Comprehensive, Evidence-Based, Consensus Guidelines for Prescription of Opioids for Chronic Non-Cancer Pain from the American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. OBJECTIVES: In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. METHODS: The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed. The multidisciplinary panel finalized 20 guideline recommendations for prescription of opioids for chronic non-cancer pain. Summary of the results showed over 90% agreement for the final 20 recommendations with strong consensus. The consensus guidelines included 4 sections specific to opioid therapy with 1) ten recommendations particular to initial steps of opioid therapy; 2) five recommendations for assessment of effectiveness of opioid therapy; 3) three recommendations regarding monitoring adherence and side effects; and 4) two general, final phase recommendations. LIMITATIONS: There is a continued paucity of literature of long-term opioid therapy addressing chronic non-cancer pain. Further, significant biases exist in the preparation of guidelines, which has led to highly variable rules and regulations across various states. CONCLUSION: These guidelines were developed based upon a comprehensive review of the literature, consensus among expert panelists, and in alignment with patient preferences, and shared decision-making so as to improve the long-term pain relief and function in patients with chronic non-cancer pain. Consequently, it was concluded - and herein recommended - that chronic opioid therapy should be provided in low doses with appropriate adherence monitoring and understanding of adverse events only to those patients with a proven medical necessity, and who exhibit stable improvement in both pain relief and activities of daily function, either independently or in conjunction with other modalities of treatments.

Comprehensive, evidence-based, consensus guidelines for prescription of opioids for chronic non-cancer pain from the American Society of Interventional Pain Physicians (ASIPP)

Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed

Efficacy, Safety, and Feasibility of the Morphine Microdose Method in Community-Based Clinics.

Objectives: The goal of this study was to assess the success of the morphine microdose method in a community pain clinic setting by monitoring follow-up frequency, dose escalation, and monotherapy/polytherapy ratio. The morphine microdose method involves a pretrial reduction or elimination of systemic opioids followed by a period of abstinence. Intrathecal (IT) morphine is then started at doses of less than 0.2 mg per day. Systemic opioid abstinence is then continued after pump implant and IT morphine monotherapy. Design: Retrospective review of medical records. Setting: Private and academic pain clinic practices. Subjects: Chronic noncancer pain patients. Methods: We reviewed the charts of 60 patients who had completed a microdose regimen and had an IT pump implanted between June 11, 2008, and October 11, 2014. During IT therapy, dose change over time, pain scores, side effects, max dose, and duration were recorded. Results: The majority of patients (35/60, 58%) were successfully managed solely on morphine microdose monotherapy. These patients did not require additional oral therapy. There was a significant reduction in mean pain scores, from 7.4 ± 0.32 before microdose therapy to 4.8 ± 0.3 after microdose therapy. Conclusions: Microdose therapy achieved analgesia, improved safety, and avoided systemic side effects. The safety of IT therapy was increased by using a lower concentration (2 mg/mL) and lower daily doses (<3 mg/d) of morphine. Furthermore, microdose therapy was feasible, safe, and cost-effective in the outpatient setting.

Closed-Loop- and Decision-Assist-Guided Fluid Therapy of Human Hemorrhage.

OBJECTIVES: We sought to evaluate the efficacy, efficiency, and physiologic consequences of automated, endpoint-directed resuscitation systems and compare them to formula-based bolus resuscitation. DESIGN: Experimental human hemorrhage and resuscitation. SETTING: Clinical research laboratory. SUBJECTS: Healthy volunteers. INTERVENTIONS: Subjects (n = 7) were subjected to hemorrhage and underwent a randomized fluid resuscitation scheme on separate visits 1) formula-based bolus resuscitation; 2) semiautonomous (decision assist) fluid administration; and 3) fully autonomous (closed loop) resuscitation. Hemodynamic variables, volume shifts, fluid balance, and cardiac function were monitored during hemorrhage and resuscitation. Treatment modalities were compared based on resuscitation efficacy and efficiency. MEASUREMENTS AND MAIN RESULTS: All approaches achieved target blood pressure by 60 minutes. Following hemorrhage, the total amount of infused fluid (bolus resuscitation: 30 mL/kg, decision assist: 5.6 ± 3 mL/kg, closed loop: 4.2 ± 2 mL/kg; p < 0.001), plasma volume, extravascular volume (bolus resuscitation: 17 ± 4 mL/kg, decision assist: 3 ± 1 mL/kg, closed loop: -0.3 ± 0.3 mL/kg; p < 0.001), body weight, and urinary output remained stable under decision assist and closed loop and were significantly increased under bolus resuscitation. Mean arterial pressure initially decreased further under bolus resuscitation (-10 mm Hg; p < 0.001) and was lower under bolus resuscitation than closed loop at 20 minutes (bolus resuscitation: 57 ± 2 mm Hg, closed loop: 69 ± 4 mm Hg; p = 0.036). Colloid osmotic pressure (bolus resuscitation: 19.3 ± 2 mm Hg, decision assist, closed loop: 24 ± 0.4 mm Hg; p < 0.05) and hemoglobin concentration were significantly decreased after bolus fluid administration. CONCLUSIONS: We define efficacy of decision-assist and closed-loop resuscitation in human hemorrhage. In comparison with formula-based bolus resuscitation, both semiautonomous and autonomous approaches were more efficient in goal-directed resuscitation of hemorrhage. They provide favorable conditions for the avoidance of over-resuscitation and its adverse clinical sequelae. Decision-assist and closed-loop resuscitation algorithms are promising technological solutions for constrained environments and areas of limited resources.

Responsible, Safe, and Effective Prescription of Opioids for Chronic Non-Cancer Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines.

BACKGROUND: Opioid use, abuse, and adverse consequences, including death, have escalated at an alarming rate since the 1990s. In an attempt to control opioid abuse, numerous regulations and guidelines for responsible opioid prescribing have been developed by various organizations. However, the US opioid epidemic is continuing and drug dose deaths tripled during 1999 to 2015. Recent data show a continuing increase in deaths due to natural and semisynthetic opioids, a decline in methadone deaths, and an explosive increase in the rates of deaths involving other opioids, specifically heroin and illicit synthetic fentanyl. Contrary to scientific evidence of efficacy and negative recommendations, a significant proportion of physicians and patients (92%) believe that opioids reduce pain and a smaller proportion (57%) report better quality of life. In preparation of the current guidelines, we have focused on the means to reduce the abuse and diversion of opioids without jeopardizing access for those patients suffering from non-cancer pain who have an appropriate medical indication for opioid use. OBJECTIVES: To provide guidance for the prescription of opioids for the management of chronic non-cancer pain, to develop a consistent philosophy among the many diverse groups with an interest in opioid use as to how appropriately prescribe opioids, to improve the treatment of chronic non-cancer pain and to reduce the likelihood of drug abuse and diversion. These guidelines are intended to provide a systematic and standardized approach to this complex and difficult arena of practice, while recognizing that every clinical situation is unique. METHODS: The methodology utilized included the development of objectives and key questions. The methodology also utilized trustworthy standards, appropriate disclosures of conflicts of interest, as well as a panel of experts from various specialties and groups. The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed, with a best evidence synthesis of the available literature, and utilized grading for recommendation as described by the Agency for Healthcare Research and Quality (AHRQ).Summary of Recommendations:i. Initial Steps of Opioid Therapy 1. Comprehensive assessment and documentation. (Evidence: Level I; Strength of Recommendation: Strong) 2. Screening for opioid abuse to identify opioid abusers. (Evidence: Level II-III; Strength of Recommendation: Moderate) 3. Utilization of prescription drug monitoring programs (PDMPs). (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 4. Utilization of urine drug testing (UDT). (Evidence: Level II; Strength of Recommendation: Moderate) 5. Establish appropriate physical diagnosis and psychological diagnosis if available. (Evidence: Level I; Strength of Recommendation: Strong) 6. Consider appropriate imaging, physical diagnosis, and psychological status to collaborate with subjective complaints. (Evidence: Level III; Strength of Recommendation: Moderate) 7. Establish medical necessity based on average moderate to severe (≥ 4 on a scale of 0 - 10) pain and/or disability. (Evidence: Level II; Strength of Recommendation: Moderate) 8. Stratify patients based on risk. (Evidence: Level I-II; Strength of Recommendation: Moderate) 9. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. (Evidence: Level I-II; Strength of Recommendation: Moderate) 10. Obtain a robust opioid agreement, which is followed by all parties. (Evidence: Level III; Strength of Recommendation: Moderate)ii. Assessment of Effectiveness of Long-Term Opioid Therapy 11. Initiate opioid therapy with low dose, short-acting drugs, with appropriate monitoring. (Evidence: Level II; Strength of Recommendation: Moderate) 12. Consider up to 40 morphine milligram equivalent (MME) as low dose, 41 to 90 MME as a moderate dose, and greater than 91 MME as high dose. (Evidence: Level II; Strength of Recommendation: Moderate) 13. Avoid long-acting opioids for the initiation of opioid therapy. (Evidence: Level I; Strength of Recommendation: Strong) 14. Recommend methadone only for use after failure of other opioid therapy and only by clinicians with specific training in its risks and uses, within FDA recommended doses. (Evidence: Level I; Strength of Recommendation: Strong) 15. Understand and educate the patients of the effectiveness and adverse consequences. (Evidence: Level I; Strength of Recommendation: Strong) 16. Similar effectiveness for long-acting and short-acting opioids with increased adverse consequences of long-acting opioids. (Evidence: Level I-II; Strength of recommendation: Moderate to strong) 17. Periodically assess pain relief and/or functional status improvement of ≥ 30% without adverse consequences. (Evidence: Level II; Strength of recommendation: Moderate) 18. Recommend long-acting or high dose opioids only in specific circumstances with severe intractable pain. (Evidence: Level I; Strength of Recommendation: Strong)iii. Monitoring for Adherence and Side Effects 19. Monitor for adherence, abuse, and noncompliance by UDT and PDMPs. (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 20. Monitor patients on methadone with an electrocardiogram periodically. (Evidence: Level I; Strength of Recommendation: Strong). 21. Monitor for side effects including constipation and manage them appropriately, including discontinuation of opioids when indicated. (Evidence: Level I; Strength of Recommendation: Strong)iv. Final Phase 22. May continue with monitoring with continued medical necessity, with appropriate outcomes. (Evidence: Level I-II; Strength of Recommendation: Moderate) 23. Discontinue opioid therapy for lack of response, adverse consequences, and abuse with rehabilitation. (Evidence: Level III; Strength of Recommendation: Moderate) CONCLUSIONS: These guidelines were developed based on comprehensive review of the literature, consensus among the panelists, in consonance with patient preferences, shared decision-making, and practice patterns with limited evidence, based on randomized controlled trials (RCTs) to improve pain and function in chronic non-cancer pain on a long-term basis. Consequently, chronic opioid therapy should be provided only to patients with proven medical necessity and stability with improvement in pain and function, independently or in conjunction with other modalities of treatments in low doses with appropriate adherence monitoring and understanding of adverse events.Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversionDisclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

Clinical and Histological Effects of the Intrathecal Administration of a Single Dose of Dexmedetomidine in Rabbits.

BACKGROUND: There is experimental evidence that dexmedetomidine has neuroprotective effects. So, it could be expected that its intrathecal or epidural administration presents no harm. However, whether dexmedetomidine is neurotoxic to the spinal cord remains to be fully elucidated. OBJECTIVE: To evaluate the effect of preservative-free dexmedetomidine administered as a subarachnoid single injection on the spinal cord and meninges of rabbits. STUDY DESIGN: Research article. SETTING: Experimental research laboratory. METHODS: Twenty young adult female rabbits, each weighing between 3200 and 4900 g, and having a spine length between 36 and 40 cm, were divided by lot into 2 groups (G): 0.9% saline in G1 and preservative-free dexmedetomidine in G2 (dose of 10 µg). After intravenous anesthesia with ketamine and xylazine, the subarachnoid space was punctured at S1-S2 under ultrasound guidance, and a random 5 µl.cm-1 of spinal length (0.2 mL) of solution (saline or dexmedetomidine) was injected. The animals remained in captivity for 21 days under medical observation and were sacrificed by decapitation. The lumbosacral spinal cord portion was removed for immunohistochemistry to assess the glial fibrillary acidic protein (GFAP), and histology was assessed using hematoxylin and eosin (HE) stain. RESULTS: None of the animals had impaired motor function or decreased nociception during the period of clinical observation. None of the animals from the control group showed signs of injuries to meninges. In the dexmedetomidine group, however, 9 animals presented with signs of meningeal injury. The main histological changes observed were areas with meningeal thickening and lymphoplasmocitary infiltration in the pia-mater and arachnoid. Further histological examination also revealed adherence areas among the pia and arachnoid. There was no signal of injury in neural tissue in any animal of both groups. LIMITATIONS: Evaluation of the possible analgesic effects of the intrathecal dexmedetomidine was not performed. CONCLUSION: On the basis of the present results, dexmedetomidine administered in the subarachnoid space in a single dose of 10 µg is capable of producing histological changes over the meninges of rabbits.

Serum cystatin C is a sensitive early marker for changes in the glomerular filtration rate in patients undergoing laparoscopic surgery.

OBJECTIVE: Pneumoperitoneum during laparoscopy results in transient oliguria and decreased glomerular filtration and renal blood flow. The presence of oliguria and elevated serum creatinine is suggestive of acute renal injury. Serum cystatin C has been described as a new marker for the detection of this type of injury. In this study, our aim was to compare the glomerular filtration rate estimated using cystatin C levels with the rate estimated using serum creatinine in patients with normal renal function who were undergoing laparoscopic surgery. METHODS: In total, 41 patients undergoing laparoscopic cholecystectomy or hiatoplasty were recruited for the study. Blood samples were collected at three time intervals: first, before intubation (T1); second, 30 minutes after the establishment of pneumoperitoneum (T2); and third, 30 minutes after deflation of the pneumoperitoneum (T3). These blood samples were then analyzed for serum cystatin C, creatinine, and vasopressin. The Larsson formula was used to calculate the glomerular filtration rate based on the serum cystatin C levels, and the Cockcroft-Gault formula was used to calculate the glomerular filtration rate according to the serum creatinine levels. RESULTS: Serum cystatin C levels increased during the study (T1 = T2T3; p<0.05). The calculated eGlomerular filtration rate-Larsson decreased, whereas the eGlomerular filtration rate-Cockcroft-Gault increased. There was no correlation between cystatin C and serum creatinine. Additionally, Pearson's analysis showed a better correlation between serum cystatin C and the eGlomerular filtration rate than between serum creatinine and the eGlomerular filtration rate. CONCLUSION: This study demonstrates that serum cystatin C is a more sensitive indicator of changes in the glomerular filtration rate than serum creatinine is in patients with normal renal function who are undergoing laparoscopic procedures.

Serum cystatin C is a sensitive early marker for changes in the glomerular filtration rate in patients undergoing laparoscopic surgery

OBJECTIVE: Pneumoperitoneum during laparoscopy results in transient oliguria and decreased glomerular filtration and renal blood flow. The presence of oliguria and elevated serum creatinine is suggestive of acute renal injury. Serum cystatin C has been described as a new marker for the detection of this type of injury. In this study, our aim was to compare the glomerular filtration rate estimated using cystatin C levels with the rate estimated using serum creatinine in patients with normal renal function who were undergoing laparoscopic surgery. METHODS: In total, 41 patients undergoing laparoscopic cholecystectomy or hiatoplasty were recruited for the study. Blood samples were collected at three time intervals: first, before intubation (T1); second, 30 minutes after the establishment of pneumoperitoneum (T2); and third, 30 minutes after deflation of the pneumoperitoneum (T3). These blood samples were then analyzed for serum cystatin C, creatinine, and vasopressin. The Larsson formula was used to calculate the glomerular filtration rate based on the serum cystatin C levels, and the Cockcroft-Gault formula was used to calculate the glomerular filtration rate according to the serum creatinine levels. RESULTS: Serum cystatin C levels increased during the study (T1 = T2<T3; p<0.05), whereas serum creatinine levels decreased (T1 = T2>T3; p<0.05). The calculated eGlomerular filtration rate-Larsson decreased, whereas the eGlomerular filtration rate-Cockcroft-Gault increased. There was no correlation between cystatin C and serum creatinine. Additionally, Pearson's analysis showed a better correlation between serum cystatin C and the eGlomerular filtration rate than between serum creatinine and the eGlomerular filtration rate. CONCLUSION: This study demonstrates that serum cystatin C is a more sensitive indicator of changes in the glomerular filtration rate than serum creatinine is in patients with normal ...

A systematic review of randomized trials on the effectiveness of opioids for cancer pain.

BACKGROUND: In all recommended guidelines put forth for the treatment of cancer pain, opioids continue to be an important part of a physician's armamentarium. Though opioids are used regularly for cancer pain, there is a paucity of literature proving efficacy for long-term use. Cancer is no longer considered a "terminal disease"; 50% to 65% of patients survive for at least 2 years, and there are about 12 million cancer survivors in the United States. There is a concern about side effects, tolerance, abuse and addiction with long-term opioid use and a need to evaluate the effectiveness of opioids for cancer pain. OBJECTIVE: The objective of this systematic review was to look at the effectiveness of opioids for cancer pain. STUDY DESIGN: A systematic review of randomized trials of opioids for cancer pain. METHODS: A comprehensive review of the current literature for randomized controlled trials (RCTs) of opioids for cancer pain was done. The literature search was done using PubMed, EMBASE, Cochrane library, clinical trials, national clearing house, Web of Science, previous narrative systematic reviews, and cross references. The studies were assessed using the modified Cochrane and Jadad criteria. Analysis of evidence was done utilizing the modified quality of evidence developed by United States Preventive Services Task Force (USPSTF). OUTCOME MEASURES: Pain relief was the primary outcome measure. Secondary outcome measures are quality of life (QoL) and side effects including tolerance and addiction. RESULTS: The level of evidence for pain relief based on the USPSTF criteria was fair for transdermal fentanyl and poor for morphine, tramadol, oxycodone, methadone, and codeine. LIMITATIONS: Randomized trials in a cancer setting are difficult to perform and justify. There is a paucity of long-term trials and this review included a follow-up period of only 4 weeks. CONCLUSION: This systematic review of RCTs of opioids for cancer pain showed fair evidence for the efficacy of transdermal fentanyl and poor evidence for morphine, tramadol, oxycodone, methadone, and codeine.

Urine drug testing in chronic pain.

Therapeutic use, overuse, abuse, and diversion of controlled substances in managing chronic non-cancer pain continue to be an issue for physicians and patients. The challenge is to eliminate or significantly curtail abuse of controlled prescription drugs while still assuring the proper treatment of those patients. Some physicians are apprehensive regarding the use of chronic opioid therapy in chronic non-cancer pain due to a perceived lack of proven evidence, the misuse of opioids, tolerance, dependence, and hyperalgesia. However, others have criticized the underuse of opioids, resulting in the undertreatment of pain. It has been the convention that federal, state, and local governments; professional associations; as well as pharmaceutical companies, physicians, accrediting bodies, medical licensure boards, and the public all share responsibility for preventing abuse of controlled prescription drugs. To overcome the critical challenge of eliminating or significantly curtailing abuse of controlled prescription drugs and at the same time assuring the appropriate treatment for those patients who can be helped by these medications, it is crucial to practice adherence or compliance monitoring of opioid therapy. Compliance monitoring has been shown to be crucial in delivering proper opioid therapy and preserving this therapy for the future. Urine drug testing (UDT) is considered one of the mainstays of adherence monitoring in conjunction with prescription monitoring programs and other screening tools, however, UDT is associated with multiple limitations secondary to potential pitfalls related to drug metabolism, reliability of the tests, and the knowledge of the pain physician. UDT is a widely available and familiar method for monitoring opioid use in chronic pain patients. UDT can provide tools for tracking patient compliance and expose possible drug misuse and abuse. UDT is one of the major tools of adherence monitoring in the assessment of the patient's predisposition to, and patterns of, drug misuse/abuse--a vital first step towards establishing and maintaining the safe and effective use of opioid analgesics in the treatment of chronic pain. This comprehensive review provides the role of UDT in monitoring chronic opioid therapy along with reliability and accuracy, appropriate use, overuse, misuse, and abuse.

Monitoring opioid adherence in chronic pain patients: assessment of risk of substance misuse.

BACKGROUND: Use of opioids for chronic non-cancer pain (CNCP) has increased in recent years because this pain had been undertreated. There was also a simultaneous increase in misuse and abuse of opioids. Deaths due to such abuse and misuse also have risen as seen in the many reports published every day in local papers as well as in the medical literature. So, it is imperative that patients who are prescribed these medications be monitored for adherence so misuse and abuse can be curtailed and opioids are available to those who genuinely need them for chronic pain control. There are various screening tools available to monitor such adherence, and there is an abundance of literature about it in addiction and psychiatric medicine. There is, though, a paucity of such literature as applied to pain medicine. OBJECTIVES: Our objectives for this review were twofold. We wanted to identify which screening tools are available to monitor opioid adherence and we wanted to see if there were prospective comparative studies of these tools to identify a single best tool that can be applied to all chronic non-cancer pain patients managed with opioids. STUDY DESIGN: We did a review of the current literature about monitoring of opioid adherence. We also looked at their use, validity, and comparative studies. METHODS: We performed a literature search using PubMed, EMBASE, and the Cochrane library. The search was conducted using the terms opioids, non-cancer pain, monitoring, and adherence. The databases from 1996 to November 2010 were reviewed. The search included prospective and retrospective studies, review articles, and FDA records. Bibliographies and cross references were reviewed when deemed appropriate. CONCLUSION: We found 52 publications, of which 22 met the criteria to be included in this manuscript. We found only one study that was prospective, and compared the various screening tools that are available to monitor opioid adherence. In the majority of the studies the number treated was small. There was not a single screening tool that can be applied universally to all patients who are on opioid therapy for chronic non-cancer pain.

Effect of progressive mandibular advancement on pharyngeal airway size in anesthetized adults.

BACKGROUND: General anesthesia in adult humans is associated with narrowing or complete closure of the pharyngeal airway. The purpose of this study was to determine the effect of progressive mandibular advancement on pharyngeal airway size in normal adults during intravenous infusion of propofol for anesthesia. METHODS: Magnetic resonance imaging was performed in nine normal adults during wakefulness and during propofol anesthesia. A commercially available intraoral appliance was used to manually advance the mandible. Images were obtained during wakefulness without the appliance and during anesthesia with the participants wearing the appliance under three conditions: without mandibular advancement, advancement to 50% maximum voluntary advancement, and maximum advancement. Using computer software, airway area and maximum anteroposterior and lateral airway diameters were measured on the axial images at the level of the soft palate, uvula, tip of the epiglottis, and base of the epiglottis. RESULTS: Airway area across all four airway levels decreased during anesthesia without mandibular advancement compared with airway area during wakefulness (P < 0.007). Across all levels, airway area at 50% advancement during anesthesia was less than that at centric occlusion during wakefulness (P = 0.06), but airway area with maximum advancement during anesthesia was similar to that during wakefulness (P = 0.64). In general, anteroposterior and lateral airway diameters during anesthesia without mandibular advancement were decreased compared with wakefulness and were restored to their wakefulness values with 50% and/or maximal advancement. CONCLUSIONS: Maximum mandibular advancement during propofol anesthesia is required to restore the pharyngeal airway to its size during wakefulness in normal adults.

Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans.

BACKGROUND: Reduced bioavailability of endothelium-derived nitric oxide associated with reperfusion could potentially exacerbate the inflammatory response during reperfusion. Evidence suggests the pharmacologic effects of inhaled nitric oxide may extend beyond the pulmonary vasculature, and this is attributed to nitric oxide-derived complexes in blood that ultimately orchestrate antiinflammatory effects. In this study, the authors evaluated the potential for inhaled nitric oxide (80 ppm) to attenuate inflammation instigated by ischemia-reperfusion in a human model using patients undergoing knee surgery where a tourniquet was used to produce a bloodless surgical field. METHODS: Inhaled nitric oxide (80 ppm) was administered before tourniquet application and continued throughout reperfusion until the completion of surgery. Venous blood samples were collected before and after reperfusion, for the measurements of nitrate and nitrite, CD11b/CD18, soluble P-selectin, and lipid hydroperoxide. Muscle biopsies were obtained from the quadriceps muscle before skin closure and analyzed for myeloperoxide, conjugated dienes, and nuclear factor-kappaB translocation. RESULTS: Administration of inhaled nitric oxide (80 ppm) significantly attenuated the inflammatory response characterized by reduced expression of CD11b/CD18, P-selectin, and nuclear factor kappaB compared with the control group. This was accompanied by increased plasma levels of nitrate and nitrite and reduced oxidative stress. CONCLUSIONS: Administration of inhaled nitric oxide at 80 ppm significantly reduces inflammation in lower extremity ischemia-reperfusion in humans. This observation supports the concept that during diseases characterized by dysfunction in nitric oxide metabolism, inhaled nitric oxide may be an effective therapy to replenish systemic nitric oxide, thus retarding inflammatory-mediated injury.

Splanchnic oxygen consumption is impaired during severe acute normovolemic anemia in anesthetized humans.

BACKGROUND: In conscious humans, reduction in hemoglobin concentration to 5 g/dl did not produce inadequate systemic oxygenation. However, systemic measures of inadequate oxygenation may not be sufficiently sensitive to detect inadequate oxygenation in individual organs such as splanchnic organs. The authors tested the hypothesis that acute normovolemic anemia to hemoglobin less than 6.0 g/dl in anesthetized humans reduces splanchnic oxygen consumption because of diminished whole body oxygen delivery. METHODS: Elective spine (n = 12) and abdominal (n = 7) surgery patients underwent acute normovolemic anemia to decrease the hemoglobin concentration close to 6.0 g/dl. The authors assessed the development of supply-dependent conditions in systemic and regional vascular beds by two primary measures before and after acute normovolemic anemia: oxygen consumption and surrogate biochemical markers of anaerobic metabolism, including plasma lactate, regional lactate kinetics, and ketone body ratio. RESULTS: When hemoglobin was reduced from 13.6 +/- 1.2 to 5.9 +/- 0.3 g/dl, oxygen supply dependency occurred in the splanchnic and preportal tissues but not at the systemic level. Regional supply dependency was accompanied by biochemical markers of anaerobic metabolism. CONCLUSIONS: In anesthetized humans, a reduction in hemoglobin to 5.9 g/dl by acute normovolemic anemia diminished splanchnic and preportal whole body oxygen delivery and impaired splanchnic and preportal oxygen consumption. This was accompanied by increased plasma levels of regional lactate and an increased beta-hydroxybutyrate-to-acetoacetate ratio. These findings suggest that the risk to the gastrointestinal tract during acute normovolemic anemia may be underestimated.

Inflammatory and redox responses to ischaemia/reperfusion in human skeletal muscle.

The objective of this study was to identify cellular and plasma marker(s) of post-I/R (ischaemia/reperfusion) in patients undergoing elective knee surgery where a tourniquet was used to facilitate a bloodless surgical field. We evaluated the inflammatory and redox response by measuring the mRNA levels of ICAM-1 (intercellular cell-adhesion molecule-1), MnSOD (manganese superoxide dismutase), GST-mu (glutathione transferase-mu) and Cu/ZnSOD (copper/zinc superoxide dismutase) in the operated muscle and blood cells pre-operatively (pre-tourniquet) and at various times after reperfusion (tourniquet release). We also measured plasma concentrations of IL (interleukin)-6, IL-8, sICAM-1 (soluble ICAM-1), IL-1beta and TNF-alpha (tumour necrosis factor-alpha) using ELISA. Our results show a strong induction of MnSOD and GST-mu in granulocytes (but not in mononuclear cells or muscle) after reperfusion (2 and 4 h). There was no change in the mRNA level of Cu/ZnSOD after reperfusion. An up-regulation of membrane ICAM-1 in muscle and a decrease in sICAM-1 in plasma were detected after reperfusion. Plasma IL-6 and IL-8 levels (but not TNF-alpha or IL-1beta) increased significantly over baseline at 2 and 4 h after reperfusion. Elevated expression of ICAM-1 in muscle, MnSOD and GST-mu in granulocytes and increased levels of plasma IL-6 and IL-8 may be considered as phase- and cell-specific markers of post-I/R of skeletal muscle in humans.

Selective activation of protein kinase C delta in human neutrophils following ischemia reperfusion of skeletal muscle.

Circulatory neutrophils are known to be critical mediators of inflammation and oxidative stress during ischemia reperfusion (I/R) injury. Recent studies have shown an important role for protein kinase C (PKC) in neutrophil survival and function. Activation of specific isotypes of PKC are known to be involved in membrane alteration and motility, oxidative phosphorylation, and apoptosis modulation of neutrophils. However, the role of PKC in neutrophil responses to I/R in the clinical setting has not been studied. In this study, we examined the neutrophil activation of PKC induced by tourniquet-controlled I/R of skeletal muscle in humans. We found that I/R rapidly activates and translocates PKC delta, but not any of the classical forms of PKC (alpha or beta) from cytosol to the particulate fraction of neutrophils. Particulate translocation of PKC delta is sustained up to 4 h after reperfusion and is associated with kinase activity. Postreperfusion activation of PKC delta in neutrophils signals proapoptosis, but does not cause immediate cell death (as revealed by neutrophil morphology study and DNA-laddering assay). This study indicates that calcium-independent novel PKC delta (nPKC delta) might be predominantly involved in regulating membrane functions and survival of neutrophils associated with post-I/R-induced inflammatory oxidative stress.

Low utility of dobutamine stress echocardiograms in the preoperative evaluation of patients scheduled for noncardiac surgery.

UNLABELLED: In this study, we examined the utility of preoperative dobutamine stress echocardiograms (DSE) obtained for 85 patients in accordance with guidelines published by the American College of Cardiology (ACC) and the American Heart Association (AHA). The medical record of each patient was reviewed to identify the clinical criteria that indicated the need for a DSE, the DSE results, therapeutic interventions rendered as a result of the DSE, and any perioperative cardiac morbidity. The DSE was positive for inducible ischemia in 4 patients (4.7%), negative in 74 (87.1%), and nondiagnostic in 7 (8.2%). DSEs that were obtained for 48 patients because of a history of diabetes mellitus, mild angina, or "minor clinical predictors" produced only negative results. Of the four patients with positive DSE results, three underwent coronary angiography, and one of those three underwent bypass grafting before surgery. An additional 29 patients received a preoperative DSE but were excluded from the study because the criteria for ordering the DSE did not meet the ACC/AHA guidelines. No patient had any perioperative morbidity related to myocardial ischemia. The total patient charge for the 85 DSEs obtained at our institution was US$104,635. Use of the ACC/AHA guidelines for preoperative DSEs does not appear to be cost-effective. However, the current algorithm could be significantly improved by altering the criteria for obtaining preoperative DSEs. IMPLICATIONS: This study was a retrospective review of 85 patient charts that found a low cost-effectiveness of using American College of Cardiology/American Heart Association guidelines for obtaining preoperative dobutamine stress echocardiograms. Suggested modifications of these guidelines should improve their specificity with no loss in sensitivity.