Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as opioid-induced hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.

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Opioid-induced hyperalgesia: a qualitative systematic review.

Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross talk of neural mechanisms of pain and tolerance. Clinicians should suspect OIH when opioid treatment's 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 original pain, and increased levels of pain with increasing dosages. The treatment involves reducing the opioid dosage, tapering them off, or supplementation with NMDA receptor modulators. This comprehensive review addresses terminology and definition, prevalence, the evidence for mechanism and physiology with analysis of various factors leading to OIH, and effective strategies for preventing, reversing, or managing OIH.

A comprehensive review of opioid-induced hyperalgesia.

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The purpose of this guideline is to present evidence-based and consensus-based recommendations for the prevention and treatment of postoperative delirium. The cornerstones of the guideline are the preoperative identification and handling of patients at risk, adequate intraoperative care, postoperative detection of delirium and management of delirious patients. The scope of this guideline is not to cover ICU delirium. Considering that many medical disciplines are involved in the treatment of surgical patients, a team-based approach should be implemented into daily practice. This guideline is aimed to promote knowledge and education in the preoperative, intraoperative and postoperative setting not only among anaesthesiologists but also among all other healthcare professionals involved in the care of surgical patients.

European Society of Anaesthesiology evidence-based and consensus-based guideline on postoperative delirium

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.

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

Background:Dexmedetomidine is a highly selective α2-adrenoceptor agonist used for short-term sedation of mechanically ventilated patients. The analgesic profile of dexmedetomidine has not been fully characterized in humans.Methods:This study was designed to compare the analgesic responses of six hea

Dexmedetomidine pharmacodynamics: part I: crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers.

Background In obese patients, reduced functional residual capacity exacerbated by supine position might decrease the effectiveness of pre-oxygenation and the tolerance to apnoea. The aim of this study was to compare the effect of body posture during pre-oxygenation, sitting or supine, on its effectiveness in obese patients. Methods Forty obese patients (BMI ≥35 kg m−2) undergoing surgery with general anaesthesia were randomly assigned to one of two groups: Group 1 (sitting, n=20) or Group 2 (supine, n=20). In the predetermined body position, pre-oxygenation was achieved with eight deep breaths within 60 s and an oxygen flow of 10 litre min−1. After rapid sequence induction of anaesthesia in decubitus position, the trachea was intubated and the patient was left apneic and disconnected from the anaesthesia circuit until Spo2 decreased to 90%. The time taken for desaturation to 90% from the end of induction of anaesthesia was recorded. Arterial blood oxygen tension was measured before (baseline) and after pre-oxygenation. Values were compared with two-way anova and unpaired Student's t-test. Results Oxygen and carbon dioxide tensions were similar between groups, both at baseline and after pre-oxygenation. However, the mean time to desaturation to 90% was significantly longer in the sitting group compared with the supine group [mean (sd): 214 (28) vs 162 (38) s, P Conclusions Pre-oxygenation in sitting position significantly extends the tolerance to apnoea in obese patients when compared with the supine position.

Pre-oxygenation in the obese patient: effects of position on tolerance to apnoea

We have prospectively assessed whether remifentanil-based anaesthesia is associated with clinically relevant acute opioid tolerance, expressed as greater postoperative pain scores or morphine consumption. Sixty patients undergoing elective gynaecological, non-laparoscopic, surgery were randomly assigned to receive remifentanil (group R, n=30) or sevoflurane (group S, n=30) based anaesthesia. Postoperative analgesia was provided with morphine through a patient-controlled infusion device. Mean (SD) remifentanil infusion rate in group R was 0.23 (0.10) microg kg(-1) min(-1) and mean inspired fraction of sevoflurane in group S was 1.75 (0.70)%. Mean (SD) cumulative morphine consumption during the first 24 postoperative hours was similar between groups: 28.0 (14.2) mg (group R) vs 28.6 (12.4) mg (group S). Pain scores, were also similar between groups during this period. These data do not support the development of acute opioid tolerance after remifentanil-based anaesthesia in this type of surgery.

No clinical evidence of acute opioid tolerance after remifentanil‐based anaesthesia

Background The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters. Methods Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg−1 bolus dose followed by a 5–20–40–120 min, 10–8–6–5 mg kg−1 h−1 infusion. Arterial blood samples were withdrawn at 1, 3, 5 min after induction, every 10–20 min during propofol infusion, and every 10–30 min for 2 h after stopping the propofol infusion. Arterial samples were processed by high-performance liquid chromatography. Time–concentration data profiles from this study were pooled with data from two other propofol PK studies available at http://www.opentci.org. Population PK modelling was performed using non-linear mixed effects model. Results The study involved 19 obese adults who contributed 163 observations. The pooled analysis involved 51 patients (weight 93 sd 24 kg, range 44–160 kg; age 46 sd 16 yr, range 25–81 yr; BMI 33 sd 9 kg m−2, range 16–52 kg m−2). A three-compartment model was used to investigate propofol PK. An allometric size model using total body weight (TBW) was superior to all other models investigated (linear TBW, free fat mass, lean body weight, normal fat mass) for all clearance parameters. Variability in V2 and Q2 was reduced by a function showing a decrease in both parameters with age. Conclusions We have derived a population PK model using obese and non-obese data to characterize propofol PK over a wide range of body weights. An allometric model using TBW as the size descriptor of volumes and clearances was superior to other size descriptors to characterize propofol PK in obese patients.

Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model

BACKGROUND: Pharmacokinetic (PK) models are used to predict drug concentrations for infusion regimens for intraoperative displays and to calculate infusion rates in target-controlled infusion systems. For propofol, the PK models available in the literature were mostly developed from particular patient groups or anesthetic techniques, and there is uncertainty of the accuracy of the models under differing patient and clinical conditions. Our goal was to determine a PK model with robust predictive performance for a wide range of patient groups and clinical conditions. METHODS: We aggregated and analyzed 21 previously published propofol datasets containing data from young children, children, adults, elderly, and obese individuals. A 3-compartmental allometric model was estimated with NONMEM software using weight, age, sex, and patient status as covariates. A predictive performance metric focused on intraoperative conditions was devised and used along with the Akaike information criteria to guide model development. RESULTS: The dataset contains 10,927 drug concentration observations from 660 individuals (age range 0.25-88 years; weight range 5.2-160 kg). The final model uses weight, age, sex, and patient versus healthy volunteer as covariates. Parameter estimates for a 35-year, 70-kg male patient were: 9.77, 29.0, 134 L, 1.53, 1.42, and 0.608 L/min for V1, V2, V3, CL, Q2, and Q3, respectively. Predictive performance is better than or similar to that of specialized models, even for the subpopulations on which those models were derived. CONCLUSIONS: We have developed a single propofol PK model that performed well for a wide range of patient groups and clinical conditions. Further prospective evaluation of the model is needed.

Luis I. Cortinez

Papers

Dexmedetomidine pharmacodynamics: part I: crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers.

Pre-oxygenation in the obese patient: effects of position on tolerance to apnoea

No clinical evidence of acute opioid tolerance after remifentanil‐based anaesthesia

Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model

A General Purpose Pharmacokinetic Model for Propofol