Analgesic efficacy of morphine sulfate immediate release vs. oxycodone/acetaminophen for acute pain in the emergency department.

OBJECTIVE: Previous research demonstrated that administration of Morphine Sulfate Immediate Release (MSIR) results in similar analgesic efficacy to Oxycodone but with significantly lesser degrees of euphoria and reward. The purpose of this study sit to investigate if MSIR combined with Acetaminophen can serve as an opioid analgesic alternative to Oxycodone combined with acetaminophen (Percocet) for acute pain in the Emergency Department (ED). METHODS: A prospective, randomized, double-blind trial of ED patients aged 18 to 64 years presenting with moderate to severe acute pain as defined by an 11-point numeric rating scale (NRS) with an initial score of ≥5 (0 = no pain and 10 = very severe pain). Patients were randomized to receive either 15 mg MSIR combined with 650 mg of Acetaminophen or 10 mg Oxycodone combined with 650 mg Acetaminophen. Patients were assessed at baseline, 30, 45 and 60 min. The primary outcome was reduction in pain at 60 min. Secondary outcomes include drug likeability and adverse events. RESULTS: 80 patients were enrolled in the study (40 per group). Demographic characteristics were similar between the groups (P > 0.05). Mean NRS pain scores at baseline were 8.44 for the MSIR group and 8.53 for the Percocet group (P = 0.788). Mean pain scores decreased over time but remained similar between the groups: 30 min (6.03 vs. 6.43; P = 0.453), 45 min (5.31 vs. 5.48; P = 0.779), and 60 min (4.22 vs. 4.87; P = 0.346). Reduction in mean NRS pain scores were statistically significant from baseline to 30, 45 and 60 min within each group (P < 0.0001 at each time point for both groups). The largest NRS mean difference was from baseline to 60 min: 4.2 (95% CI: 3.43 to 5.01) for MSIR group and 3.61 (95% CI: 2.79 to 4.43) for Percocet group. No clinically significant changes or any serious adverse events were observed in either group. CONCLUSION: MSIR provides similar analgesic efficacy as Percocet for short-term pain relief in the ED, similar rates of nausea/vomiting, and lower rates of likeability of the drug.

A nurse-driven analgesia and sedation protocol reduces length of PICU stay and cumulative dose of benzodiazepines after corrective surgery for tetralogy of Fallot.

PURPOSE: Analgesia and sedation protocols are reported to reduce the requirement of sedative and analgesic agents, duration of mechanical ventilation, and length of pediatric intensive care unit (PICU) stay. However, these studies often were conducted based on inhomogeneous cohorts. The aim of this study was the evaluation of a nurse-driven analgesia and sedation protocol in a homogenous population of infants following corrective surgery for tetralogy of Fallot (TOF). DESIGN AND METHODS: This retrospective analysis was conducted in a cardiac PICU of a tertiary referral center. Two cohorts of patients who underwent corrective surgery for TOF below the age of 7 months, were retrospectively evaluated before and after implementation of a nurse-driven analgesia and sedation protocol. We compared peak and cumulative doses of midazolam, morphine, and clonidine, length of PICU stay and time on mechanical ventilation. RESULTS: A total of 33 patients were included in the preimplementation period and 32 during the postimplementation period. Implementation of the nurse-driven analgesia and sedation protocol had no effect on time on mechanical ventilation (72 hr [24-141] vs. 49 hr [24-98]), but significantly on length of PICU stay (7 days [5-14] vs. 5 days [4-7]). Cumulative doses of midazolam (7.37 mg/kg [4.70-17.65] vs. 5.0 mg/kg [2.70-9.12]) as well as peak doses of midazolam (0.22 mg·kg-1 ·hr-1 [0.20-0.33] vs. 0.15 mg·kg-1 ·hr-1 [0.13-0.20]) and morphine (50.0 µg·kg-1 ·hr-1 [39.7-79.9] vs. 42.5 µg·kg-1 ·hr-1 [29.7-51.8]) were significantly reduced. The postimplemantation group showed no increase in postoperative complications and adverse events. PRACTICE IMPLICATIONS: The implementation of a nurse-driven analgesia and sedation protocol is safe in infants following corrective surgery for TOF. It reduces significantly the length of PICU stay, cumulative and peak doses of midazolam and peak doses of morphine.

Intranasal Sufentanil Versus Intravenous Morphine for Acute Pain in the Emergency Department: A Randomized Pilot Trial.

BACKGROUND: Patients in the United States frequently seek medical attention in the emergency department (ED) to address their pain. The intranasal (i.n.) route provides a safe, effective, and painless alternative method of drug administration. Sufentanil is an inexpensive synthetic opioid with a high therapeutic index and rapid onset of action, making it an attractive agent for management of acute pain in the ED. OBJECTIVE: The objective of our study was to evaluate the safety and efficacy of i.n. sufentanil as the primary analgesic for acute pain in the ED. METHODS: This was a single-center, prospective, randomized, double-blind, double-dummy, controlled trial that evaluated the use of i.n. sufentanil 0.7 µg/kg via mucosal atomizer device vs. intravenous morphine 0.1 mg/kg in adult patients who presented to the ED with acute pain. The primary outcome was patient's pain score at 10 min after administration of intervention. Secondary outcomes were adverse events, the need for rescue analgesia, and patient satisfaction after treatment. RESULTS: Thirty patients were enrolled in each group. There was no significant difference in pain scores at 10 min after administration of intervention (sufentanil: 2.0, interquartile range = 2.0-3.3 vs. morphine: 3.0, interquartile range = 2.0-5.3, p = 0.198). No serious adverse events were reported. Rescue analgesia was not requested in either group. No significant difference in median satisfaction scores was found. CONCLUSION: The use of i.n. sufentanil at 0.7 µg/kg/dose resulted in rapid and safe analgesia with comparable efficacy to i.v. morphine for up to 30 min in patients who presented with acute pain in the ED.

Does co-treatment with ultra-low-dose naloxone and morphine provide better analgesia in renal colic patients?

OBJECTIVE: This study attempted to evaluate the efficacy of ultra-low-dose intravenous (IV) naloxone combined with IV morphine, as compared to IV morphine alone, in terms of reducing pain and morphine-induced side effects in patients with renal colic. METHODS: In this double-blind clinical trial, 150 patients aged 34 to 60 years old who presented to the emergency department (ED) with renal colic were randomly allocated to either an intervention group that received ultra-low-dose IV naloxone combined with IV morphine or to a control group that received morphine plus a placebo. The severity of pain, sedation, and nausea were assessed and recorded for all patients at entrance to the ED (T1), then at 20 (T2), 40 (T3), 60 (T4), 120 (T5), and 180 (T6) minutes after starting treatment. The Numeric Rating Scale (NRS) was used for the assessment of pain and nausea intensities, and the Ramsay Sedation Scale (RSS) was used to assess sedation. RESULTS: A GEE model revealed that patients in the naloxone group had non-significantly reduced pain scores compared to those in the morphine group (coefficient = -0.68; 95% CI: -1.24 to -0.11, Wald X2 (1) = 5.41, p = 0.02). The sedation outcome demonstrated no statistically significant differences at T1 to T4 among patients with renal colic compared to the ones who only received morphine. At T5 and T6, 1.5% vs. 20% and 1.5% vs. 16.9% of subjects from the naloxone group versus the morphine group obtained RSS scores equal to 3, respectively (p = 0.001 and p = 0.004, respectively). CONCLUSIONS: Compared to patients who only received IV morphine, co-treatment of ultra-low-dose naloxone with morphine could not provide better analgesia and sedation/agitation states in renal colic patients.

The implementation and evaluation of an evidence-based statewide prehospital pain management protocol developed using the national prehospital evidence-based guideline model process for emergency medical services.

BACKGROUND: In 2008, the National Highway Traffic Safety Administration funded the development of a model process for the development and implementation of evidence-based guidelines (EBGs) for emergency medical services (EMS). We report on the implementation and evaluation of an evidence-based prehospital pain management protocol developed using this model process. METHODS: An evidence-based protocol for prehospital management of pain resulting from injuries and burns was reviewed by the Protocol Review Committee (PRC) of the Maryland Institute for Emergency Medical Services Systems (MIEMSS). The PRC recommended revisions to the Maryland protocol that reflected recommendations in the EBG: weight-based dosing and repeat dosing of morphine. A training curriculum was developed and implemented using Maryland's online Learning Management System and successfully accessed by 3,941 paramedics and 15,969 BLS providers. Field providers submitted electronic patient care reports to the MIEMSS statewide prehospital database. Inclusion criteria were injured or burned patients transported by Maryland ambulances to Maryland hospitals whose electronic patient care records included data for level of EMS provider training during a 12-month preimplementation period and a 12-month postimplementation period from September 2010 through March 2012. We compared the percentage of patients receiving pain scale assessments and morphine, as well as the dose of morphine administered and the use of naloxone as a rescue medication for opiate use, before and after the protocol change. RESULTS: No differences were seen in the percentage of patients who had a pain score documented or the percent of patients receiving morphine before and after the protocol change, but there was a significant increase in the total dose and dose in mg/kg administered per patient. During the postintervention phase, patients received an 18% higher total morphine dose and a 14.9% greater mg/kg dose. CONCLUSIONS: We demonstrated that the implementation of a revised statewide prehospital pain management protocol based on an EBG developed using the National Prehospital Evidence-based Guideline Model Process was associated with an increase in dosing of narcotic pain medication consistent with that recommended by the EBG. No differences were seen in the percentage of patients receiving opiate analgesia or in the documentation of pain scores.

Stability of heroin, 6-monoacetylmorphine, and morphine in biological samples and validation of an LC-MS assay for delayed analyses of pharmacokinetic samples in rats.

Degradation of heroin to 6-monoacetylmorphine (6-MAM) and then morphine happens rapidly in vivo and in vitro. The rates of heroin and 6-MAM degradation depend on the type of biological samples, and the duration and conditions of storage. In order to optimize conditions for measuring heroin and its metabolites in samples collected for pharmacokinetic studies in rats, we investigated the time course of degradation of heroin, 6-MAM, and morphine in four biological matrices: rat blood, rat brain homogenate, bovine serum, and human plasma under various conditions. Analyte concentrations were measured by LC-MS. The goal was to identify conditions that allow maximum flexibility in scheduling sample collection and analysis, as well as gain more information on the stability of heroin in blood and tissue samples. A solid-phase extraction method with ice-cold solvents, sodium fluoride (NaF) and a low pH (3.0) maintained sample stability. Quality controls were within 94.0-105% of the target value. Variability was 4.0-8.9% for all analytes within the range of 5-200 ng/mL for heroin, 5-1000 ng/mL for 6-MAM, and 10-200 ng/mL for morphine. Heroin degradation to 6-MAM was faster in rat whole blood than in plasma, and faster in rat plasma than in rat brain homogenate. Maintaining NaF at 4 mg/mL throughout processing enhanced stability; higher NaF concentrations added to whole blood caused hemolysis. Samples processed through solid phase extraction and stored as dried pellets at 80°C constituted the most stable environment for heroin, and was superior to the storing of samples in solution prior to or after extraction. Nevertheless, post-extraction heroin and 6-MAM levels declined by 6.7-8.3% over one week in rat plasma under these conditions, and by <1-4.7% in bovine serum or human plasma.

Development and validation of an HPLC/MS/MS method for the determination of sufentanil and morphine in human plasma.

A sensitive and fast HPLC/MS/MS method for measurement of sufentanil and morphine in plasma was developed and validated. A single liquid-liquid extraction in alkaline medium was used for the cleanup of plasma, and fentanyl was added as an internal standard (IS). The analyses were carried out using a C18 column and the mobile phase acetonitrile-5 mM ammonium acetate + 0.25% formic acid (70 + 30, v/v). The triple-quadrupole mass spectrometer equipped with an electrospray source in positive mode was set up in the selective reaction monitoring mode to detect precursor --> product ion transition 387.0 > 238.0, 285.7 > 165.1, and 337.0 > 188.0 for sufentanil, morphine, and IS, respectively. The method was linear in the 0.05 (LOQ) - 500 ng/mL range for sufentanil and 10 (LOQ) - 1000 ng/mL range for morphine. Good selectivity, linearity, precision, accuracy, and robustness were obtained for the HPLC/MS/MS method. The proposed method was successfully applied for the determination of sufentanil and morphine in patients undergoing cardiac surgery.

6-Acetylmorphine detected in the absence of morphine in pain management patients.

Liquid chromatography tandem mass spectrometry was used to identify and confirm the presence of 6-acetylmorphine and morphine in 22,361 urines of pain management patients. Thirty urines tested positive for 6-acetylmorphine above a cutoff of 10 ng/mL. Twenty-three percent of the patients with urinary concentrations of 6-acetylmorphine above 10 ng/mL had urinary morphine concentrations below 300 ng/mL.

Normal-release oral morphine starting dose in cancer patients with pain.

OBJECTIVES: To evaluate whether the current European Association for Palliative Care recommendation regarding the starting dose of 5 mg of normal-release morphine (NRM) sulfate oral solution every 4 hours in opioid naive patients or 10 mg in patients already being treated with "weak" opioids is effective and could be proposed as starting routine dose in clinical practice. Secondary aims were to estimate the percentage of patients who were high responders to NRM and to study the association of baseline patient characteristics with both high analgesic responsivity and the need of opioid dose escalation. METHODS: Consecutive strong opioid-naive patients with cancer pain were enrolled in a multicenter uncontrolled phase 4 clinical trial. Oral NRM was administered at 2 different dosages: 5 and 10 mg every 4 hours, respectively, for opioids-naive (group A) and nonopioids-naive (group B) patients as starting therapy. Average daily dosages of NRM and opioid escalation index (OEI) were calculated and the reduction in pain score was tested through Student t test both in group A and in group B patients. RESULTS: One hundred fifty-nine consecutive patients were enrolled and data analysis was conducted on 151 (95%) patients. On an average the OEIs were: 3.2 in group A and 6.5 in group B and a significant reduction in pain score both after 3 and 5 days from baseline (P<0.001) was shown in both groups. In multivariate analysis both Karnofsky Performance Status and episodic pain showed to be independent prognostic factors of a high analgesic response. The presence of neuropathic pain showed to be associated with a higher OEI. DISCUSSION: These data show that empiric standard doses of NRM during titration, recommended by European Association for Palliative Care, are effective in clinical practice.

Quality assessment of morphine hydrochloride solutions.

The therapeutic substances in solution prepared in pharmaceutical laboratories (prescribed drugs) must preserve their activity. Therefore, they must be stable throughout the period of storage in home conditions. The maintenance of stability is particularly difficult for morphine hydrochloride solutions administered orally to cancer patients at the last stage of the disease being at home. This study, aiming at the assessment of stability of morphine hydrochloride solutions, was performed on samples of 0.5% water solutions of the drug alone, 0.25% and 0.5% solutions of the drug in water with chloroform as well as injection solutions (Morphinum hydrochloricum, 20 mg, Polfa Warsaw). All the samples were kept at 20 degrees C for six months. Throughout this time observations were made to detect changes in their appearence and pH values. Their qualitative composition was determined by TLC and the content of morphine was checked by UV spectrophotometry in an environment of 0.1 mol/l of hydrochloric acid at 285 nm. Results of the kinetic study permitted drawing conclusions as to the mechanism of the decomposition of morphine hydrochloride in the solutions studied - according to a simple first order reaction and determination of the rate constants (k, s(-1)) of the process. Results of the chromatographic and spectrophotometric study did not show differences in the stability of water and chloroform/water solutions of morphine hydrochloride studied after 4 weeks and 6 months. After that time the decrease of morphine content was 10 and 25%, respectively.

Opioid analgesic prescribing and use - an audit of analgesic prescribing by general practitioners and The Multidisciplinary Pain Centre at Royal Brisbane Hospital.

AIMS: This study evaluated the use of and need for opioids in patients attending the Multidisciplinary Pain Centre at the Royal Brisbane Hospital (RBH). METHODS: All consecutive in-patient admissions in 1998 were reviewed. A 10-point scoring system based on the World Health Organization (WHO) analgesic ladder was devised to facilitate comparison of analgesic prescribing on admission and at the time of discharge. A conversion table was used to standardize opioid analgesic doses to an oral morphine equivalent. RESULTS: Of the 370 patients reviewed, 233 (81%) were by their general practitioners. Records of 288 (78%) were available for full review and 270 (94%) of these had noncancer pain. On admission, 239 (83%) were taking an opioid analgesic, with 135 (47%) taking strong opioids (e.g. morphine, oxycodone, methadone). There was a significant decrease in the mean total daily oral morphine equivalent prescribed on discharge 36.9 mg (95% CI: 33.4, 40.4) compared with that on admission 88.7 mg (95% CI: 77.6, 99.8) (P < 0.001). There was a significant decrease (P < 0.05) in the proportion of patients taking a primary opioid on discharge 153 (58%) compared with admission 239 (83%), although the proportion of patients taking a strong opioid on discharge 150 (52%) compared with admission 135 (47%) was not significantly different (P > 0.05). The proportion of patients taking a laxative showed a significant increase on discharge 110 (73%) compared with admission 38 (28%) (P < 0.05). CONCLUSIONS: Our analgesic prescribing scoring system and opioid conversion table have the potential to be developed further as tools for assessing opioid analgesic prescribing. The significant decrease in total daily oral morphine equivalents signifies the value of prescribing in accordance with the WHO analgesic ladder, and the necessity of general practitioner education. The management of chronic pain is complex, and it requires interventions additional to pharmacological therapy. Evaluation by a multidisciplinary team, coupled with experience in and an understanding of analgesic prescribing and rehabilitation provides an effective basis for improving the management of patients with chronic pain.