Larry F. Chu

Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations.

Opioid-induced hyperalgesia (OIH) is most broadly defined as a state of nociceptive sensitization caused by exposure to opioids. The state is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain may actually become more sensitive to certain painful stimuli. The type of pain experienced may or may not be different from the original underlying painful condition. Although the precise molecular mechanism is not yet understood, it is generally thought to result from neuroplastic changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive pathways. OIH seems to be a distinct, definable, and characteristic phenomenon that may explain loss of opioid efficacy in some cases. Clinicians should suspect expression of OIH when opioid treatment effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the pain as previously observed. This review highlights the important mechanistic underpinnings and clinical ramifications of OIH and discusses future research directions and the latest clinical evidence for modulation of this potentially troublesome clinical phenomenon.

Analysis of 4999 online physician ratings indicates that most patients give physicians a favorable rating.

Background Many online physician-rating sites provide patients with information about physicians and allow patients to rate physicians. Understanding what information is available is important given that patients may use this information to choose a physician. Objectives The goals of this study were to (1) determine the most frequently visited physician-rating websites with user-generated content, (2) evaluate the available information on these websites, and (3) analyze 4999 individual online ratings of physicians. Methods On October 1, 2010, using Google Trends we identified the 10 most frequently visited online physician-rating sites with user-generated content. We then studied each site to evaluate the available information (eg, board certification, years in practice), the types of rating scales (eg, 1–5, 1–4, 1–100), and dimensions of care (eg, recommend to a friend, waiting room time) used to rate physicians. We analyzed data from 4999 selected physician ratings without identifiers to assess how physicians are rated online. Results The 10 most commonly visited websites with user-generated content were HealthGrades.com, Vitals.com, Yelp.com, YP.com, RevolutionHealth.com, RateMD.com, Angieslist.com, Checkbook.org, Kudzu.com, and ZocDoc.com. A total of 35 different dimensions of care were rated by patients in the websites, with a median of 4.5 (mean 4.9, SD 2.8, range 1–9) questions per site. Depending on the scale used for each physician-rating website, the average rating was 77 out of 100 for sites using a 100-point scale (SD 11, median 76, range 33–100), 3.84 out of 5 (77%) for sites using a 5-point scale (SD 0.98, median 4, range 1–5), and 3.1 out of 4 (78%) for sites using a 4-point scale (SD 0.72, median 3, range 1–4). The percentage of reviews rated ≥75 on a 100-point scale was 61.5% (246/400), ≥4 on a 5-point scale was 57.74% (2078/3599), and ≥3 on a 4-point scale was 74.0% (740/1000). The patient’s single overall rating of the physician correlated with the other dimensions of care that were rated by patients for the same physician (Pearson correlation, r = .73, P < .001). Conclusions Most patients give physicians a favorable rating on online physician-rating sites. A single overall rating to evaluate physicians may be sufficient to assess a patient’s opinion of the physician. The optimal content and rating method that is useful to patients when visiting online physician-rating sites deserves further study. Conducting a qualitative analysis to compare the quantitative ratings would help validate the rating instruments used to evaluate physicians.

Prescription opioid analgesics rapidly change the human brain

&NA; Chronic opioid exposure is known to produce neuroplastic changes in animals; however, it is not known if opioids used over short periods of time and at analgesic dosages can similarly change brain structure in humans. In this longitudinal, magnetic resonance imaging study, 10 individuals with chronic low back pain were administered oral morphine daily for 1 month. High‐resolution anatomical images of the brain were acquired immediately before and after the morphine administration period. Regional changes in gray matter volume were assessed on the whole brain using tensor‐based morphometry, and those significant regional changes were then independently tested for correlation with morphine dosage. Thirteen regions evidenced significant volumetric change, and degree of change in several of the regions was correlated with morphine dosage. Dosage‐correlated volumetric decrease was observed primarily in the right amygdala. Dosage‐correlated volumetric increase was seen in the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons. Follow‐up scans that were conducted an average of 4.7 months after cessation of opioids demonstrated many of the morphine‐induced changes to be persistent. In a separate study, 9 individuals consuming blinded placebo capsules for 6 weeks evidenced no significant morphologic changes over time. The results add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward‐ and affect‐processing circuitry. Morphologic changes occur rapidly in humans during new exposure to prescription opioid analgesics. Further research is needed to determine the clinical impact of those opioid‐induced gray matter changes. After 1 month of daily opioid analgesic consumption, chronic pain patients showed morphologic changes in several reward‐processing and limbic areas of the brain.

Communication in critical care environments: mobile telephones improve patient care.

Most hospital policies prohibiting the use of wireless devices cite reports of disruption of medical equipment by cellular telephones. There have been no studies to determine whether mobile telephones may have a beneficial impact on safety. At the 2003 meeting of the American Society of Anesthesiologists 7878 surveys were distributed to attendees. The five-question survey polled anesthesiologists regarding modes of communication used in the operating room/intensive care unit and experience with communications delays and medical errors. Survey reliability was verified using test-retest analysis and proportion agreement in a convenience sample of 17 anesthesiologists. Four-thousand-eighteen responses were received. The test-retest reliability of the survey instrument was excellent (Kappa = 0.75; 95% confidence interval, 0.56–0.94). Sixty-five percent of surveyed anesthesiologists reported using pagers as their primary mode of communications, whereas only 17% used cellular telephones. Forty-five percent of respondents who use pagers reported delays in communications compared with 31% of cellular telephone users. Cellular telephone use by anesthesiologists is associated with a reduction in the risk of medical error or injury resulting from communication delay (relative risk = 0.78; 95% confidence interval, 0.6234–0.9649). The small risks of electromagnetic interference between mobile telephones and medical devices should be weighed against the potential benefits of improved communication.

Ketamine does not increase pulmonary vascular resistance in children with pulmonary hypertension undergoing sevoflurane anesthesia and spontaneous ventilation.

BACKGROUND:The use of ketamine in children with increased pulmonary vascular resistance is controversial. In this prospective, open label study, we evaluated the hemodynamic responses to ketamine in children with pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg). METHODS:Children aged 3 mo to 18 yr with pulmonary hypertension, who were scheduled for cardiac catheterization with general anesthesia, were studied. Patients were anesthetized with sevoflurane (1 minimum alveolar anesthetic concentration [MAC]) in air while breathing spontaneously via a facemask. After baseline catheterization measurements, sevoflurane was reduced (0.5 MAC) and ketamine (2 mg/kg IV over 5 min) was administered, followed by a ketamine infusion (10 &mgr;g · kg−1 · min−1). Catheterization measurements were repeated at 5, 10, and 15 min after completion of ketamine load. Data at various time points were compared (ANOVA, P < 0.05). RESULTS:Fifteen patients (age 147, 108 mo; median, interquartile range) were studied. Diagnoses included idiopathic pulmonary arterial hypertension (5), congenital heart disease (9), and diaphragmatic hernia (1). At baseline, median (interquartile range) baseline pulmonary vascular resistance index was 11.3 (8.2) Wood units; 33% of patients had suprasystemic mean pulmonary artery pressures. Heart rate (99, 94 bpm; P = 0.016) and Pao2 (95, 104 mm Hg; P = 007) changed after ketamine administration (baseline, 15 min after ketamine; P value). There were no significant differences in mean systemic arterial blood pressure, mean pulmonary artery pressure, systemic or pulmonary vascular resistance index, cardiac index, arterial pH, or Paco2. CONCLUSIONS:In the presence of sevoflurane, ketamine did not increase pulmonary vascular resistance in spontaneously breathing children with severe pulmonary hypertension.

Analgesic tolerance without demonstrable opioid-induced hyperalgesia: A double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain

Summary After 1 month of oral morphine therapy, chronic low‐back pain patients developed tolerance but not opioid‐induced hyperalgesia. Improvements in pain and functional ability were observed. Abstract Although often successful in acute settings, long‐term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently opioid‐induced hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low‐back pain were titrated to comfort or dose‐limiting side effects in a prospective, randomized, double‐blind, placebo‐controlled clinical trial using sustained‐release morphine or weight‐matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine‐treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop opioid‐induced hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine‐treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self‐reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low‐back pain developed tolerance but not opioid‐induced hyperalgesia. Improvements in pain and functional ability were observed.

Anesthesia 2.0: internet-based information resources and Web 2.0 applications in anesthesia education.

Purpose of review Informatics is a broad field encompassing artificial intelligence, cognitive science, computer science, information science, and social science. The goal of this review is to illustrate how Web 2.0 information technologies could be used to improve anesthesia education. Recent findings Educators in all specialties of medicine are increasingly studying Web 2.0 technologies to maximize postgraduate medical education of housestaff. These technologies include microblogging, blogs, really simple syndication (RSS) feeds, podcasts, wikis, and social bookmarking and networking. ‘Anesthesia 2.0’ reflects our expectation that these technologies will foster innovation and interactivity in anesthesia-related web resources which embraces the principles of openness, sharing, and interconnectedness that represent the Web 2.0 movement. Although several recent studies have shown benefits of implementing these systems into medical education, much more investigation is needed. Summary Although direct practice and observation in the operating room are essential, Web 2.0 technologies hold great promise to innovate anesthesia education and clinical practice such that the resident learner need not be in a classroom for a didactic talk, or even in the operating room to see how an arterial line is properly placed. Thoughtful research to maximize implementation of these technologies should be a priority for development by academic anesthesiology departments. Web 2.0 and advanced informatics resources will be part of physician lifelong learning and clinical practice.

From mouse to man : the 5-HT3 receptor modulates physical dependence on opioid narcotics

Objectives Addiction to opioid narcotics represents a major public health challenge. Animal models of one component of addiction, physical dependence, show this trait to be highly heritable. The analysis of opioid dependence using contemporary in-silico techniques offers an approach to discover novel treatments for dependence and addiction. Methods In these experiments, opioid withdrawal behavior in 18 inbred strains of mice was assessed. Mice were treated for 4 days with escalating doses of morphine before the administration of naloxone allowing the quantification of opioid dependence. After haplotypic analysis, experiments were designed to evaluate the top gene candidate as a modulator of physical dependence. Behavioral studies as well as measurements of gene expression on the mRNA and protein levels were completed. Finally, a human model of opioid dependence was used to quantify the effects of the 5-HT3 antagonist ondansetron on signs and symptoms of withdrawal. Results The Htr3a gene corresponding to the 5-HT3 receptor emerged as the leading candidate. Pharmacological studies using the selective 5-HT3 antagonist ondansetron supported the link in mice. Morphine strongly regulated the expression of the Htr3a gene in various central nervous system regions including the amygdala, dorsal raphe, and periaqueductal gray nuclei, which have been linked to opioid dependence in previous studies. Using an acute morphine administration model, the role of 5-HT3 in controlling the objective signs of withdrawal in humans was confirmed. Conclusion These studies show the power of in-silico genetic mapping, and reveal a novel target for treating an important component of opioid addiction.

Single-Dose, Extended-Release Epidural Morphine (DepoDur™) Compared to Conventional Epidural Morphine for Post-Cesarean Pain

BACKGROUND: A single-dose of neuraxial morphine sulfate provides good post-Cesarean analgesia; however, its efficacy is limited to the first postoperative day. In a recent phase III study, extended-release epidural morphine (EREM) formulation provided more effective, prolonged analgesia after Cesarean delivery, compared to conventional epidural morphine. However, the study protocol did not allow for the use of nonsteroidal antiinflammatory drugs, used various postoperative analgesics, and monitoring and treatment of respiratory depression were not standardized. Our aims in this study were to compare postoperative analgesic consumption, pain scores and side effects of EREM with conventional morphine for the management of post-Cesarean pain in a setting more reflective of current obstetric practice. METHODS: Seventy healthy parturients undergoing elective Cesarean delivery were enrolled in this randomized, double-blind study. Using a combined spinal epidural technique, patients received an intrathecal injection of bupivacaine 12 mg and fentanyl 10 mcg. After closure of the fascia, a single-dose of either conventional morphine 4 mg or EREM 10 mg was administered epidurally. Postoperatively, all patients received ibuprofen 600 mg orally every 6 h. Oral oxycodone and IV morphine were available for breakthrough pain. All patients received pulse oximetry and respiratory monitoring for 48 h post-Cesarean delivery. RESULTS: Single-dose EREM significantly improved pain scores at rest and during activity. The median (interquartile range) of supplemental opioid medication usage for 48 h post-Cesarean (in milligram-morphine equivalents) decreased from 17 (22) to 10 (17) mg with EREM compared to conventional epidural morphine (P = 0.037). Both drugs were well tolerated with no significant difference in adverse event profiles. CONCLUSION: EREM provides superior and prolonged post-Cesarean analgesia compared to conventional epidural morphine with no significant increases in adverse events.

No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans

ABSTRACT It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in “acute tolerance.” The aim of this double‐blind, placebo‐controlled study in thirty‐six healthy human volunteers was to examine whether a 3‐h intravenous infusion delivering two different but clinically relevant doses of the μ‐opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3‐h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3‐h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady‐state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3‐h infusion. The study was adequately powered to detect a decrease in potency of 5–24% for analgesia, 20–48% for respiratory depression, and 32% for sedative effects. These results suggest that short‐term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects.