Pregnancy outcome following opioid exposure: A cohort study.

INTRODUCTION: Opioids constitute a cornerstone of pain relief treatment. However, opioid safety during pregnancy has not been well established. Recent studies reported an association between in utero opioid exposure and spina bifida. METHODS: In order to further evaluate the association of opioids exposure during pregnancy with adverse pregnancy outcomes, we conducted a large historical cohort by linking four databases: medications dispensations, births, pregnancy terminations for medical reasons and infant hospitalizations during the years of 1999-2009. Confounders that were controlled for included maternal age, ethnicity, maternal diabetes, smoking status, parity, obesity, year and folic acid intake. A secondary analysis for total major malformations and for spina bifida was performed using propensity score matching for first trimester exposure. RESULTS: Of the 101,586 women included in the study, 3003 were dispensed opioids during the first trimester. Intrauterine exposure to opioids was not associated with overall major malformations (adjusted odds ratio (aOR) 0.97, 95% CI 0.83-1.13), cardiovascular malformations (aOR = 0.89, 95% CI 0.70-1.13) other malformations by systems or spina bifida in particular. However, the risk for spina bifida among newborns and abortuses who were exposed to codeine was four times higher than that of the unexposed (aOR = 4.42, 95% CI 1.60-12.23). This association remained significant in a secondary analysis using propensity score matching. Third trimester exposure to opioids was not associated with low birth weight (aOR = 1.08, 95% CI 0.77-1.52), perinatal death (aOR = 1.38, 95% CI 0.64-2.99) and other adverse pregnancy outcomes. CONCLUSIONS: These findings suggest that opioids exposure (as a homogenous group) is not a significant risk factor for overall major malformations. Exposure to codeine during the first trimester was found to be associated with increased risk of spina bifida. However, this finding was based on a small number of cases and need to be verified in future work.

Dextrophropoxyphene effects on QTc-interval prolongation: Frequency and characteristics in relation to plasma levels.

OBJECTIVE: To evaluate frequency and risk factors for dextropropoxypheneinduced QT-interval prolongation in the clinical setting. DESIGN: Prospective, noninterventional, observational, longitudinal cohort approach. Electrocardiograms were blindly evaluated by independent professionals. SETTING: General ward of a public hospital of metropolitan Buenos Aires. PATIENTS, PARTICIPANTS: Ninety-two patients with indication of receiving dextropropoxyphene for analgesic purposes were included consecutively. All patients finished the study. INTERVENTIONS: All patients were monitored with electrocardiographic controls (previous to drug administration and during steady state) to diagnose and quantify changes in the duration of the QTc interval. MAIN OUTCOME MEASURE: Frequency of drug-induced QTc interval prolongation, QTc interval correlation with plasma drug, and metabolite levels. RESULTS: Ninety-two patients were studied (50 percent males). All patients received a (mean ± SD [range]) dextropropoxyphene dose of 125 ± 25[100-150] mg/d. Dextropropoxyphene and norpropoxyphene concentrations were 112 ± 38[45-199] and 65 ± 33[13-129] ng/mL, respectively. The intra-treatment QTc interval was >450 ms in only one patient (only with the Hodge correction). There were no cases of QTc > 500 ms, and there were no significant differences in the results considering different correction formulas (Bazzet, Fridericia, Framingham, Hodges). Dextropropoxyphene concentrations correlated with QTc (R > 0.45) interval and ΔQTc (R 0.52-0.87), whereas norpropoxyphene correlation was even greater for QTc (R > 0.40-0.64) and ΔQTc (R > 0.47-0.92). Depending on the QTc correction formula, eight patients presented ΔQTc > 30 ms and one patient with ΔQTc > 60 ms. No patient presented arrhythmia during the study. CONCLUSIONS: The authors did not observe a relationship between dextropropoxyphene and QTc interval prolongation at the therapeutic doses used in Argentina.

[Opioid prescription changes in Sweden 2000­2015]. / Dynamiken i förskrivningen av opioider i Sverige 2000­2015 - Markanta omfördelningar inom opioidgruppen, men ingen ¼epidemi«.

Opioid prescription changes in Sweden 2000-2015 In contrast to the well-established ¼opioid epidemic« in the US, very little is known about how the prescription of opioids in Sweden has developed during the last decade. Aggregated data from the open Statistical database of the Swedish Board of Health and Welfare were analyzed descriptively. The yearly prevalence of opioid prescription did not change 2006-2015, but there were dramatic shifts in the choice of opioids. During this period, dextropropoxyphene was pulled off the market. Tramadol was used by fewer individuals (-54 % over the decade), but dosages expressed as Defined Daily Dose/patient/year (DDD/pat/y) increased (+41 %). In contrast, oxycodone and morphine were used by more individuals (+465 % and +137 %, respectively), but DDD/pat/y decreased during the period (-56% and -54%). Studies on non-aggregated data from available registries are needed to further elucidate the circumstances and possible consequences of these shifts in opioid prescription patterns.

Assessing the impact of prescribing directives on opioid prescribing practices among Veterans Health Administration providers.

PURPOSE: The study aimed to test whether directives on opioid prescribing released by the Veterans Health Administration (VHA) or the Food and Drug Administration (FDA) had an impact on prescribing among VHA providers. METHODS: We used the VHA's linked pharmacy and patient medical records database to identify new prescriptions written for propoxyphene, fentanyl, and controlled release (CR) oxycodone between 1/1/2000 and 12/31/2009. We plotted the monthly proportion of these prescriptions that complied with components of four specific safety alerts or directives for these substances issued by the VHA or FDA between 1/1/2001 and 12/31/2008. We modeled compliance using interrupted time series analysis and a generalized additive model with the addition of an indicator variable to flag prescriptions that followed the directive's release date. RESULTS: A total of 32.2 million new prescriptions for fentanyl, oxycodone CR, and propoxyphene were written for VHA patients meeting inclusion criteria. Compliance with guidelines in the directives increased steadily throughout the entire study period, with no clinically meaningful inflection point near the date of each directive's release. Generalized additive modeling and interrupted time series analysis found that the indicator flag slightly improved the fit of the data, but visual inspection of the plots revealed no change at a level of practical significance. CONCLUSIONS: While prescribing compliance increased throughout the period, release of FDA and VHA alerts and guidelines did not appear to contribute to this change. Given the fivefold increase in the rate of drug-related overdose deaths since 1990, identifying effective methods to communicate safety messages and change prescriber behavior remains a priority for future work. Copyright © 2016 John Wiley & Sons, Ltd.

The influence of propoxyphene withdrawal on opioid use in veterans.

PURPOSE: Our aim is to determine if propoxyphene withdrawal from the US market was associated with opioid continuation, continued chronic opioid use, and secondary propoxyphene-related adverse events (emergency department visits, opioid-related events, and acetaminophen toxicity). METHODS: Medical service use and pharmacy data from 19/11/08 to 19/11/11 were collected from the national Veterans Healthcare Administration healthcare databases. A quasi-experimental pre-post retrospective cohort design utilizing a historical comparison group provided the study framework. Logistic regression controlling for baseline covariates was used to estimate the effect of propoxyphene withdrawal. RESULTS: There were 24,328 subjects (policy affected n = 10,747; comparison n = 13,581) meeting inclusion criteria. In the policy-affected cohort, 10.6% of users ceased using opioids, and 26.6% stopped chronic opioid use compared with 3.8% and 13.5% in the historical comparison cohort, respectively. Those in the policy-affected cohort were 2.7 (95%CI: 2.5-2.8) and 3.2 (95%CI: 2.9-3.6) times more likely than those in the historical comparison cohort to discontinue chronic opioid and any opioid use, respectively. Changes in adverse events and Emergency Department (ED) visits were not different between policy-affected and historical comparison cohorts (p > 0.05). CONCLUSIONS: The withdrawal of propoxyphene-containing products resulted in rapid and virtually complete elimination in propoxyphene prescribing in the veterans population; however, nearly 90% of regular users of propoxyphene switched to an alternate opioid, and three quarters continued to use opioids chronically.

The effects of spinal, inhalation, and total intravenous anesthetic techniques on ischemia-reperfusion injury in arthroscopic knee surgery.

PURPOSE: To compare the effects of different anesthesia techniques on tourniquet-related ischemia-reperfusion by measuring the levels of malondialdehyde (MDA), ischemia-modified albumin (IMA) and neuromuscular side effects. METHODS: Sixty ASAI-II patients undergoing arthroscopic knee surgery were randomised to three groups. In Group S, intrathecal anesthesia was administered using levobupivacaine. Anesthesia was induced and maintained with sevoflurane in Group I and TIVA with propofol in Group T. Blood samples were obtained before the induction of anesthesia (t1), 30 min after tourniquet inflation (t2), immediately before (t3), and 5 min (t4), 15 min (t5), 30 min (t 6), 1 h (t7), 2 h (t8), and 6 h (t9) after tourniquet release. RESULTS: MDA and IMA levels increased significantly compared with baseline values in Group S at t2-t 9 and t2-t7. MDA levels in Group T and Group I were significantly lower than those in Group S at t2-t8 and t2-t9. IMA levels in Group T were significantly lower than those in Group S at t2-t7. Postoperatively, a temporary 1/5 loss of strength in dorsiflexion of the ankle was observed in 3 patients in Group S and 1 in Group I. CONCLUSIONS: TIVA with propofol can make a positive contribution in tourniquet-related ischemia-reperfusion.

Medical expulsive therapy using alfuzosin for patient presenting with ureteral stone less than 10mm: a prospective randomized controlled trial.

OBJECTIVES: To assess the spontaneous passage rate for patients being treated with alfuzosin 10mg daily after presenting with an acute ureteral stone compared with a control group, and to assess the respective pain control status. METHODS: This was a prospective randomized controlled trial. Patients presenting with an acute ureteral stone (size 5-10mm) were enrolled and randomized into a medical expulsive therapy (MET) group or control group. The MET group received alfuzosin slow release (SR) 10mg daily for 4weeks and dologesic (paracetamol+dextropropoxyphene, four tablets daily on demand) for 2weeks. The control group received the same analgesics for 2weeks only. Diclofenac sodium SR 100mg daily for 2weeks was added in case of suboptimal pain control. All the patients were assessed through phone interview at week 2 and with kidney-ureter-bladder X-ray at week 5 to check for any evidence of stone passage. RESULTS: A total of 67 patients were included in the analysis. The overall spontaneous passage rate was increased by 31.8% with MET (P=0.006). For an upper ureteral stone, the rate was increased by 51.3% (P=0.01). The MET group used significantly less dicolofenac sodium (1.5 tablets vs 6.7 tablets, P=0.031). CONCLUSIONS: MET using alfuzosin SR 10mg daily is effective to enhance the ureteral stone spontaneous passage rate, particularly for upper ureteral stones. Fewer analgesic drugs are consumed and more patients can avoid ureteroscopic lithotripsy and/or extracorporeal shock wave lithotripsy.

The comparative safety of opioids for nonmalignant pain in older adults.

BACKGROUND: Severe nonmalignant pain affects a large proportion of adults. Optimal treatment is not clear, and opioids are an important option for analgesia. However, there is relatively little information about the comparative safety of opioids. Therefore, we sought to compare the safety of opioids commonly used for nonmalignant pain. METHODS: We devised a propensity-matched cohort analysis that used health care utilization data collected from January 1, 1996, through December 31, 2005. Study participants were Medicare beneficiaries from 2 US states who were new initiators of opioid therapy for nonmalignant pain, including codeine phosphate, hydrocodone bitartrate, oxycodone hydrochloride, propoxyphene hydrochloride, and tramadol hydrochloride; none had a cancer diagnosis, and none were using hospice or nursing home care. Our main outcome measures were incidence rates and rate ratios (RRs) with 95% confidence intervals (CIs) for cardiovascular events, fractures, gastrointestinal events, and several composite end points. RESULTS: We matched 6275 subjects in each of the 5 opioid groups. The groups were well matched on baseline characteristics. The risk of cardiovascular events was similar across opioid groups 30 days after the start of opioid therapy, but it was elevated for codeine (RR, 1.62; 95% CI, 1.27-2.06) after 180 days. Compared with hydrocodone, after 30 days of opioid exposure the risk of fracture was significantly reduced for tramadol (RR, 0.21; 95% CI, 0.16-0.28) and propoxyphene (0.54; 0.44-0.66) users. The risk of gastrointestinal safety events did not differ across opioid groups. All-cause mortality was elevated after 30 days for oxycodone (RR, 2.43; 95% CI, 1.47-4.00) and codeine (2.05; 1.22-3.45) users compared with hydrocodone users. CONCLUSIONS: The rates of safety events among older adults using opioids for nonmalignant pain vary significantly by agent. Causal inference requires experimental designs, but these results should prompt caution and further study.

Why pick on propoxyphene? The evidence demands it.

While propoxyphene may have filled a niche when it was first marketed in 1957, newer, safer agents are now available. Multiple experts list the drug as one to avoid in the elderly patient. Evidence-based practice requires its use be minimized, especially in individuals over the age of 65.

Disproportionately high rate of epileptic seizure in patients abusing dextropropoxyphene.

Dextropropoxyphene (DPP), a weak opioid, is often abused as a psychoactive substance. In this retrospective chart review to document, characterize and put in perspective the often-obtained history of epileptic seizures in patients with DPP abuse, we analyzed the case files of all patients with DPP abuse registered in our center (a tertiary-care drug de-addiction clinic in north India) from May 1, 2001 until April 30, 2007 and those with use of other opioids during the same period. Non-drug-related seizures were excluded from analysis. Out of 312 patients with DPP abuse, 63 (20.2%) had epileptic seizures related to DPP use, in contrast to 0.4% -4.2% of other opioid users. The seizures were mostly characterized as generalized tonic-clonic seizures (87.3%), occurring around two hours following a higher-than-usual dose of DPP. Those with seizures had significantly greater duration of DPP use and higher rates of medical comorbidity compared to patients without seizure. Age, duration of use and medical comorbidity were better predictors of seizure than dosage of drug or use of multiple drugs. Thus, DPP-induced epileptic seizures are common (one in five), and much more frequent than seizures in patients using other opioids. The awareness of this phenomenon has implications for diagnosis and management, as well as for drug regulation policy.

Use of dextropropoxyphene + acetaminophen fixed-dose combination in psychiatric hospital in Bahrain: is there a cause for concern?

There are concerns about the safety of the dextropropoxyphene and acetaminophen fixed-dose combination, particularly in patients with psychiatric morbidity, which has led to a phased withdrawal of this fixed-dose combination in many countries. A retrospective prescription audit was conducted to evaluate the dextropropoxyphene + acetaminophen fixed-dose combination prescribing pattern in the major psychiatric hospital of Bahrain. The data analysis was performed using SPSS/PC+ version 14.0. Prescriptions with the dextropropoxyphene + acetaminophen fixed-dose combination comprised 11.8% of all dispensed prescriptions and in most instances for outpatients undergoing substance abuse rehabilitation. Nearly half of the patients received >or=20 tablets of this fixed-dose combination (mean +/- SD: 30.9 +/- 13.1; range 20-126) as multiple doses. The dextropropoxyphene + acetaminophen fixed-dose combination was often co-prescribed with psychotropics, such as benzodiazepines (BZDs) (25.4%), BZDs + antidepressants (62.9%), BZDs + antipsychotics (3.7%) and BZDs + anticonvulsants (1.9%). Approximately 40% of prescriptions with the dextropropoxyphene + acetaminophen fixed-dose combination were written 'as required' (prn), basis. Despite poor safety and efforts to restrict or withdraw worldwide, the dextropropoxyphene + acetaminophen fixed-dose combination continues to be irrationally prescribed to outpatients undergoing substance abuse rehabilitation in Bahrain. Health policy decision-makers should introduce a phased withdrawal of this drug from clinical use. In the meanwhile, it is important to create awareness among prescribers of the risks associated with over-dosage of the dextropropoxyphene + acetaminophen fixed-dose combination and its interaction with other psychotropic medications.

[Assessment of quality in day-case hand surgery]. / Démarche d'assurance qualité en chirurgie ambulatoire de la main.

OBJECTIVE: To determine the level of satisfaction in terms of pain relief and comfort among patients receiving different postoperative analgesia protocols after hand surgery under regional anaesthesia in a day care unit. METHODS: Cohort study among patients after hand surgery under regional anaesthesia during two consecutive three months time periods, with patient stratification according to the expected pain level with different balanced analgesia protocols (group A: carpal tunnel, group B: other surgery without bone involvement, group C: bone surgery). A telephone survey, scoring analgesia and comfort, each with a numerical (0-10) scale was conducted on days 1 and 7. During the first period analgesia for groups A and B was the same (acetaminophen-dextropropoxyphene or acetaminophen-codeine) and group C patients were treated with acetaminophen-ketoprofen-tramadol. In the second period analgesia was reduced for group A (acetaminophen alone) and increased for group B (acetaminophen-ketoprofen-tramadol) and group C (duration increased from 3 to 7 days). RESULTS: For carpal tunnel surgery, analgesia with acetaminophen alone was efficient, (Pain scale [PS] d0=2[0-10], PS d1=1 [0-10] and PS d2-d4=0,5 [0-10]). This surgery does not elicit important pain, there is no benefit in adding other analgesics. For group B, a significant improvement in postoperative pain was observed (postoperative d1 p<0.03) with a major increase in side effects (2/57 vs 17/48 p<0.001). For group C, therapeutic changes were ineffective (PS d0=2 vs 3.5 et PS d1=3 vs 5 [NS]) and we noticed an increase in side effects (p<0.05). One third of all patients are totally satisfied on day 7, logistic regression showing the role of inefficient analgesia in late postoperative period (PS>2 between d2-d4). Between day 1 and day 7, 20% of the patients change their point of view, those who feel less satisfied on day 7 complained of a more severe postoperative pain between day 2 and 4 (p<0.001) and between day 5-7 (p<0.01). CONCLUSION: For hand surgery on day case, quality of late postoperative analgesia (day 2-day 7) is strongly related to patient's satisfaction on day 7.

D-propoxyphene and dipyrone co-administration produces greater antinociception and fewer adverse effects than single treatments in rats.

D-propoxyphene is a commonly prescribed opiate analgesic. Its use is limited by unwanted side effects at high doses and tolerance development after chronic administration. Dipyrone (also known as metamizol) is a non-steroidal anti-inflammatory drug extensively used in Latin America and Europe. The objective of this work was to evaluate the antinociceptive efficacy of a dipyrone/D-propoxyphene combination and the development of tolerance to its repeated administration in the tail flick test in rats. Male Wistar rats (200+/-20 g) were i.v. injected twice daily (8 h apart) with 0.31 mg/kg D-propoxyphene, 400 mg/kg dipyrone, or the combination of these drugs, at the same doses, until complete tolerance was observed. A time course of the effects for each administration was determined. At the doses tested, D-propoxyphene and dipyrone produced mild antinociception per se. Repeated administration resulted in complete tolerance to their antinociceptive effects by the sixth dose. The D-propoxyphene/dipyrone combination produced more antinociception than expected by the sum of individual drug effects. With this treatment, tolerance developed at the 15th administration. In animals already tolerant to D-propoxyphene or dipyrone alone, subsequent administration of the combination partially restored the antinociceptive effect. These results suggest that the use of this combination provides advantages over single drug therapies.

Death from undiagnosed glioblastoma multiforme and toxic self-medication presenting with concurrent dysfunctional behavior.

We encountered a decedent with an unexpected glioblastoma multiforme. A 61-year-old retired African-American woman was found dead in her home, fully clothed in her bathtub, with a pillow under her head. At autopsy, the brain showed a glioblastoma multiforme. Toxicology showed elevated hydrocodone, propoxyphene, acetaminophen, and positive paroxetine. The presence of a brain tumor likely caused a severe headache. The use of her medications could have indicated a reaction to the escalating pain of the brain trauma, and overuse could be consistent with escalating pain or loss of rational thought processes. The present case is interesting in that it had evidence of behavioral dysfunction that could be related to the brain tumor, and death arising from the glioblastoma multiforme (cerebral hemorrhage and edema) with concurrent multiple drug intoxication.

Dextropropoxyphene: welcome withdrawal from a French hospital's formulary.

Decision to exclude dextropropoxyphene from the list of drugs available at Toulouse University Hospital: more prescriptions of paracetamol as monotherapy and fewer prescriptions of step-2 analgesics.