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1.  Perspectives on the Role of Fospropofol in the Monitored Anesthesia Care Setting 
Monitored anesthesia care (MAC) is a safe, effective, and appropriate form of anesthesia for many minor surgical procedures. The proliferation of outpatient procedures has heightened interest in MAC sedation agents. Among the most commonly used MAC sedation agents today are benzodiazepines, including midazolam, and propofol. Recently approved in the United States is fospropofol, a prodrug of propofol which hydrolyzes in the body by alkaline phosphatase to liberate propofol. Propofol liberated from fospropofol has unique pharmacological properties, but recently retracted pharmacokinetic (PK) and pharmacodynamic (PD) evaluations make it difficult to formulate clear conclusions with respect to fospropofol's PK/PD properties. In safety and efficacy clinical studies, fospropofol demonstrated dose-dependent sedation with good rates of success at doses of 6.5 mg/kg along with good levels of patient and physician acceptance. Fospropofol has been associated with less pain at injection site than propofol. The most commonly reported side effects with fospropofol are paresthesia and pruritus. Fospropofol is a promising new sedation agent that appears to be well suited for MAC sedation, but further studies are needed to better understand its PK/PD properties as well its appropriate clinical role in outpatient procedures.
doi:10.1155/2011/458920
PMCID: PMC3085302  PMID: 21541247
2.  Fast-Acting Sublingual Zolpidem for Middle-of-the-Night Wakefulness 
Sleep Disorders  2014;2014:527109.
Sleep disorders (somnipathies) are conditions characterized by disruptions of sleep quality or of sleep pattern. They can involve difficulty falling asleep (prolonged sleep onset latency), difficulty staying asleep (disturbance of sleep maintenance), sleep of poor quality (unrefreshing), or combinations of these and can lead to poor health and quality of life problems. A subtype of sleep-maintenance insomnia is middle-of-the-night wakefulness, a relatively common occurrence. Zolpidem, a nonbenzodiazepine benzodiazepine receptor agonist, allosterically modulates an ion channel and increases the influx of Cl−, thereby dampening the effect of excitatory (sleep disrupting) input. Recently, product label changes to some zolpidem containing products have been implemented by the FDA in order to reduce the risk associated with their morning after residual side effects. A new formulation of zolpidem tartrate (Intermezzo) sublingual tablet, an approved product indicated exclusively for the treatment of middle-of-the-night wakefulness and difficulty returning to sleep, did not have its label changed. We present a short summary of its basic science and clinical attributes in light of the recent regulatory changes for zolpidem products.
doi:10.1155/2014/527109
PMCID: PMC3932650  PMID: 24649369
3.  Tramadol/paracetamol fixed-dose combination in the treatment of moderate to severe pain 
Journal of Pain Research  2012;5:327-346.
Pain is the most common reason patients seek medical attention and pain relief has been put forward as an ethical obligation of clinicians and a fundamental human right. However, pain management is challenging because the pathophysiology of pain is complex and not completely understood. Widely used analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) have been associated with adverse events. Adverse event rates are of concern, especially in long-term treatment or at high doses. Paracetamol and NSAIDs are available by prescription, over the counter, and in combination preparations. Patients may be unaware of the risk associated with high dosages or long-term use of paracetamol and NSAIDs. Clinicians should encourage patients to disclose all medications they take in a “do ask, do tell” approach that includes patient education about the risks and benefits of common pain relievers. The ideal pain reliever would have few risks and enhanced analgesic efficacy. Fixed-dose combination analgesics with two or more agents may offer additive or synergistic benefits to treat the multiple mechanisms of pain. Therefore, pain may be effectively treated while toxicity is reduced due to lower doses. One recent fixed-dose combination analgesic product combines tramadol, a centrally acting weak opioid analgesic, with low-dose paracetamol. Evidence-based guidelines recognize the potential value of combination analgesics in specific situations. The current guideline-based paradigm for pain treatment recommends NSAIDs for ongoing use with analgesics such as opioids to manage flares. However, the treatment model should evolve how to use low-dose combination products to manage pain with occasional use of NSAIDs for flares to avoid long-term and high-dose treatment with these analgesics. A next step in pain management guidelines should be targeted therapy when possible, or low-dose combination therapy or both, to achieve maximal efficacy with minimal toxicity.
doi:10.2147/JPR.S33112
PMCID: PMC3442743  PMID: 23055775
NSAIDs; opioids; combination analgesics; moderate pain; severe pain; analgesics; tramadol/paracetamol
4.  Pain Management in the Elderly: An FDA Safe Use Initiative Expert Panel's View on Preventable Harm Associated with NSAID Therapy 
Optimization of current pain management strategies is necessary in order to reduce medication risks. Promoting patient and healthcare provider education on pain and pain medications is an essential step in reducing inadequate prescribing behaviors and adverse events. In an effort to raise awareness on medication safety, the FDA has launched the Safe Use Initiative program. The program seeks to identify areas with the greatest amount of preventable harm and help promote new methods and practices to reduce medication risks. Since the establishment of the program, FDA's Safe Use initiative staff convened a panel of key opinion leaders throughout the medical community to address pain management in older adults (≥65 years of age). The aim of the expert panel was to focus on areas where significant risk occurs and where potential interventions will be feasible, implementable, and lead to substantial impact. The panel suggested one focus could be the use of NSAIDs for pain management in the elderly.
doi:10.1155/2012/196159
PMCID: PMC3287013  PMID: 22400024
5.  Prophylaxis of Postoperative Nausea and Vomiting in Adolescent Patients: A Review with Emphasis on Combination of Fixed-Dose Ondansetron and Transdermal Scopolamine 
Journal of Drug Delivery  2011;2011:426813.
Postoperative nausea and vomiting (PONV) is a relatively common occurrence (20–30%) that delays discharge and, if persistent, can lead to serious complications. The incidence of PONV is a function of patient characteristics, the type and duration of surgery, the type of anesthesia, and the choice of pre-, intra-, and postoperative pharmacotherapy. There are no completely effective antiemetic agents for this condition, but recommendations for treatment strategies are separately available for pediatric and adult patients. Left unclear is whether adolescents should be guided by the pediatric or the adult recommendations. We review the developmental physiology of the relevant physiological factors (absorption, distribution, metabolism, and elimination). We also review the clinical evidence regarding the safety and efficacy of a fixed-dose combination of ondansetron (4 mg, i.v.) and transdermal scopolamine (1.5 mg).
doi:10.1155/2011/426813
PMCID: PMC3134884  PMID: 21773046
6.  Opioid formulations with sequestered naltrexone: a perspective review 
In response to good-intentioned efforts to correct the traditional undertreatment of pain, opioid prescribing experienced a dramatic increase over the past decade. But there is now concern that the pendulum has swung too far in the opposite direction, with a rise in morbidity and mortality associated with prescription opioid misuse and abuse. Yet despite potential problems, opioids are a mainstay for the treatment of pain and are an important component of a comprehensive pain management strategy. Therefore, the overall goal of pain management is to decrease pain and to improve patient functioning and quality of life, while monitoring for adverse effects or aberrant behaviors. That is, to balance effective chronic pain management with appropriate use of opioids. Toward this end, several abuse deterrent strategies (formulations) have been, and continue to be, developed. Several major ones are reviewed here. These products should be a first step in trying to address diversion and abuse in a manner that does not discriminate against any particular patient and aligns with universal prescribing precautions. They should also comprise only one aspect of an overall opioid risk management plan.
doi:10.1177/2042098614526769
PMCID: PMC4110852  PMID: 25083268
abuse deterrent; analgesic; chronic pain; opioid; opioid risk management
7.  The effect of transdermal scopolamine for the prevention of postoperative nausea and vomiting 
Postoperative nausea and vomiting (PONV) is one of the most common and undesirable complaints recorded in as many as 70–80% of high-risk surgical patients. The current prophylactic therapy recommendations for PONV management stated in the Society of Ambulatory Anesthesia (SAMBA) guidelines should start with monotherapy and patients at moderate to high risk, a combination of antiemetic medication should be considered. Consequently, if rescue medication is required, the antiemetic drug chosen should be from a different therapeutic class and administration mode than the drug used for prophylaxis. The guidelines restrict the use of dexamethasone, transdermal scopolamine, aprepitant, and palonosetron as rescue medication 6 h after surgery. In an effort to find a safer and reliable therapy for PONV, new drugs with antiemetic properties and minimal side effects are needed, and scopolamine may be considered an effective alternative. Scopolamine is a belladonna alkaloid, α-(hydroxymethyl) benzene acetic acid 9-methyl-3-oxa-9-azatricyclo non-7-yl ester, acting as a non-selective muscarinic antagonist and producing both peripheral antimuscarinic and central sedative, antiemetic, and amnestic effects. The empirical formula is C17H21NO4 and its structural formula is a tertiary amine L-(2)-scopolamine (tropic acid ester with scopine; MW = 303.4). Scopolamine became the first drug commercially available as a transdermal therapeutic system used for extended continuous drug delivery during 72 h. Clinical trials with transdermal scopolamine have consistently demonstrated its safety and efficacy in PONV. Thus, scopolamine is a promising candidate for the management of PONV in adults as a first line monotherapy or in combination with other drugs. In addition, transdermal scopolamine might be helpful in preventing postoperative discharge nausea and vomiting owing to its long-lasting clinical effects.
doi:10.3389/fphar.2014.00055
PMCID: PMC3988383  PMID: 24782768
nausea; vomiting; antiemetic; postoperative; prophylaxis; transdermal scopolamine; pharmacokinetics; pharmacodynamics
8.  Mitigating the risk of opioid abuse through a balanced undergraduate pain medicine curriculum 
Journal of Pain Research  2013;6:791-801.
Chronic pain is highly prevalent in the United States and Canada, occurring in an estimated 30% of the adult population. Despite its high prevalence, US and Canadian medical schools provide very little training in pain management, including training in the safe and effective use of potent analgesics, most notably opioids. In 2005, the International Association for the Study of Pain published recommendations for a core undergraduate pain management curriculum, and several universities have implemented pilot programs based on this curriculum. However, when outcomes have been formally assessed, these initiatives have resulted in only modest improvements in physician knowledge about chronic pain and its treatment. This article discusses strategies to improve undergraduate pain management curricula and proposes areas in which those efforts can be augmented. Emphasis is placed on opioids, which have great potency as analgesics but also substantial risks in terms of adverse events and the risk of abuse and addiction. The authors conclude that the most important element of an undergraduate pain curriculum is clinical experience under mentors who are capable of reinforcing didactic learning by modeling best practices.
doi:10.2147/JPR.S47192
PMCID: PMC3862507  PMID: 24353438
chronic pain; curricular content; medical education; opioids; pain education; pain knowledge; physician training; teaching
9.  Tramadol/Paracetamol Fixed-Dose Combination for Chronic Pain Management in Family Practice: A Clinical Review 
ISRN Family Medicine  2013;2013:638469.
The family practitioner plays an important role in the prevention, diagnosis, and early management of chronic pain. He/she is generally the first to be consulted, the one most familiar with the patients and their medical history, and is likely the first to be alerted in case of inadequate pain control or safety and tolerability issues. The family practitioner should therefore be at the center of the multidisciplinary team involved in a patient's pain management. The most frequent indications associated with chronic pain in family practice are of musculoskeletal origin, and the pain is often multimechanistic. Fixed-dose combination analgesics combine compounds with different mechanisms of action; their broader analgesic spectrum and potentially synergistic analgesic efficacy and improved benefit/risk ratio might thus be useful. A pain specialist meeting held in November 2010 agreed that the fixed-dose combination tramadol/paracetamol might be a useful pharmacological option for chronic pain management in family practice. The combination is effective in a variety of pain conditions with generally good tolerability. Particularly in elderly patients, it might be considered as an alternative to conventional analgesics such as NSAIDs, which should be used rarely with caution in this population.
doi:10.5402/2013/638469
PMCID: PMC4041254  PMID: 24959571
10.  Designing Opioids That Deter Abuse 
Pain Research and Treatment  2012;2012:282981.
Prescription opioid formulations designed to resist or deter abuse are an important step in reducing opioid abuse. In creating these new formulations, the paradigm of drug development target should be introduced. Biological targets relating to the nature of addiction may pose insurmountable hurdles based on our current knowledge and technology, but products that use behavioral targets seem logical and feasible. The population of opioid abusers is large and diverse so behavioral targets are more challenging than they appear at first glance. Furthermore, we need to find ways to correlate behavioral observations of drug liking to actual use and abuse patterns. This may involve revisiting some pharmacodynamic concepts in light of drug effect rather than peak concentration. In this paper we present several new opioid analgesic agents designed to resist or deter abuse using physical barriers, the inclusion of an opioid agonist or antagonist, an aversive agent, and a prodrug formulation. Further, this paper also provides insight into the challenges facing drug discovery in this field. Designing and screening for opioids intended to resist or deter abuse is an important step to meet the public health challenge of burgeoning prescription opioid abuse.
doi:10.1155/2012/282981
PMCID: PMC3503437  PMID: 23213510
11.  Controlled release formulation of oxycodone in patients with moderate to severe chronic osteoarthritis: a critical review of the literature 
Journal of Pain Research  2012;5:77-87.
Osteoarthritis (OA) is a physically and emotionally debilitating disease that predominantly affects the aging adult population. Current pharmacologic treatment options primarily consist of nonsteroidal anti-inflammatory drugs and/or acetaminophen, but associated side effects, analgesic limitations, especially in the elderly, and the need for around-the-clock analgesia have led physicians to search for alternative analgesics. Opioids have shown effectiveness at mitigating both chronic cancer and noncancer pain, and their ability to be placed into controlled release (CR) formulations suggests that they may prove efficacious for OA patients. One formulation, oxycodone CR, has shown effectiveness in cancer pain patients and in some trials of noncancer low back pain. In this review, the objective was to synthesize the reported findings by researchers in this field and present an up-to-date look at the efficacy, safety, and tolerability of oxycodone CR in OA patients. Public literature databases were searched using specific keywords (eg, oxycodone CR) for studies assessing the efficacy and safety profile of oxycodone CR and its use in patients with OA. A total of eleven articles that matched the criteria were identified, which included three placebo-controlled trials, six comparative trials, one pharmacokinetic study in the elderly, and one long-term safety trial. Analysis of the studies revealed that oxycodone CR is reasonably efficacious, safe, and tolerable when used to manage moderate to severe chronic OA pain, with similar side effects to that of other opioids.
doi:10.2147/JPR.S21965
PMCID: PMC3346069  PMID: 22570559
oxycodone; extended release; controlled release; opioid; osteoarthritis
12.  Pain Treatment in Arthritis-Related Pain: Beyond NSAIDs 
Managing pain from chronic conditions, such as, but not limited to, osteoarthritis and rheumatoid arthritis, requires the clinician to balance the need for effective analgesia against safety risks associated with analgesic agents. Osteoarthritis and rheumatoid arthritis pain is incompletely understood but involves both nociceptive and non-nociceptive mechanisms, including neuropathic mechanisms. Prevailing guidelines for arthritis-related pain do not differentiate between nociceptive and non-nociceptive pain, sometimes leading to recommendations that do not fully address the nature of pain. NSAIDs are effective in treating the nociceptive arthritis-related pain. However, safety concerns of NSAIDs may cause clinicians to undertreat arthritis-related pain. In this context, combination therapy may be more appropriate to manage the different pain mechanisms involved. A panel convened in November 2010 found that among the currently recommended analgesic products for arthritis-related pain, fixed-low-dose combination products hold promise for pain control because such products allow lower doses of individual agents resulting in decreased toxicity and acceptable efficacy due to synergy between the individual drugs. Better evidence and recommendations are required to improve treatment of chronic arthritis-related pain.
doi:10.2174/1874312901206010320
PMCID: PMC3527878  PMID: 23264838
Osteoarthritis; rheumatoid arthritis; analgesia; fixed-dose combination products; NSAID; paracetamol; tramadol.
13.  Naltrexone extended-release injection: an option for the management of opioid abuse 
The United States Food and Drug Administration (FDA) approved naltrexone, a synthetic competitive antagonist at opioid receptors, in oral form in 1984 for use in the management of opioid abuse and addiction. Because naltrexone and its major metabolite, 6-β-naltrexone, are both competitive antagonists at opioid receptors – and thereby inhibit opioid agonist-induced effects including those desired by abusers – it was hypothesized that once maintained on naltrex-one, opioid-induced desirable effects would be diminished to the point that relapse to illicit use would decline because it was no longer rewarding. However, good medication compliance is a requisite for such a strategy to be effective and a systematic review of oral naltrexone concluded that this method of treatment was not superior for any outcomes measured (ie, retention, abstinence, or side effects) to placebo, psychotherapy, benzodiazepines, or buprenorphine treatment. In addition, the retention rate on oral naltrexone was very low (less than 30%). Recently, the FDA approved an extended-release formulation (intramuscular depot injection) of naltrexone for prevention of relapse to opioid dependence following opioid detoxification and to be used along with counseling and social support. Since it needs to be administered only monthly, as opposed to the daily administration required for the oral formulation, naltrexone injection has the potential for increasing adherence and retention rates. Concerns include liver damage at high doses (oral formulation) and possible opioid overdose if an attempt is made to surmount receptor antagonism by taking higher doses of an opioid agonist or if opioid receptors become “sensitized” under long-term antagonism. The focus of the present review is the current information regarding the safety and efficacy of naltrexone extended-release therapy.
doi:10.2147/SAR.S17920
PMCID: PMC3846318  PMID: 24474859
opioid dependence; relapse prevention; depot injection; extended-release naltrexone
14.  Analgesic combinations 
When the pathophysiology of a medical condition is multi-modal, i.e., related to multiple physiological causes or mediated by multiple pathways, the optimal strategy can be to use a drug or a combination of drugs that contribute multiple mechanisms to the therapeutic endpoint. In such situations, a rational multi-modal approach can also result in the fewest adverse effects. We discuss the quantitative analysis of multi-modal action using the treatment of pain as a practical example and give examples of its application to some widely used analgesic drugs.
doi:10.1016/j.jpain.2009.12.010
PMCID: PMC2920146  PMID: 20338825
Analgesic; drug combination; isobole; multi-modal; synergy
15.  Anesthetic Routines: The Anesthesiologist's Role in GI Recovery and Postoperative Ileus 
All patients undergoing bowel resection experience postoperative ileus, a transient cessation of bowel motility that prevents effective transit of intestinal contents or tolerance of oral intake, to varying degrees. An anesthesiologist plays a critical role, not only in the initiation of surgical anesthesia, but also with the selection and transition to effective postoperative analgesia regimens. Attempts to reduce the duration of postoperative ileus have prompted the study of various preoperative, perioperative, and postoperative regimens to facilitate gastrointestinal recovery. These include modifiable variables such as epidural anesthesia and analgesia, opioid-sparing anesthesia and analgesia, fluid restriction, colloid versus crystalloid combinations, prokinetic drugs, and use of the new peripherally acting mu-opioid receptor (PAM-OR) antagonists. Review and appropriate adaptation of these multiple modifiable interventions by anesthesiologists and their surgical colleagues will facilitate implementation of a best-practice management routine for bowel resection procedures that will benefit the patient and the healthcare system.
doi:10.4061/2011/976904
PMCID: PMC3168940  PMID: 21991449
16.  Restoration of disk height through non-surgical spinal decompression is associated with decreased discogenic low back pain: a retrospective cohort study 
Background
Because previous studies have suggested that motorized non-surgical spinal decompression can reduce chronic low back pain (LBP) due to disc degeneration (discogenic low back pain) and disc herniation, it has accordingly been hypothesized that the reduction of pressure on affected discs will facilitate their regeneration. The goal of this study was to determine if changes in LBP, as measured on a verbal rating scale, before and after a 6-week treatment period with non-surgical spinal decompression, correlate with changes in lumbar disc height, as measured on computed tomography (CT) scans.
Methods
A retrospective cohort study of adults with chronic LBP attributed to disc herniation and/or discogenic LBP who underwent a 6-week treatment protocol of motorized non-surgical spinal decompression via the DRX9000 with CT scans before and after treatment. The main outcomes were changes in pain as measured on a verbal rating scale from 0 to 10 during a flexion-extension range of motion evaluation and changes in disc height as measured on CT scans. Paired t-test or linear regression was used as appropriate with p < 0.05 considered to be statistically significant.
Results
We identified 30 patients with lumbar disc herniation with an average age of 65 years, body mass index of 29 kg/m2, 21 females and 9 males, and an average duration of LBP of 12.5 weeks. During treatment, low back pain decreased from 6.2 (SD 2.2) to 1.6 (2.3, p < 0.001) and disc height increased from 7.5 (1.7) mm to 8.8 (1.7) mm (p < 0.001). Increase in disc height and reduction in pain were significantly correlated (r = 0.36, p = 0.044).
Conclusions
Non-surgical spinal decompression was associated with a reduction in pain and an increase in disc height. The correlation of these variables suggests that pain reduction may be mediated, at least in part, through a restoration of disc height. A randomized controlled trial is needed to confirm these promising results.
Clinical trial registration number
NCT00828880
doi:10.1186/1471-2474-11-155
PMCID: PMC2912793  PMID: 20615252
17.  Anesthesiologists' practice patterns for treatment of postoperative nausea and vomiting in the ambulatory Post Anesthesia Care Unit 
BMC Anesthesiology  2006;6:6.
Background
When patients are asked what they find most anxiety provoking about having surgery, the top concerns almost always include postoperative nausea and vomiting (PONV). Only until recently have there been any published recommendations, mostly derived from expert opinion, as to which regimens to use once a patient develops PONV. The goal of this study was to assess the responses to a written survey to address the following questions: 1) If no prophylaxis is administered to an ambulatory patient, what agent do anesthesiologists use for treatment of PONV in the ambulatory Post-Anesthesia Care Unit (PACU)?; 2) Do anesthesiologists use non-pharmacologic interventions for PONV treatment?; and 3) If a PONV prophylaxis agent is administered during the anesthetic, do anesthesiologists choose an antiemetic in a different class for treatment?
Methods
A questionnaire with five short hypothetical clinical vignettes was mailed to 300 randomly selected USA anesthesiologists. The types of pharmacological and nonpharmacological interventions for PONV treatment were analyzed.
Results
The questionnaire was completed by 106 anesthesiologists (38% response rate), who reported that on average 52% of their practice was ambulatory. If a patient develops PONV and received no prophylaxis, 67% (95% CI, 62% – 79%) of anesthesiologists reported they would administer a 5-HT3-antagonist as first choice for treatment, with metoclopramide and dexamethasone being the next two most common choices. 65% (95% CI, 55% – 74%) of anesthesiologists reported they would also use non-pharmacologic interventions to treat PONV in the PACU, with an IV fluid bolus or nasal cannula oxygen being the most common. When PONV prophylaxis was given during the anesthetic, the preferred PONV treatment choice changed. Whereas 3%–7% of anesthesiologists would repeat dose metoclopramide, dexamethasone, or droperidol, 26% (95% confidence intervals, 18% – 36%) of practitioners would re-dose the 5-HT3-antagonist for PONV treatment.
Conclusion
5-HT3-antagonists are the most common choice for treatment of established PONV for outpatients when no prophylaxis is used, and also following prophylactic regimens that include a 5HT3 antagonist, regardless of the number of prophylactic antiemetics given. Whereas 3% – 7% of anesthesiologists would repeat dose metoclopramide, dexamethasone, or droperidol, 26% of practitioners would re-dose the 5-HT3-antagonist for PONV treatment.
doi:10.1186/1471-2253-6-6
PMCID: PMC1525160  PMID: 16740165

Results 1-18 (18)