain specialists should aggressively continue the search for safer and more effective therapies.

Psychiatric Comorbidity Is Associated Prospectively with Diminished Opioid Analgesia and Increased Opioid Misuse in Patients with Chronic Low Back Pain.

BACKGROUND: Opioids are frequently prescribed for chronic low back pain (CLBP), but there are little prospective data on which patient subgroups may benefit. Psychiatric comorbidity, such as high levels of depression and anxiety symptoms (termed comorbid negative affect [NA]), is a common presentation and may predict diminished opioid analgesia and/or increased opioid misuse. METHODS: The authors conducted a 6½-month prospective cohort study of oral opioid therapy, with an active drug/placebo run-in period, in 81 CLBP patients with low, moderate, and high levels of NA. Treatment included an opioid titration phase with a prescribing physician blinded to NA group assignment and a 4-month continuation phase, during which subjects recorded daily pain levels using an electronic diary. The primary outcome was the percent improvement in average daily pain, summarized weekly. RESULTS: There was an overall 25% dropout rate. Despite the high NA group being prescribed a higher average daily dose of morphine equivalents, linear mixed model analysis revealed that the 24 study completers in each of the high NA and low NA groups had an average 21 versus 39% improvement in pain, respectively (P < 0.01). The high NA group also had a significantly greater rate of opioid misuse (39 vs. 8%, P < 0.05) and significantly more and intense opioid side effects (P < 0.01). CONCLUSIONS: These results indicate that the benefit and risk considerations in CLBP patients with high NA versus low NA are distinctly different. Thus, NA is an important phenotypic variable to characterize at baseline, before deciding whether to prescribe opioids for CLBP.

Pain intensity and interference with functioning and well-being in subgroups of patients with chronic pain treated with once-daily hydrocodone tablets.

BACKGROUND: A previous 52-week trial of patients with chronic noncancer, non-neuropathic pain (CNNP) showed clinically meaningful improvement in pain intensity, pain interference, and physical health-related quality of life (HRQL) following daily treatment with an extended-release, once-daily hydrocodone (Hysingla(®) ER; HYD) bitartrate tablet. OBJECTIVE: To examine treatment response within patient subgroups and to assess between-subgroup differences in effectiveness and side effect profile. METHODS: Data were from an open-label 52-week trial of treatment with HYD tablets (20-120 mg, once-daily) for patients with moderate-to-severe CNNP. Binary subgroups were defined for the following six factors: age, gender, opioid experience, baseline pain severity, history of depression, and stable HYD dose at completion of a 45-day dose-titration period. Univariable and multivariable models examined changes in average pain intensity (API; 11-point numeric rating scale), pain interference (Brief Pain Inventory-Interference subscale [BPI-I]), physical and mental HRQL (36-item Short Form health survey Physical and Mental Component Summaries [PCS and MCS]), and sleep quality (Medical Outcomes Study Sleep Scale Sleep Problems Index [SPI]) from baseline to maintenance, and subgroup differences in adverse events. RESULTS: All subgroups showed clinically meaningful improvements in API, BPII, and PCS scores; no subgroups showed improvements in MCS or SPI. Between subgroup comparisons found greater improvements for opioid-naïve patients and for patients with severe baseline pain. Incidence of adverse events differed minimally between subgroups. CONCLUSION: Regardless of subgroup, patients with CNNP treated with HYD showed clinically meaningful improvements in pain intensity, pain interference, and physical HRQL, although not in mental HRQL or sleep quality. Improvements were generally larger for opioid-naïve patients and patients with severe baseline pain.

Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain.

BACKGROUND: Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla™ ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post-hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23-31% of the study populations). METHODS: Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0-10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. RESULTS: In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double-blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. CONCLUSION: In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD's safety and tolerability profiles were similar to other opioid analgesics.

Medical resource use and costs among pain patients with potential opioid-tolerability issues.

OBJECTIVE: To estimate excess medical resource use and costs associated with prescription opioid (RxO) tolerability issues. DESIGN: This was an observational, retrospective analysis of deidentified administrative claims data. SETTING: The study included commercially insured patients treated in different healthcare settings captured in the Truven MarketScan claims database. PATIENTS: Patients aged 18-64 years initiating treatment with an RxO (index) and continuously treated with pain relievers over a 6-month period were selected. "Switchers" were patients who discontinued their index RxO and switched to non-RxO pain relievers < 30 days post-index, and whose last pain reliever in the 6-month follow-up period was not an RxO. Such switching was considered a proxy for RxO-tolerability issues. "Continuous RxO users" were patients who remained on the index RxO for the follow-up period. Switchers and continuous RxO users were matched 1:1 on propensity score, baseline medical costs, index RxO days supply, and short-/long-acting index RxO. MAIN OUTCOME MEASURES: Six-month follow-up medical resource use and costs were compared between matched switchers and continuous RxO users. RESULTS: A total of 10,704 pairs of switchers and continuous RxO users were matched. In the 6-month follow-up period, switchers had more outpatient (7.5 vs 6.8; p < 0.001) and inpatient (0.05 vs 0.04; p = 0.002) visits and longer inpatient stays (0.26 days vs 0.19; p = 0.006) compared to continuous RxO users. Switchers also had higher total medical costs ($4,522 vs $3,657; p < 0.001). CONCLUSIONS: Switchers incur greater medical resource use and costs than similar patients continuously treated with their index RxO.

Use of prescription opioids with abuse-deterrent technology to address opioid abuse.

OBJECTIVE: The development of new formulations of extended-release (ER) opioids with abuse-deterrent technology attempts to deter prescription opioid abuse while maintaining appropriate access to care for pain patients. This study examined the degree to which some patients may avoid switching to reformulated ER opioids with abuse-deterrent technology and the extent to which those patients are more likely to be abusers. RESEARCH DESIGN AND METHODS: We analyzed Truven MarketScan pharmacy and medical claims data following the introduction of two reformulated ER opioids with abuse-deterrent technology. Adults aged 18-64 who were continuous users of extended-release oxycodone HCl (ER oxycodone) or extended-release oxymorphone HCl (ER oxymorphone) in a 6 month period prior to the introduction of the respective reformulations of those products were identified and categorized based on whether they switched to the reformulation, switched to other ER/long-acting (LA) opioids (without abuse-deterrent technology), or discontinued ER/LA opioid treatment in a 6 month post-reformulation period. Abusers were identified using ICD-9-CM diagnosis codes for opioid abuse/dependence. Pearson's chi-squared tests and Fisher's exact tests were then used to compare rates of abuse between patients who avoided switching to a reformulated ER opioid. Sensitivity analyses examined several definitions used in this analysis. MAIN OUTCOME MEASURES: ER/LA opioid utilization; rates of diagnosed opioid abuse. RESULTS: A total of 31%-50% of patients avoided switching to reformulated ER opioids. Rates of diagnosed opioid abuse were higher among these patients compared to patients who transitioned to the reformulated ER opioids. LIMITATIONS: Due to the observational research design, caution is warranted in causal interpretation of the findings. The study was conducted among commercially insured continuous ER oxycodone or ER oxymorphone users; future research should consider additional patient populations, such as non-continuous users and those without commercial insurance (i.e., Medicare, Medicaid, uninsured). CONCLUSIONS: Some patients switched to other ER/LA opioids without abuse-deterrent technology or discontinued ER/LA opioid treatment when their existing ER treatment was reformulated. Rates of opioid abuse were higher among patients who switched to other ER/LA opioids or discontinued ER/LA opioid treatment, suggesting that abusers may seek more easily abuseable alternatives such as prescription opioids without abuse-deterrent technology.

Medical cost savings associated with an extended-release opioid with abuse-deterrent technology in the US.

OBJECTIVES: In the US, prescription opioids with technology designed to deter abuse have been introduced to deter drug abuse without hindering appropriate access for pain patients. The objective of this study was to estimate changes in medical costs following the introduction of a new formulation of extended-release (ER) oxycodone HCl (oxycodone) with abuse-deterrent technology in the US. METHODS: Health insurance claims data were used to estimate changes in rates of diagnosed opioid abuse among continuous users of extended-release opioids (EROs) following the introduction of reformulated ER oxycodone in August 2010. This study also calculated the excess medical costs of diagnosed opioid abuse using a propensity score matching approach. These findings were integrated with published government reports and literature to extrapolate the findings to the national level. All costs were inflated to 2011 US dollars. RESULTS: The introduction of reformulated ER oxycodone was associated with relative reductions in rates of diagnosed opioid abuse of 22.7% (p < 0.001) and 18.0% (p = 0.034) among commercially-insured and Medicaid patients, respectively. There was no significant change among Medicare-eligible patients. The excess annual per-patient medical costs associated with diagnosed opioid abuse were $9456 (p < 0.001), $10,046 (p < 0.001), and $11,501 (p < 0.001) for commercially-insured, Medicare-eligible, and Medicaid patients, respectively. Overall, reformulated ER oxycodone was associated with annual medical cost savings of ∼$430 million in the US. LIMITATIONS: Because of the observational research design of this study, caution is warranted in any causal interpretation of the findings. Portions of the study relied on prior literature, government reports, and assumptions to extrapolate the national medical cost savings. CONCLUSIONS: This study provides evidence that reformulated ER oxycodone has been associated with reductions in abuse rates and substantial medical cost savings. Payers and policy-makers should consider these benefits as they devise and implement new guidelines and policies in this therapeutic area.

The subjective psychoactive effects of oral dronabinol studied in a randomized, controlled crossover clinical trial for pain.

BACKGROUND: Many cannabinoid medications are approved in North America or in phase III trials, such as dronabinol, nabilone, or nabiximols. Little is known about their subjective psychoactive effects when used for pain management. We hypothesized that when used for pain, dronabinol has psychoactive effects in a dose-response relationship, whose peak effects are comparable with smoking marijuana. METHODS: This was a randomized controlled trial of single dose placebo, 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana. Participants completed the Addiction Research Center Inventory (ARCI) hourly for 8 hours during 3 monitored sessions. Comparison sample was the ARCI ratings in participants with no pain (N=20), monitored every 30 minutes after smoking a 1.99% THC (low) and a 3.51% (high strength) marijuana cigarette. RESULTS: The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo (P<0.05). Average daily morphine use, total pain relief (TOTPAR), age, sex, and baseline pain level were not significant covariates. ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes (P=0.80, 10 mg=low strength, 20 mg=high strength). CONCLUSIONS: In pain patients, oral dronabinol has similar psychoactive effects to smoking marijuana. This risk must be considered in any decision to prescribe cannabinoid medications for pain.

Systematic literature review and meta-analysis of the efficacy and safety of prescription opioids, including abuse-deterrent formulations, in non-cancer pain management.

OBJECTIVE: This study was conducted to compare safety and efficacy outcomes between opioids formulated with technologies designed to deter or resist tampering (i.e., abuse-deterrent formulations [ADFs]) and non-ADFs for commonly prescribed opioids for treatment of non-cancer pain in adults. METHODS: PubMed and Cochrane Library databases were searched for opioid publications between September 1, 2001 and August 31, 2011, and pivotal clinical trials from all years; abstracts from key pain conferences (2010-2011) were also reviewed. One hundred and ninety-one publications were initially identified, 68 of which met eligibility criteria and were systematically reviewed; a subset of 16 involved a placebo group (13 non-ADFs vs placebo, 3 ADFs vs placebo) and reported both efficacy and safety outcomes, and were included for a meta-analysis. Summary estimates of standardized difference in mean change of pain intensity (DMCPI), standardized difference in sum of pain intensity difference (DSPID), and odds ratios (ORs) of each adverse event (AE) were computed through random-effects estimates for ADFs (and non-ADFs) vs placebo. Indirect treatment comparisons were conducted to compare ADFs and non-ADFs. RESULTS: Summary estimates for standardized DMCPI and for standardized DSPID indicated that ADFs and non-ADFs showed significantly greater efficacy than placebo in reducing pain intensity. Indirect analyses assessing the efficacy outcomes between ADFs and non-ADFs indicated that they were not significantly different (standardized DMCPI [0.39 {95% confidence interval (CI) 0.00-0.76}]; standardized DSPID [-0.22 {95% CI -0.74 to 0.30}]). ADFs and non-ADFs both were associated with higher odds of AEs than placebo. Odds ratios from indirect analyses comparing AEs for ADFs vs non-ADFs were not significant (nausea, 0.87 [0.24-3.12]; vomiting, 1.54 [0.40-5.97]; dizziness/vertigo, 0.61 [0.21-1.76]; headache, 1.42 [0.57-3.53]; somnolence/drowsiness, 0.47 [0.09-2.58]; constipation, 0.64 [0.28-1.49]; pruritus 0.41 [0.05-3.51]). CONCLUSION: ADFs and non-ADFs had comparable efficacy and safety profiles, while both were more efficacious than placebo in reducing pain intensity.

Relationship of negative affect and outcome of an opioid therapy trial among low back pain patients.

OBJECTIVES: Patients with chronic noncancer pain frequently report symptoms of depression and anxiety (negative affect), which are associated with higher ratings of pain intensity and a greater likelihood of being prescribed chronic opioid therapy. The purpose of this secondary analysis was to test the hypothesis that initial levels of negative affect can predict treatment-related outcomes in a double-blind, placebo-controlled study of extended-release (ER) hydromorphone among opioid-tolerant patients with chronic low back pain. METHODS: Four hundred fifty-nine (N = 459) patients participated in the titration/conversion phase of a multicenter study, of which 268 were randomized to receive once-daily hydromorphone or placebo. All patients completed the Hospital Anxiety and Depression Scale (HADS) at baseline and were divided evenly into Low (N = 157), Moderate (N = 155), and High (N = 147) negative affect groups based on their scores. Group differences in numerical pain intensity measures at home and in the clinic, Roland-Morris Disability ratings, and measures of symptoms from the Subjective Opiate Withdrawal Scale (SOWS) throughout the trial were analyzed. RESULTS: Two hundred sixty-eight of the initial 459 subjects who entered the 2 to 4-week titration/conversion phase (pretreatment) were successfully randomized to either placebo or ER hydromorphone; a total of 110 patients then completed this double-blind phase of the study. Those in the Moderate and High negative affect groups tended to drop out more often during the titration/conversion phase because of the adverse effects or lack of efficacy of their prescribed opioid than those in the Low negative mood group (P < 0.05). Overall, those patients in the Moderate and High groups reported significantly higher pain intensity scores in at-home and in-clinic pain intensity ratings (P < 0.05), greater disability on the Roland-Morris Scale (P < 0.01), and more withdrawal symptoms on the SOWS (P < 0.05) than those in the Low group. Higher negative affect scores also predicted less favorable ratings of the study drug during the titration phase (P < 0.05). Interestingly, the High negative affect group showed the most improvement in pain in the placebo condition (P < 0.05). CONCLUSIONS: Negative affect is associated with diminished benefit during a trial of opioid therapy and is predictive of dropout in a controlled clinical trial.

Research design considerations for clinical studies of abuse-deterrent opioid analgesics: IMMPACT recommendations.

Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Because of the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability, (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation, (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse, and (4) postmarketing epidemiological studies.

Craving of prescription opioids in patients with chronic pain: a longitudinal outcomes trial.

UNLABELLED: Little is known about whether patients with chronic pain treated with opioids experience craving for their medications, whether contextual cues may influence craving, or if there is a relationship between craving and medication compliance. We hypothesized that craving for prescription opioids would be significantly correlated with the urge for more medication, preoccupation with the next dose, and current mood symptoms. We studied craving in 62 patients with chronic pain who were at low or high risk for opioid misuse, while they were enrolled in an RCT to improve prescription opioid medication compliance. Using electronic diaries, patients completed ratings of craving at monthly clinic visits and daily during a 14-day take-home period. Both groups consistently endorsed craving, whose levels were highly correlated (P < .001) with urge, preoccupation, and mood. The intervention to improve opioid compliance in the high-risk group was significantly associated with a rate of decrease in craving over time in comparison to a high-risk control group (P < .05). These findings indicate that craving is a potentially important psychological construct in pain patients prescribed opioids, regardless of their level of risk to misuse opioids. Targeting craving may be an important intervention to decrease misuse and improve prescription opioid compliance. PERSPECTIVE: Patients with noncancer pain can crave their prescription opioids, regardless of their risk for opioid misuse. We found craving to be highly correlated with the urge to take more medication, fluctuations in mood, and preoccupation with the next dose, and to diminish with a behavioral intervention to improve opioid compliance.

Assessment and treatment of abuse risk in opioid prescribing for chronic pain.

Opioid analgesics provide effective treatment for noncancer pain, but many physicians have concerns about adverse effects, tolerance, and addiction. Misuse of opioids is prominent in patients with chronic back pain and early recognition of misuse risk could help physicians offer adequate patient care while implementing appropriate levels of monitoring to reduce aberrant drug-related behaviors. In this review, we discuss opioid abuse and misuse issues that often arise in the treatment of patients with chronic back pain and present an overview of assessment and treatment strategies that can be effective in improving compliance with the use of prescription opioids for pain. Many persons with chronic back pain have significant medical, psychiatric and substance use comorbidities that affect treatment decisions and a comprehensive evaluation that includes a detailed history, physical, and mental health evaluation is essential. Although there is no "gold standard" for opioid misuse risk assessment, several validated measures have been shown to be useful. Controlled substance agreements, regular urine drug screens, and interventions such as motivational counseling have been shown to help improve patient compliance with opioids and to minimize aberrant drug-related behavior. Finally, we discuss the future of abuse-deterrent opioids and other potential strategies for back pain management.

Efficacy of subcutaneous methylnaltrexone in the treatment of opioid-induced constipation: a responder post hoc analysis.

OBJECTIVE: Methylnaltrexone, a selective peripherally acting mu-opioid receptor antagonist, effectively treats opioid-induced constipation (OIC) in patients with advanced illness and shows efficacy in patients with chronic nonmalignant pain. The objective was to identify patients who achieved maximal treatment effect based on response to initial four methylnaltrexone doses. DESIGN: A post hoc analysis of a randomized, double-blind, placebo-controlled study evaluating patients with OIC and chronic nonmalignant pain who received 12 mg subcutaneous methylnaltrexone daily for 4 weeks was performed to determine if response to the first four methylnaltrexone doses predicted overall response during the study. Patients receiving ≥8 doses were included. OUTCOME MEASURES: Patients having ≥3 rescue-free bowel movements (RFBMs)/week; change from baseline in RFBMs/week; percentage of doses with RFBMs within 4 hours after dosing. RESULTS: Of 137 patients, 58 patients (42.3%) had RFBMs after ≥2 of four doses. Among those with response to ≥2 of four doses, 81% had ≥3 RFBMs/week vs. 43% for those with response to <2 of four (P < 0.0001). Those with RFBMs after ≥2 of first four doses averaged 4.8 RFBMs/week vs. 2.0 RFBMs/week for those with <2 of four (P < 0.0001). Percentage of subsequent injections resulting in RFBMs within 4 hours was 45.9 ± 27.6 for those with response to ≥2 of four doses vs. 17.1 ± 19.1 for those with response to <2 of four (P < 0.0001). Abdominal pain was the most frequently reported adverse event. CONCLUSION: Early response to ≥2 of first four doses of methylnaltrexone identified patients who demonstrated a particularly robust effect of treatment over the duration of use.

Injury and liability associated with cervical procedures for chronic pain.

BACKGROUND: Prompted by an increase in interventional pain treatments performed at the level of the cervical spine, we investigated the characteristics and patterns of injury in malpractice claims collected from January 1, 2005 to December 31, 2008. METHODS: We compared claims arising from cervical pain treatments with all other chronic pain claims collected from the American Society of Anesthesiologists' closed claims database between 2005 and 2008. Claims for spinal cord injury underwent in-depth analysis for mechanisms of injury and use of sedation during the procedure. RESULTS: Claims related to cervical interventions represented 22% (64/294) of chronic pain treatment claims. Patients who underwent cervical procedures were healthier (American Society of Anesthesiologists' score, 1-2; P < 0.001) and were more often women (P = 0.011). Of the patients who underwent a cervical procedure, 59% experienced spinal cord damage compared with 11% of patients with other chronic pain (P < 0.001), with direct needle trauma as the predominant cause (31%). General anesthesia or sedation was used in 67% of cervical procedure claims associated with spinal cord injuries but in only 19% of cervical procedure claims not associated with spinal cord injuries (P < 0.001). Of the patients who underwent cervical procedures and had spinal cord injuries, 25% were nonresponsive during the procedure compared with 5% of the patients who underwent cervical procedures and did not have spinal cord injuries (P < 0.05, κ = 0.52). CONCLUSIONS: Injuries related to cervical interventional pain treatment were often severe and related to direct needle trauma to the spinal cord. Traumatic spinal cord injury was more common in patients who received sedation or general anesthesia and in those who were unresponsive during the procedure. Further studies are crucial to define the usefulness of cervical interventions and to improve their safety.

Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study.

UNLABELLED: Methylnaltrexone is effective for opioid-induced constipation (OIC) in advanced illness patients. This 4-week, double-blind, randomized, placebo-controlled study investigated the effect of subcutaneous methylnaltrexone on OIC in patients receiving opioids for chronic, nonmalignant pain. Patients (N = 460) received subcutaneous methylnaltrexone 12 mg once daily (QD) or every other day (alternating with placebo) compared with placebo. Assessments included bowel movement count, time of bowel movement, straining, sense of complete evacuation, Bristol Stool Form Scales, and quality of life. Within 4 hours of first dose, 34.2% of patients in both methylnaltrexone groups had rescue-free bowel movements (RFBMs) versus 9.9% on placebo (P < .001). The estimated number needed to treat was about 4. On average, 28.9% of methylnaltrexone QD and 30.2% of methylnaltrexone alternate-day dosing resulted in RFBMs within 4 hours versus 9.4% QD and 9.3% alternate-day placebo injections (both P < .001). Both methylnaltrexone groups had significantly shorter time to first RFBM (P < .001) and greater increase in number of weekly RFBMs (P < .05) versus placebo. Adverse events included abdominal pain, diarrhea, nausea, and hyperhidrosis. Bristol Stool Form Scale scores (P = .002) and sensation of complete evacuation (P < .04) were significantly superior with methylnaltrexone QD; both methylnaltrexone groups reported no or mild straining during RFBMs in the first 2 weeks (P < .02). At 4 weeks, a significantly greater improvement in patient-reported, constipation-specific quality of life was seen in the alternate-day dosing (P < .05) and QD (P < .001) groups. PERSPECTIVE: We present data demonstrating that subcutaneous methylnaltrexone 12 mg given once daily (QD) or every other day provides significant relief of OIC and was generally well tolerated in patients with chronic, nonmalignant pain. These results expand on prior effectiveness observed for the treatment of OIC in advanced illness patients to a broader population.