Adverse Effects Of Opioid Analgesics Research Articles

Analgesic Techniques for Rib Fractures-A Comprehensive Review Article.

Rib fractures are a common traumatic injury that has been traditionally treated with systemic opioids and non-opioid analgesics. Due to the adverse effects of opioid analgesics, regional anesthesia techniques have become an increasingly promising alternative. This review article aims to explore the efficacy, safety, and constraints of medical management and regional anesthesia techniques in alleviating pain related to rib fractures. Recently, opioid analgesia, thoracic epidural analgesia (TEA), and paravertebral block (PVB) have been favored options in the pain management of rib fractures. TEA has positive analgesic effects, and many studies vouch for its efficacy; however, it is contraindicated for many patients. PVB is a viable alternative to those with contraindications to TEA and exhibits promising outcomes compared to other regional anesthesia techniques; however, a failure rate of up to 10% and adverse complications challenge its administration in trauma settings. Serratus anterior plane blocks (SAPB) and erector spinae blocks (ESPB) serve as practical alternatives to TEA or PVB with lower incidences of adverse effects while exhibiting similar levels of analgesia. ESPB can be performed by trained emergency physicians, making it a feasible procedure to perform that is low-risk and efficient in pain management. Compared to the other techniques, intercostal nerve block (ICNB) had less analgesic impact and required concurrent intravenous medication to achieve comparable outcomes to the other blocks. The regional anesthesia techniques showed great success in improving pain scores and expediting recovery in many patients. However, choosing the optimal technique may not be so clear and will depend on the patient's case and the team's preferences. The peripheral nerve blocks have impressive potential in the future and may very well surpass neuraxial techniques; however, further research is needed to prove their efficacy and weaknesses.

Neural and molecular investigation into the paraventricular thalamic-nucleus accumbens circuit for pain sensation and non-opioid analgesia

The paucity of medications with novel mechanisms for pain treatment combined with the severe adverse effects of opioid analgesics has led to an imperative pursuit of non-opioid analgesia and a better understanding of pain mechanisms. Here, we identify the putative glutamatergic inputs from the paraventricular thalamic nucleus to the nucleus accumbens (PVTGlut→NAc) as a novel neural circuit for pain sensation and non-opioid analgesia. Our in vivo fiber photometry and in vitro electrophysiology experiments found that PVTGlut→NAc neuronal activity increased in response to acute thermal/mechanical stimuli and persistent inflammatory pain. Direct optogenetic activation of these neurons in the PVT or their terminals in the NAc induced pain-like behaviors. Conversely, inhibition of PVTGlut→NAc neurons or their NAc terminals exhibited a potent analgesic effect in both naïve and pathological pain mice, which could not be prevented by pretreatment of naloxone, an opioid receptor antagonist. Anterograde trans-synaptic optogenetic experiments consistently demonstrated that the PVTGlut→NAc circuit bi-directionally modulates pain behaviors. Furthermore, circuit-specific molecular profiling and pharmacological studies revealed dopamine receptor 3 as a candidate target for pain modulation and non-opioid analgesic development. Taken together, these findings provide a previously unknown neural circuit for pain sensation and non-opioid analgesia and a valuable molecular target for developing future safer medication.

Development and validation of a risk-score model for opioid overdose using a national claims database

Opioid overdose can be serious adverse effects of opioid analgesics. Thus, several strategies to mitigate risk and reduce the harm of opioid overdose have been developed. However, despite a marked increase in opioid analgesic consumption in Korea, there have been no tools predicting the risk of opioid overdose in the Korean population. Using the national claims database of the Korean population, we identified patients who were incidentally prescribed non-injectable opioid analgesic (NIOA) at least once from 2017 to 2018 (N = 1,752,380). Among them, 866 cases of opioid overdose occurred, and per case, four controls were selected. Patients were randomly allocated to the development (80%) and validation (20%) cohort. Thirteen predictive variables were selected via logistic regression modelling, and a risk-score was assigned for each predictor. Our model showed good performance with c-statistics of 0.84 in the validation cohort. The developed risk score model is the first tool to identify high-risk patients for opioid overdose in Korea. It is expected to be applicable in the clinical setting and useful as a national level surveillance tool due to the easily calculable and identifiable predictors available from the claims database.

Contribution of G-Protein α-Subunits to Analgesia, Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine.

While opioids produce both analgesia and side effects by action at μ-opioid receptors (MORs), at spinal and supraspinal sites, the potency of different opioids to produce these effects varies. While it has been suggested that these differences might be because of bias for signaling via β-arrestin versus G-protein α-subunits (Gα), recent studies suggest that G-protein-biased MOR agonists still produce clinically important side effects. Since bias also exists in the role of Gα subunits, we evaluated the role of Gαi/o subunits in analgesia, hyperalgesia, and hyperalgesic priming produced by fentanyl and morphine, in male rats. We found that intrathecal treatment with oligodeoxynucleotides antisense (AS-ODN) for Gαi2, Gαi3, and Gαo markedly attenuated hyperalgesia induced by subanalgesic dose (sub-AD) fentanyl, while AS-ODN for Gαi1, as well as Gαi2 and Gαi3, but not Gαo, prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Gαi1 and Gαi2 unexpectedly enhanced analgesia induced by analgesic dose (AD) fentanyl, while Gαi1 AS-ODN markedly reduced AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E2-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in Gαi3 and Gαo AS-ODN-treated rats, respectively. In contrast, none of the Gαi/o AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Gαi/o subunits is necessary for the analgesia and side effects of two of the most clinically used opioid analgesics. The design of opioid analgesics that demonstrate selectivity for individual Gαi/o may produce a more limited range of side effects and enhanced analgesia.SIGNIFICANCE STATEMENT Biased μ-opioid receptor (MOR) agonists that preferentially signal through G-protein α-subunits over β-arrestins have been developed as an approach to mitigate opioid side effects. However, we recently demonstrated that biased MOR agonists also produce hyperalgesia and priming. We show that oligodeoxynucleotide antisense to different Gαi/o subunits play a role in hyperalgesia and analgesia induced by subanalgesic and analgesic dose (respectively), of fentanyl and morphine, as well as in priming. Our findings have the potential to advance our understanding of the mechanisms involved in adverse effects of opioid analgesics that could assist in the development of novel analgesics, preferentially targeting specific G-protein α-subunits.

Adverse effects of opioid analgesics from the central nervous system

Opioid analgesic drugs are widely used in the treatment of moderate to severe pain as well as symptomatic treatment of dyspnoea. However, the use of opioids may cause central adverse effects, such as delirium, cognitive impairment, sedation, hallucinations, myocloni, seizures, hyperalgesia, sleep and mood disorders. The ability to diagnose and properly manage the above adverse effects is important for the proper treatment of patients receiving opioid analgesics.

Associations of mental health and family background with opioid analgesic therapy: a nationwide Swedish register-based study.

There is evidence of greater opioid prescription to individuals in the United States with mental health conditions. Whether these associations generalize beyond the US prescription environment and to familial mental health and socioeconomic status (SES) has not been examined comprehensively. This study estimated associations of diverse preexisting mental health diagnoses, parental mental health history, and SES in childhood with opioid analgesic prescription patterns nationwide in Sweden. Using register-based data, we identified 5,071,193 (48.4% female) adolescents and adults who were naive to prescription opioid analgesics and followed them from 2007 to 2014. The cumulative incidence of any dispensed opioid analgesic within 3 years was 11.4% (95% CI, 11.3%-11.4%). Individuals with preexisting self-injurious behavior, as well as opioid and other substance use, attention-deficit/hyperactivity, depressive, anxiety, and bipolar disorders had greater opioid therapy initiation rates than did individuals without the respective conditions (hazard ratios from 1.24 [1.20-1.27] for bipolar disorder to 2.12 [2.04-2.21] for opioid use disorder). Among 1,298,083 opioid recipients, the cumulative incidence of long-term opioid therapy (LTOT) was 7.6% (7.6%-7.7%) within 3 years of initiation. All mental health conditions were associated with greater LTOT rates (hazard ratios from 1.66 [1.56-1.77] for bipolar disorder to 3.82 [3.51-4.15] for opioid use disorder) and were similarly associated with concurrent benzodiazepine-opioid therapy. Among 1,482,462 adolescents and young adults, initiation and LTOT rates were greater for those with parental mental health history or lower childhood SES. Efforts to understand and ameliorate potential adverse effects of opioid analgesics must account for these patterns.

Pentazocine, a Kappa-Opioid Agonist, Is Better Than Diclofenac for Analgesia in Acute Pancreatitis: A Randomized Controlled Trial.

The ideal analgesic is not known for patients with acute pancreatitis (AP). Concerns have been raised about serious adverse effects of opioid analgesics increasing the severity of AP. We hypothesized that nonsteroidal anti-inflammatory drugs might be better analgesics because of their anti-inflammatory effect. Our objective was to compare pentazocine, an opioid, and diclofenac, a nonsteroidal anti-inflammatory drug, for adequate analgesia in patients with AP. In a double-blind randomized controlled trial, patients with AP were randomized to either intravenous diclofenac 75 mg or pentazocine 30 mg. Fentanyl was given as a rescue analgesic through a patient-controlled analgesia pump. Primary outcome was pain relief measured objectively by the dose of fentanyl required as the rescue analgesic, pain-free period, and numbers of effective and ineffective demands of fentanyl. Secondary outcome was adverse events. Fifty patients were randomized, 24 to the pentazocine group and 26 to the diclofenac group. Baseline characteristics were comparable between the groups. Pentazocine was found to be better than diclofenac in terms of significantly lower dose of the rescue analgesic (fentanyl) required (126 μg (interquartile range (IQR) 65-218 μg) vs 225.5 μg (IQR 133-427 μg); P = 0.028) and longer pain-free period (31.1 ± 8.2 vs 27.9 ± 6.6 hours, P = 0.047). The number of effective and ineffective demands was lower in the pentazocine group compared with the diclofenac group (11.5 (IQR 8-15) vs 16 (IQR 13-20), P = 0.098) although not statistically significant. Adverse events were similar between the groups. Pentazocine, a kappa-opioid receptor agonist, was significantly better than diclofenac for pain relief in AP (Trial registration number: CTRI/2016/09/007326).

Transversus abdominis plane block with liposomal bupivacaine for pain control after cesarean delivery: a retrospective chart review.

BackgroundAdverse effects of opioid analgesics and potential for chronic use are limitations in the cesarean setting. Regional anesthesia using transversus abdominis plane (TAP) block post-cesarean delivery may improve analgesia and reduce opioid consumption. Effectiveness of TAP block using liposomal bupivacaine (LB) to reduce post-cesarean pain is unknown.MethodsWe performed a single-center retrospective chart review of patients aged ≥18 years who underwent cesarean delivery with a multimodal pain management protocol with or without TAP block with LB 266 mg. Assessments included postsurgical opioid consumption; area under the curve (AUC) of numeric rating scale pain scores from 0 to 3 days; proportion of opioid-free patients; discharge- and post-anesthesia care unit (PACU)-ready time; times to ambulation, solid food, and bowel movement; hospital length of stay (LOS); and adverse events (AEs). Data were analyzed in the total population and in first- and repeat-cesarean subgroups using Wilcoxon, chi-squared, and Student’s t-tests.ResultsOf 201 patients, 101 were treated with LB TAP block (LB-TAPB) and 100 without LB-TAPB. Treatment with LB-TAPB vs without LB-TAPB significantly reduced mean post-surgical opioid consumption (total, 47%; first-cesarean, 54%; repeat-cesarean, 42%; P<0.001 each) and mean AUC of pain scores (total, 46%; first-cesarean, 57%; repeat-cesarean, 40%; P<0.001 each). Patients treated with LB-TAPB had significantly shorter mean discharge-ready times (2.9 vs 3.6 days; P=0.006), PACU-ready times (138 vs 163 minutes; P=0.028), and LOS (2.9 vs 3.9 days; P<0.001). LB-TAPB significantly decreased mean times to ambulation and solid food by 39% and 31% (P<0.01 each), respectively, and numerically reduced mean time to bowel movement (26%; P=0.05). Fewer patients treated with LB-TAPB vs without LB-TAPB reported an AE (34% vs 50%; P=0.026).ConclusionThese results suggest multimodal pain management incorporating TAP block with LB 266 mg is an effective approach to reducing opioid requirements and improving analgesia post-cesarean delivery.

Pentazocine, a Kappa-Opioid Agonist, Is Better Than Diclofenac for Analgesia in Acute Pancreatitis: A Randomised Controlled Trial

Background: The ideal analgesic is not known for patients with acute pancreatitis (AP). Concerns have been raised about serious adverse effects of opioid analgesics increasing the severity of AP. We hypothesized that non-steroidal anti-inflammatory drugs (NSAIDs) might be better analgesics due to their anti-inflammatory effect. Our objective was to compare pentazocine, an opioid, and diclofenac, an NSAID for adequate analgesia in patients with AP. Methods: In a double-blind randomised controlled trial, patients with AP were randomised to either intravenous Diclofenac 75 mg or Pentazocine 30 mg. Fentanyl was given as a rescue analgesic through a patient controlled analgesia pump. Primary outcome was pain relief measured objectively by the dose of fentanyl required as rescue analgesic, pain-free period, and numbers of good and bad demands of fentanyl. Secondary outcome was adverse events. Findings: Fifty patients were randomised: 24 to pentazocine group and 26 to diclofenac group. Baseline characteristics were comparable between the groups. Pentazocine was found to be better than diclofenac in terms of significantly lower dose of rescue analgesic (fentanyl) required [126 μg (range 0-960 μg) vs. 225·5 μg (range 0-810 μg); p = 0·028], and longer pain-free period (31·1±8·2 hours vs. 27·9±6·6 hours, p=0·047). The number of good and bad demands was lower in the pentazocine compared with diclofenac group [11·5 (range 0-92) vs. 16 (range 0-85), p=0·098] although not statistically significant. Adverse events were similar between the groups. Interpretation: Pentazocine, a kappa opioid receptor agonist, was significantly better than Diclofenac for pain relief in AP. Clinical Trial Number: (Trial registration number: CTRI/2016/09/007326) Funding Statement: The authors state: None, and It was an investigator initiated study. Declaration of Interests: None of the authors have any conflict of interest. Ethics Approval Statement: The study was approved by the institutional ethics committee (IECPG 69/27·11·2015). An informed written consent was taken from the participants.

Plasticity of α2-adrenergic spinal antinociception following nerve injury: Selective, bidirectional interaction with the delta opioid receptor

Interactions of opioid receptors with other receptor families can be made use of to improve analgesia and reduce adverse effects of opioid analgesics. We investigated interactions of the α2-adrenergic receptor (α2AR) with opioid receptors of the mu (MOR) and delta (DOR) types in the spinal dorsal horn in an animal model of neuropathic pain induced by spinal nerve ligation. Nine days after nerve injury, immunoreactivity for the α2AR subtype A (α2AAR) was increased both in tissue homogenates and at pre- and post-synaptic sites in transverse sections. The efficacy of spinally administered α2AAR agonist guanfacine at reducing C-fiber-evoked field potentials was increased in nerve-ligated rats. This reducing effect was impaired by simultaneous administration of DOR antagonist naltrindole, but not MOR antagonist CTOP, suggesting that concurrent DOR activation was required for α2AAR-mediated inhibition. While DOR agonist deltorphin II and MOR agonist DAMGO both effectively depressed C-fiber-evoked spinal field potentials, DOR- but not MOR-mediated depression was enhanced by subclinical guanfacine. In conscious, nerve-ligated rats, chronically administered deltorphin II produced stable thermal and mechanical antinociception over the 9 following days after nerve injury without apparent signs of habituation. Such an effect was dramatically enhanced by co-administration of a low dose of guanfacine, which reversed thermal and mechanical thresholds to levels near those prior to injury. The results suggest that spinal, α2AAR-mediated antinociception is increased after nerve injury and based on DOR co-activation. We demonstrate in vivo that α2AAR/DOR interaction can be exploited to provide effective behavioral antinociception during neuropathic pain.

Trends in Prescription Opioid Use in Pediatric Emergency Department Patients

In recent years, there has been increased emphasis on treating pain in emergency departments (EDs), coinciding with mounting concerns regarding the abuse potential of prescription opioids. In this study, we describe trends in opioid prescribing in pediatric patients in the US EDs over the past decade. Data from the 2001-2010 National Hospital Ambulatory Medical Care Survey were analyzed and pain-related visits were identified. Pain-related ED visits by pediatric patients (≤19 y) where an opioid analgesic was administered or prescribed were tabulated by age category and year. Specific opioids analyzed included codeine, hydrocodone, hydromorphone, morphine, and oxycodone. The use patterns of nonopioid pain relievers were also investigated. Results were further stratified by Drug Enforcement Agency schedule and pain-related diagnosis. The overall use of opioid analgesics in pain-related pediatric ED visits increased from 11.2% to 14.5% between 2001 and 2010 (P = 0.015). The use of Drug Enforcement Agency schedule II agents doubled from 3.6% in 2001 to 7.0% in 2010 (P < 0.001), whereas there was no significant increase in the use of schedule III, IV, and V agents (P = 0.34). Hydrocodone was the most frequently prescribed opioid analgesic. Increased opioid use was most dramatic in ED visits that involved adolescents. There was no significant increase in the use of nonopioid analgesics in pediatric ED patients (P = 0.086). Opioid use for pain-related pediatric ED visits has increased significantly from 2001 to 2010, particularly among adolescents. Emergency department providers must be vigilant in balancing pain relief with minimizing the adverse effects of opioid analgesics.

Non-Analgesic Effects of Opioids: Management of Opioid-Induced Constipation by Peripheral Opioid Receptor Antagonists: Prevention or Withdrawal?

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

Opioid antagonists for prevention and treatment of opioid-induced gastrointestinal effects

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects, among which constipation is the most disabling as laxatives often fail to provide satisfactory relief. This review highlights recent advances in the specific control of opioid-induced constipation by opioid receptor antagonists with limited systemic bioavailability or a peripherally restricted site of action. The specific management of opioid-induced bowel dysfunction is currently based on three drug entities: oral alvimopan for the shortening of postoperative ileus associated with opioid-induced pain control after bowel resection, subcutaneous methylnaltrexone for the reduction of opioid-induced constipation in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the treatment of noncancer and cancer pain. All three drug entities have been shown to attenuate opioid-induced motor stasis in the gut with a favorable adverse effect profile, while the analgesic effect of opioids remains unabated. The availability of opioid receptor antagonists with restricted access to the central nervous system provides a novel opportunity to specifically control opioid-induced constipation and other peripheral adverse effects of opioid analgesics. Further studies are needed to evaluate the long-term efficacy, safety and cost-effectiveness of this approach.

Multimodal analgesia for controlling acute postoperative pain

Multimodal analgesia is needed for acute postoperative pain management due to adverse effects of opioid analgesics, which can impede recovery; a problem that is of increasing concern with the rapid increase in the number of ambulatory surgeries. Yet, the literature on multimodal analgesia often shows variable degrees of success, even with studies utilizing the same adjuvant medication. Nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors consistently reduce postoperative opioid consumption. The N-methyl-D-aspartate antagonists have produced variable results in studies, which may be due to the dose and timing of drug administration. Alpha-2 adrenergic agonists have been useful as adjuvant for regional analgesia but not when administered orally. The alpha-2-delta receptor modulators such as gabapentin have shown early promising results in multimodal analgesia. Local anesthetic injection at the surgical site, though not as a preemptive analgesic, has recently been demonstrated to be beneficial in multimodal analgesia. No new adjuvants have appeared in the last year, which robustly reduce opioid consumption and opioid-related adverse effects. There is a continuing need to explore new drug combinations to achieve all of the purported goals of multimodal anesthesia.

Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.

Prospective sonographic evaluation of fentanyl side effects on the neonatal gallbladder

In an effort to minimise the stress and pain of mechanically ventilated neonates, the application of opioids has increased markedly. Abdominal adverse effects of opioid analgesics are constipation and increased pressure in the biliary system. Our aim was to evaluate the impact of continuous intravenous infusion of fentanyl on the volume of the neonatal gallbladder and to assess potential gastrointestinal side effects. We prospectively matched pairs of 40 mechanically ventilated neonates (28-42 gestational weeks) under total parenteral nutrition and midazolam sedation. One group (20 patients) received continuous fentanyl infusions (dose 0.5-2 microg kg(-1) h(-1)) the other group (20 patients) served as controls. Sonographic measurements of gallbladder length, depth and width were performed to calculate gallbladder volume using the ellipsoid method. Repeated ultrasound images, date of meconium release and serum bilirubin levels were documented. Fentanyl application was not associated with gallbladder sludge/stones, gallbladder hydrops, hyperbilirubinemia or prolonged meconium release. Neonatal gallbladder length, width and volume did not differ significantly (data expressed as mean, standard deviation, median, interquartile range: length (cm) 3.16+/-0.68, 3.3, 0.675 vs 3.06+/-0.62, 3.3, 1.1; P=0.645; width (cm) 1.02+/-0.23, 1.0, 0.28 vs 0.89+/-0.27, 0.9, 0.38, P=0.12; volume (cm(3)) 1.52+/-0.67, 1.7, 0.86 vs 1.22+/-0.77, 1.09, 1.19, P=0.20). In our study fentanyl caused no major complications in the biliary system and intestine of ventilated preterm and term neonates. Sonographic investigations of the gallbladder under fentanyl treatment may be dispensable. Further investigations are required to assess adverse gastrointestinal effects.

緩和ケア領域におけるＱＯＬ評価の試み―日本語版ＥＱ‐５Ｄを用いて―

Palliative care for cancer patients should consider individual preferences with the focus on health-related quality of life (HRQOL). In this regard, the recent participation of clinical pharmacists as important members of the palliative treatment team has achieved efficient management of medicines and effective symptom control.Assessment of HRQOL is necessary for improving medical services provided to patients by the palliative care team (PCT). EuroQol 5-Dimension (EQ-5D) is a questionnaire for this purpose which is being widely used by clinical researchers in a variety of clinical areas, e.g. diabetes mellitus, cerebrovascular diseases and rheumatic disease, and the objective of this study was to examine the possibility of the PCT using EQ-5D. Validity was assessed by reliability analysis of EQ-5D scale scores, correlation measures of pain at rest and with movement in a range of from 0 to 10, adverse effects of opioid analgesics (nausea, constipation and drowsiness) in a range from 0 to 3, total dosing days of opioid analgesics and lifespan with utility-based scores.Thirteen cancer patients in whose medication the PCT had intervened were enrolled. The Cronbach alpha score was calculated as 0.7801. Correlations were found between utility-based scores and pain at rest (r=-0.553, P 0.05).These findings suggest that EQ-5D may be adopted by the PCT in Japan for measuring utility-based HRQOL for cancer patients, though further investigation will be necessary.

CNS Adverse Effects of Opioids in Cancer Patients

Most of the adverse effects of Opioid analgesics are related to effects on the CNS. This article reviews the causes and treatment of the most frequent CNS adverse effects of Opioid analgesics prescribed for the relief of cancer-related pain. Such effects can occur during short term treatment of opioid-naive patients (e.g. sedation, nausea, vomiting, respiratory depression, mood changes, difficult micturition) and during long term treatment of patients in chronic pain (e.g. delirium, hyperalgesia, generalised myoclonus, tonic-clonic seizures), and can be classified according to their clinical relevance. The symptoms can be associated with high concentrations of Opioids and their metabolites in CSF, but can also be caused by pharmacological interactions between Opioids and other drugs commonly used in clinical practice. Moreover, they may be related to the accumulation of active metabolites in patients with renal impairment. Opioid rotation, hydration of the patient and suspension of drugs that can interfere with the pharmacokinetics of Opioids are suggested approaches to treatment. Psychostimulants can be used to treat opioid-induced sedation. Naloxone can be used to reverse severe respiratory depression caused by high doses of Opioids. Haloperidol and midazolam are useful for the treatment of opioid-induced hyperactive delirium.