Clinical analgesic assay of repeated and single doses of heroin and hydromorphone. A multidimensional comparison of morphine and hydromorphone patient-controlled analgesia. Epidural hydromorphone for postcesarean analgesia. [Postoperative pain therapy with hydromorphone and metamizole. A prospective randomized study in intravenous patient-controlled analgesia (PCA)]. Comparative efficacy of patient-controlled administration of morphine, hydromorphone, or sufentanil for the treatment of oral mucositis pain following bone marrow transplantation. Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery. Safety and efficacy of hydromorphone as an analgesic alternative to morphine in acute pain: a randomized clinical trial. Morphine and hydromorphone epidural analgesia. A prospective, randomized comparison. Patient-controlled analgesia for mucositis pain in children: a three-period crossover study comparing morphine and hydromorphone. Relative analgesic potencies of morphine and hydromorphone in postoperative pain. Continuous subcutaneous infusion of morphine vs. hydromorphone: a controlled trial. A randomized, double-blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. Canadian Palliative Care Clinical Trials Group. Comparative efficacy of oral extended-release hydromorphone and immediate-release hydromorphone in patients with persistent moderate to severe pain: two randomized controlled trials. Epidural morphine vs hydromorphone in post-caesarean section patients. Comparative clinical efficacy and safety of immediate release and controlled release hydromorphone for chronic severe cancer pain. Comparison of hydromorphone and meperidine for ureteral colic. Effect of pre-emptive hydromorphone administration on postoperative pain relief--a randomized controlled trial. Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain. Epidural hydromorphone with and without epinephrine for post-operative analgesia after cesarean delivery. Epidural patient-controlled analgesia: influence of bupivacaine and hydromorphone basal infusion on pain control after cesarean delivery. A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Epidural morphine and neostigmine for postoperative analgesia after orthopedic surgery. Oral tramadol, a mu-opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain. A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts. Intravenous versus epidural administration of hydromorphone. Effects on analgesia and recovery after radical retropubic prostatectomy. Morphine differentially affects the sensory and affective pain ratings in neurogenic and idiopathic forms of pain. Postoperative analgesia with hydromorphone and meperidine: a double-blind comparison. Analgesic efficacy of a combination of hydrocodone with ibuprofen in postoperative pain. A comparison of oral transmucosal fentanyl citrate and oral hydromorphone for inpatient pediatric burn wound care analgesia. Nalbuphine, acetaminophen, and their combination in postoperative pain. Evaluation of two opioid-acetaminophen combinations and placebo in postoperative oral surgery pain. Comparative clinical efficacy and safety of a novel controlled-release oxycodone formulation and controlled-release hydromorphone in the treatment of cancer pain. Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial. Premedication with low dose oral clonidine does not enhance postoperative analgesia of intrathecal morphine. Oral clonidine premedication enhances postoperative analgesia by epidural morphine.
A direct comparison of the analgesic activities of heroin and hydromorphone was carried out in cancer patients with postsurgical pain. Intramuscular doses of 5 and 10 mg of heroin were compared with 1 and 2 mg of hydromorphone in a randomized, double-blind, 4-point parallel group assay. Design innovations in the study provided that about half the patients would receive prior repeated doses of the same drug as the test medication, and half would receive the alternate medication. Both test drugs were found to be potent, relatively short acting analgesics with similar profiles of action. Hydromorphone was about 5 times as potent as heroin on a milligram basis. The comparison of those patients who had repeated doses of the same treatment prior to the test dose and those who had repeated doses of the alternate drug demonstrated no significant effect on the relative potency estimates. Side effect occurrence was similar for both drugs, with sleepiness the most prominent effect. The study supports the view that hydromorphone and heroin produce similar clinical effects, and that either drug may adequately substitute for the other. Covariate analysis indicated that time since last analgesic was positively related to analgesia, and amount of prior opioid had a negative relationship. To a lesser extent, increase in patient age was associated with an increase in analgesic scores. Taking these covariates into account served to increase the sensitivity of the analysis. Although patient-controlled analgesia (PCA) pumps have been in use for more than a decade, the optimal PCA analgesic has yet to be identified. Many drugs are used; however, morphine remains the "gold standard" of opioid analgesics worldwide. The present study evaluated morphine and hydromorphone (Dilaudid) PCA with respect to analgesic efficacy, side effects, mood, and cognitive function. Sixty-one opioid naive patients undergoing lower abdominal surgery participated in the double-blind protocol. Verbal rating scores, use of medication, and side effects for the two medications were recorded. Cognitive functioning was assessed by computation of Digit Symbol and Trails Making B Tests. Self-reported affective state (mood) was measured by Profile of Mood States (POMS) inventory. Both medications provided adequate analgesia without a difference in side effects. Cognitive performance was poorer in the hydromorphone group (P < 0.05). Patients receiving hydromorphone reported less anger/hostility (P < 0.01) and generally better mood elevations on the other subscales than those receiving morphine. A similar incidence of side effects and dose medication can be anticipated with morphine and hydromorphone. When considering cognitive effects, morphine had less adverse consequences, while hydromorphone appeared to result in improved mood. We conclude that hydromorphone may provide a suitable alternative to morphine. The efficacy of epidurally administered hydromorphone for postcesarean analgesia was evaluated in a prospective, randomized, double-blind study. Patients in group H (N = 26) received 1.0 mg of hydromorphone in preservative-free saline (total volume = 10 mL), administered epidurally. Patients in group B (N = 26) received 10 mL of 0.25% bupivacaine, administered epidurally. Both groups subsequently received intramuscular injections of hydromorphone as needed. There were significant differences between the two groups in pain score, patient assessment of analgesia quality, time to first analgesic intervention, and total dosage of hydromorphone during the first 24 hours. Nausea/vomiting and pruritus occurred more frequently in group H. No patient had a respiratory rate less than or equal to 10. There were no statistically significant differences between groups in mean times to first ambulation, first void, first passage of flatus, or hospital discharge. Most potent opioid analgesics available in Germany have been investigated for use in postoperative patient-controlled analgesia (PCA). To conclude an older comparative series, it was the aim of the present study to define analgesic potency, side effects and patient acceptance of hydromorphone and its interaction with the non-opioid analgesic metamizole. A total of 120 patients recovering from elective abdominal or orthopaedic surgery, performed under standardised general anaesthesia, were randomised into 3 double-blind treatment groups to receive intravenous PCA demand doses of hydromorphone 283 micrograms (low dose, LD), 566 micrograms (high dose, HD) or a combination of hydromorphone 283 micrograms and metamizole 50 mg (low dose hydromorphone + metamizole, LM). Demand-independent low-dose background infusions were added to deliver hydromorphone at 67.9 micrograms/h in all groups, with additional metamizole at 12 mg/h in group LM. Lockout times were set to 2 min. After an average observation time of 24.5 +/- 2.6 h (mean, SD) since start of PCA, cumulative PCA hydromorphone doses in groups LD, HD and LM were 7.8 +/- 3.3, 12.1 +/- 4.8 and 7.5 +/- 2.0 mg, respectively, with the well known large inter-individual variability in all groups. Although hydromorphone consumption was significantly higher in group HD, self-reported pain intensities (VAS, retrospective pain scores) were quite comparable between the groups. Low dose, PCA bolus-linked metamizole did not significantly reduce hydromorphone consumption nor improve patient acceptance. Side-effects were typical for potent postoperative opioids, but never required special treatment; haemodynamic or respiratory complications were not observed in any patient. It can be concluded by comparison with other PCA opioid investigations performed under the same study protocol that hydromorphone is about 3-4 times as potent an analgesic as morphine under the conditions of intravenous postoperative PCA. Due to a favourable patient acceptance, hydromorphone can be recommended as a suitable alternative to other opioids for the treatment of postoperative pain. A total of 119 bone marrow transplant patients suffering from oral mucositis pain were enrolled in a randomized, double-blind, parallel-group trial comparing the efficacy of patient-controlled analgesia with morphine, hydromorphone and sufentanil. Patient ratings of pain and side-effects on visual analog scales were gathered daily from the start of patient-controlled analgesia (PCA) therapy until the discontinuation of opioid treatment either because of resolution of oral mucositis pain, intolerable side-effects, inadequate pain control, or complications related to transplantation. Of the 119 enrolled subjects, 100 met the evaluable criteria of developing oral mucositis and remaining on the study for at least 2 days. Multivariate analysis of the outcome measures indicated that the analgesia achieved in all three opioid groups was nearly equivalent, while measures of side-effects, especially for the combination of sedation, sleep and mood disturbances, were statistically lower in the morphine group than in hydromorphone or sufentanil groups. Patients in the hydromorphone group exhibited the most variability in pain control. Event analysis also indicated significant differences in time to treatment failure between the three groups, with the morphine arm exhibiting clear superiority. The proportion of patients discontinued because of inadequate pain relief was much higher in the sufentanil group (7/36) as compared to the hydromorphone (0/34) or the morphine group (1/30). The daily opioid consumption pattern showed a continual dose escalation during the first week of therapy for all groups, coincident with worsening mucositis. Morphine consumption reached a plateau by day 5, whereas hydromorphone and sufentanil consumption continued to rise until days 7 and 9, respectively. Sufentanil dose requirement increased by approximately 10-fold compared to morphine and hydromorphone, whose requirements increased only 5-fold, suggesting the possibility of development of acute pharmacological tolerance in some patients with this phenylpiperidine opioid. This study provides support for the recommendation that morphine is the opioid of first choice when patient-controlled analgesia is employed for the treatment of severe oropharyngeal pain in bone marrow transplantation (BMT) patients. The safety and side-effects profile of epidural administration of a hydrophilic (morphine), highly lipophilic (fentanyl) and a drug with intermediate hydrophilic and lipophilic activity (hydromorphone) were compared in 90 children undergoing orthopaedic procedures. Ninety patients were randomly assigned (30 in each group) to receive epidural morphine, hydromorphone, or fentanyl for postoperative analgesia. Respiratory effects, nausea, somnolence, urinary retention, pruritus and visual pain scales were evaluated and compared during a 30-h period following surgery. In the morphine group, 25% showed respiratory depression with oxygen saturation below 90% but there was no incidence of respiratory depression in the fentanyl or hydromorphone groups. Somnolence was prominent in some of the patients in all the groups, but was more prolonged in the morphine group. Statistically, there was no significant difference in nausea between the groups, but pruritus was more severe and frequent in the morphine group. The incidence of urinary retention in the morphine group was higher compared with the fentanyl and hydromorphone groups. In conclusion, epidural hydromorphone, demonstrating less side-effects, is preferable to morphine and fentanyl for epidural analgesia in children. We compare a standard weight-based dose of intravenous hydromorphone (Dilaudid) to a standard weight-based dose of intravenous morphine in adults presenting to the ED with acute severe pain.
                This was a prospective, randomized, double-blind, clinical trial conducted in an academic medical center. Of the 198 adult patients presenting to the ED with acute severe pain who were randomized to receive either intravenous hydromorphone at 0.015 mg/kg or intravenous morphine at 0.1 mg/kg, 191 patients had sufficient data for analysis. The main outcome measure was the difference between the 2 groups in pain reduction at 30 minutes as measured on a validated numeric rating scale. Adverse effects, pain reduction at 5 minutes and 2 hours postbaseline, and additional analgesics and antiemetics were tracked as secondary outcome measures.
                The mean change of pain from baseline to 30 minutes postbaseline in patients allocated to intravenous hydromorphone was -5.5 numeric rating scale units versus -4.1 in patients allocated to intravenous morphine (difference -1.3; 95% confidence interval -2.2 to -0.5). Adverse effects were similar in both groups, with the exception of pruritus, which did not occur in patients receiving hydromorphone (0% versus 6% [difference -6%; 95% confidence interval -11% to -1%]). No patient required naloxone.
                For the treatment of acute, severe pain in the emergency department, intravenous hydromorphone at 0.015 mg/kg represents a feasible alternative to intravenous morphine at 0.1 mg/kg. Because evidence from uncontrolled, unblinded studies suggested fewer side effects from epidural hydromorphone than from epidural morphine, we employed a randomized, blinded study design to compare the side effects of lumbar epidural morphine and hydromorphone in 55 adult, non-obstetric patients undergoing major surgical procedures. A bolus dose of epidural study drug was given at least 1 h prior to the conclusion of surgery, followed by a continuous infusion of the same drug for two postoperative days. Infusions were titrated to patient comfort. Visual analog scale (VAS) pain scores, VAS sedation scores, and subjective ratings of nausea and pruritus were assessed twice daily. The two treatments provided equivalent analgesia. Sedation scores and prevalence of nausea did not differ significantly between groups. Prevalence of pruritus, however, differed significantly on postoperative day 1, with moderate to severe pruritus reported by 44.4% of patients in the morphine group versus 11.5% in the hydromorphone group (P < .01). On post-operative day 2, reports of pruritus by patients receiving morphine remained higher than those among the hydromorphone-treated subjects, although this difference was no longer statistically significant (32% vs. 16.7%, P = .18). We conclude that lumbar epidural morphine and hydromorphone afford comparable analgesia, but the occurrence of moderate to severe pruritus on the first postoperative day is reduced by the use of hydromorphone. (1) To test the safety and efficacy of a clinical protocol for administering opioid by using patient-controlled analgesia (PCA) for the management of mucositis pain in children after bone marrow transplantation, (2) to compare the efficacy, side-effect profile, and potency ratio of morphine with those of hydromorphone by using PCA as the method of opioid administration, and (3) to obtain pharmacokinetic data on hydromorphone and morphine in this population of children.
                In this double-blind, three-period crossover study, patients were randomly assigned to receive either morphine (group 1) or hydromorphone (group 2) initially by means of PCA on days 1, 2, and 3 (period 1), to be followed on days 4, 5, and 6 (period 2) with the alternative opioid, followed by the opioid used at the commencement of the study on days 7, 8, and 9 (period 3). A clinical protocol for calculating the PCA commencement opioid dose and subsequent opioid-dose escalation was tested by measures of safety and efficacy. Measures of pain intensity and opioid side effects were made during the three periods. On the last study day (day 10), patients received a continuous infusion of opioid derived from the previous 24-hour PCA opioid requirement, and blood specimens were collected and stored for subsequent opioid analysis.
                Ten patients were enrolled in this study. Rapid escalation in opioid requirement commonly occurred at the commencement of PCA, followed by a variable plateau phase and then deescalation of opioid requirement after mucositis resolution. The measures demonstrated the safety and efficacy of the clinical protocol. In the concentrations used, there was no statistical difference between the mean daily pain, sedation, nausea and vomiting, and pruritus scores for both opioids (Friedman test). The analysis of variance of the log-total opioid doses per patient during periods 1, 2, and 3 indicated that patients used 27% more hydromorphone than expected from its presumed 7:1 ratio relative to morphine potency used in the PCA infusions. The mean plasma hydromorphone concentration was 4.7 ng/ml (range, 1.9 to 8.9 ng/ml), and the mean clearance was 51.7 ml/min per kilogram of body weight (range, 28.6 to 98.2 ml/min per kilogram). The mean plasma morphine, morphine-6-glucuronide, and morphine-3-glucuronide concentrations were 40.0 ng/ml (range, 15 to 62.5), 168.2 ng/ml (range, 54.4 to 231.9), and 391.0 ng/ml (range, 149.4 to 921.7), respectively. The mean morphine clearance was 34.3 ml/min per kilogram of body weight (range, 19.3 to 58.3). The mean molar ratios of morphine-6-glucuronide/morphine, morphine-3-glucoronide/morphine, and morphine-3-glucuronide/morphine-6-glucuronide were 2.48 (range, 1.4 to 3.3), 5.82 (range, 3.4 to 9.1), and 2.46 (range, 1.1 to 3.3), respectively.
                The safety and efficacy of a clinical protocol for the administration of opioids by means of PCA for mucositis pain after bone marrow transplantation was demonstrated. In this small study, hydromorphone was not superior to morphine in terms of analgesia or the side-effect profile: a larger study would be needed to show a difference. The clearances of hydromorphone and morphine in the children studied were generally greater than those previously recorded, but this finding may be related to disease or treatment variables. Apart from clearance, the morphine pharmacokinetics in the study population were similar to those previously recorded. Hydromorphone may be less potent in this population of children than indicated by adult equipotency tables. Because of discrepancies in the estimates of the relative analgesic potencies of hydromorphone and morphine, the drugs were compared in two four-point, double-blind bioassays. In the first study, hydromorphone, 1 and 2 mg, was compared with morphine, 5 and 10 mg, in 31 postoperative patients; in the second, hydromorphone, 0.5 and 1 mg, was compared with morphine, 5 and 10 mg, in 112 postoperative patients. Subjective responses to nurse-observer questions were used to quantitate analgesia for postoperative pain. Hydromorphone is more potent than commonly believed: approximately 0.9 to 1.2 mg is equianalgesic with 10 mg of morphine, with a similar incidence of side effects. Seventy-four patients were included in a double-blind, randomized, controlled trial comparing the analgesic efficacy and adverse effects of hydromorphone and morphine delivered by continuous subcutaneous infusion. Patients completed the Memorial Pain Assessment Card and a checklist of opioid-related adverse effects immediately before commencing subcutaneous infusion and 24, 48, and 72 hours later. An assessment tool was developed for the 60 patients who were too ill to complete their own questionnaire. The tool demonstrated excellent inter-rater reliability. Thirty-four percent of patients in the hydromorphone group and 27% of those in the morphine group died before completion of the study (P = 0.66). The hydromorphone group required more analgesia for breakthrough pain in the first 24 hours of the study (P = 0.03) and had a greater improvement in the behavior of frowning on movement and the comfort visual analogue scale (P = 0.08) over the course of the study. Adverse effects were rare and similar in both groups. This study found hydromorphone to be at least as effective as morphine when delivered by continuous subcutaneous infusion. To evaluate the safety and efficacy of a new slow-release preparation of hydromorphone (SRH) in the treatment of cancer pain.
                Ninety-five adult patients from three Canadian Palliative Care Centers with no evidence of mental impairment received treatment for cancer pain with an oral opioid analgesic. After informed consent was obtained, patients underwent titration to a stable dose of immediate-release hydromorphone (IRH) for 48 hours, and were then randomized to receive IRH or SRH for 5 days in a double-blind basis. During day 6, a crossover took place, and patients received the alternate drug for 5 days. Pain intensity was assessed using a visual analog scale (VAS) and ordinal scale (OS). Side effects were assessed using VAS. Patients and investigators made a blinded global rating of efficacy a blinded final choice between SRH and IRH.
                In 75 assessable patients, pain intensity of the VAS and OS were (mean +/- SD) 27 +/- 21 and 1.3 +/- 0.6 on IRH, versus 29 +/- 21 (P = .13) and 1.3 +/- 0.6 (P = .19) on SRH, respectively. The total number of extra doses of opioids, global rating, and final blinded choice by both patients and investigators were not significantly different between IRH and SRH. Differences in side effects were not significant.
                Our findings suggest that SRH is as safe and effective as IRH in the treatment of cancer pain. Two multicenter, randomized, double-blind, crossover studies with identical designs evaluated the efficacy of oral extended-release hydromorphone (HHER) administered q24h compared with immediate-release hydromorphone (HHIR) dosed four times daily in patients with persistent moderate to severe pain. Patients titrated to a stable HHER dose were randomized to individualized doses of HHER or HHIR for 3 to 7 days before crossover to the second treatment. Primary efficacy end point was the mean of average pain intensity (API) scores, rated on a 0- to 10-point numeric scale, over the last 2 days before the pharmacokinetics/pharmacodynamics day of each double-blind period. Difference between treatments (HHER - HHIR) in study 1 was 0.17 with a 90% confidence interval (CI) (-0.01, 0.34); in study 2, difference was 0.07 with a 90% CI (-0.12, 0.26). There were no significant differences between treatments in API scores or amount of rescue medication used at any time interval within the 24-hour dosing period. No reduction in pain control occurred in patients administered HHER at the end of the 24-hour dosing period. Most treatment-emergent adverse events were opioid-related. In these studies, HHER administered q24h and HHIR dosed four times daily provided comparable analgesia at an equivalent total daily dose. The purpose of this randomized controlled double blind study was to compare the efficacy of pain relief and the side effects of epidural hydromorphone and morphine in post-Caesarean patients.
                In all patients, epidural anaesthesia was induced using carbonated lidocaine 2% with 1:200,000 epinephrine and 50 micrograms fentanyl, given in incremental doses. Patients in Group 1 (n = 24) received 0.6 mg hydromorphone and patients in Group 2 (n = 22) received 3 mg morphine after delivery of the infant. Pain, pruritus and nausea were measured using a visual analog scale (at times: baseline, on admission to the recovery room, 3, 6, 12, 18 and 24 hr postoperatively), by the number of requests for additional medications and by an overall satisfaction score.
                There was no difference between the groups in pain relief of in the incidence and severity of side effects. Pruritus was more pronounced within the first six hours in Group 1 and at 18 hr in Group 2.
                Hydromorphone provides no clinical benefit over epidural morphine for post operative analgesia following Caesarean section. The short elimination half-life of hydromorphone necessitates 4-hourly dosing to maintain optimal levels of analgesia in patients with chronic cancer pain. The purpose of this study was to compare the clinical efficacy and safety of controlled release hydromorphone administered every 12 hours and immediate release hydromorphone administered every 4 hours in patients with chronic severe cancer pain.
                Forty-eight patients with stable chronic severe cancer pain were randomized, in a double-masked crossover study, to controlled release hydromorphone every 12 hours or immediate release hydromorphone every 4 hours for 7 days each. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed using a VAS. Assessments were made by the patient four times a day at 7:00 a.m., 11:00 a.m., 3:00 p.m., and 7:00 p.m. Use of rescue hydromorphone also was recorded by the patient.
                Forty-five patients completed the study (26 women, 19 men; mean age, 57.1 +/- 13.6 years) and received a mean daily dose of 76 +/- 133 mg (range, 6-768 mg). There were no significant differences between controlled release hydromorphone and immediate release hydromorphone in overall VAS pain intensity scores (19 +/- 14 vs. 20 +/- 14 mm), ordinal pain intensity scores (1.2 +/- 0.8 vs. 1.2 +/- 0.8) and pain scores by day of treatment or time of day. The daily rescue analgesic consumption during controlled release hydromorphone and immediate release hydromorphone did not differ significantly overall (1.1 +/- 1.1 vs. 1.0 +/- 1.1 doses per day) or with respect to time of day. There were no significant differences in overall VAS sedation scores (18 +/- 18 mm vs. 19 +/- 18 mm) and in overall mean VAS nausea scores (12 +/- 15 mm vs. 11 +/- 14 mm) between controlled release hydromorphone and immediate release hydromorphone.
                Controlled release hydromorphone administered every 12 hours is as effective as immediate release hydromorphone administered every 4 hours in the management of patients with chronic severe cancer pain. The benefits of controlled release hydromorphone lie in the convenience of its capsule formulation, which can be sprinkled on soft food, and its 12-hour duration of action, which allows patients uninterrupted sleep and improved compliance. To compare the efficacies of meperidine and hydromorphone in the treatment for ureteral colic in the emergency department (ED).
                A prospective, double-blind, randomized clinical trial was conducted over six months at a tertiary referral center with 93,000 annual ED visits. Seventy-three patients completed the study. The patients received either 1 mg of hydromorphone or 50 mg of meperidine IV at t = 0. Pain intensity was determined using a 10-cm visual analog scale at t = 0, 15, 30, 60, and 120 minutes. A second dose of the study drug could be given between t = 15 and t = 120 minutes when the clinician believed the initial dose was ineffective. Patients requiring more than one additional dose of analgesia were treated as nonresponders and were removed from the study.
                Thirty-six patients received hydromorphone and 37 received meperidine. The initial pain intensities (hydromorphone group = 8.4 +/- 1.5; meperidine group = 8.5 +/- 2.1), age distributions, sex distributions, and side effects of the two groups were comparable. Pain relief was better (p < 0.05) with hydromorphone at t = 15, 30, 60, and 120 minutes. The hydromorphone group required rescue analgesia less often (31% vs 68%, p < 0.01), had fewer IV pyelographies (IVPs) (28% vs 54%, p < 0.05), and had a lower proportion of hospital admissions (25% vs 49%, p = 0.08).
                For the fixed doses used in this study, the adult ureteral colic patients receiving hydromorphone achieved more pain relief, required less rescue medication, underwent fewer IVPs, and avoided hospital admission more frequently than did those receiving meperidine. Pre-emptive analgesia represents a treatment strategy which tries to prevent the development of pain by inhibiting central reactions to peripheral sensory stimuli. In a prospective randomized double-blind placebo-controlled study, the effect of oral premedication with 4 mg of a slow-release hydromorphone preparation on postoperative piritramide consumption and subjective pain perception is being evaluated.
                96 women undergoing hysterectomy were randomly assigned to four study groups. Patients from groups 1 and 2 received hydromorphone and placebo respectively two hours before surgery, while those from groups 3 and 4 were given the same substances one hour after the end of the operation. Postoperative pain relief was provided by a patient-controlled infusion pump with piritramide. The intensity of postoperative pain as perceived by the patients was quantified on a visual analogue scale. Piritramide consumption and pain scores were recorded at 1 and 24 hours after surgery. Approval of the local Ethics Committee had been obtained beforehand as well as written informed consent from the patients.
                No significant differences in piritramide consumption were observed in between the four study groups. Visual analogue scale (VAS) ratings at 1 and 24 hours after surgery did not show any significant differences either--irrespective of whether the patients had received hydromorphone or placebo preoperatively or postoperatively.
                In our study, oral administration of 4 mg of slow-release hydromorphone did not show any greater pre-emptive analgesic effect than placebo. To compare the safety and efficacy of subcutaneous and intravenous infusion of opioid analgesics, a randomised, double-blind, crossover trial was carried out in inpatients. 15 patients with severe cancer pain received two 48 h infusions of hydromorphone--one subcutaneously and one intravenously in randomly allocated order. The study was made double-blind by the use of two infusion pumps throughout; during the active subcutaneous infusion the intravenous pump delivered saline and vice versa. Serial measurements of pain intensity, pain relief, mood, and sedation by means of visual analogue scales showed no clinically or statistically significant difference between the two infusion routes. Side-effects were slight, and the mean number of morphine injections for breakthrough pain did not differ significantly between the routes (4.8 [SD 4.5] for intravenous vs 5.3 [5.6] for subcutaneous). Plasma hydromorphone concentrations measured at 24 h and 48 h of infusion showed stable steady-state pharmacokinetics; the mean bioavailability from subcutaneous infusion was 78% of that with intravenous infusion. Because of the simplicity, technical advantages, and cost-effectiveness of continuous subcutaneous opioid infusion into the chest wall or trunk, intravenous opioid infusion for the management of severe cancer pain should be abandoned. The efficacy of epidural hydromorphone alone or in combination with epinephrine for postoperative analgesia was evaluated in 30 healthy women who underwent cesarean delivery with epidural anesthesia. They were assigned randomly to receive either 1.5 mg hydromorphone alone (N = 15) or 1.5 mg hydromorphone with 1/200,000 epinephrine (N = 15). Duration of analgesia (mean +/- SD) was 24.3 +/- 9.4 hours after the epidural injection of hydromorphone plus epinephrine. This was significantly greater (p less than 0.01) than the duration of 18.2 +/- 5.9 hours after the same dose of plain hydromorphone. Analgesia was more rapid in onset and significantly better at the 0.5, 1, 3, and 12 hours postoperatively in the hydromorphone-epinephrine group. Side effects including pruritus (73%), nausea (20%), and vomiting (15%) were of similar frequency with and without epinephrine. Although mean venous PCO2 (PvCO2) levels three and six hours after the hydromorphone-epinephrine dose were elevated significantly over the pre-drug PvCO2 levels, no respiratory depression was detected by an apnea monitor to which all patients were connected. The addition of epinephrine to epidural hydromorphone hastened onset and prolonged the duration of analgesia after cesarean section. Epidural administration of hydromorphone was evaluated using a patient-controlled analgesia (PCA) delivery system in 170 healthy women undergoing elective cesarean delivery with epidural bupivacaine who were randomly assigned to one of four epidural PCA treatment groups: group I, hydromorphone alone by bolus administration; group II, hydromorphone, with a continuous (basal) infusion; group III, hydromorphone in combination with 0.08% bupivacaine by bolus administration; or group IV, hydromorphone and bupivacaine, with a concurrent infusion of both drugs. Patients in group I required significantly less opioid medication (2.1 +/- 1.1 mg [mean +/- SD]) during the first 24 h than patients in group II (3.3 +/- 1.3 mg). Similarly, patients in group III self-administered significantly less hydromorphone (2.0 +/- 1.0 mg) and bupivacaine (23.3 +/- 11.4 mg) during the first 24 h of PCA therapy, compared with patients in group IV (hydromorphone [2.7 +/- 1.1 mg] and bupivacaine [31.5 +/- 11.6 mg]). The concomitant use of a local anesthetic or basal opioid infusion with hydromorphone via epidural PCA did not decrease the number of PCA demands or delivered doses. In addition, patients in all four groups had similar pain, sedation, discomfort, fatigue, and anxiety scores. The frequency of awakening at night to self-administer analgesic medication was not decreased when a basal infusion was used.(ABSTRACT TRUNCATED AT 250 WORDS) Buprenorphine is a partial agonist at the mu-opioid receptor that has been proposed as an alternative to traditional full agonist maintenance therapy for the treatment of opioid addiction. We report on a clinical trial in which the relative safety and efficacy of long-term fixed-dose buprenorphine maintenance was examined in comparison to low- and high-dose methadone maintenance.
                Two hundred twenty-five treatment-seeking opioid addicts (46 women, 179 men) were randomly assigned to receive, in a double-blind manner, either 8 mg/d of buprenorphine, 30 mg/d of methadone, or 80 mg/d of methadone maintenance over a 1-year period. Objective and subjective measures of efficacy (urine toxicology, retention, craving, and withdrawal symptoms) were examined at the study midpoint and at termination, and safety data were tabulated over the entire 52-week study period.
                Patients assigned to high-dose methadone maintenance performed significantly better on measures of retention, opioid use, and opioid craving than either the low-dose methadone or the buprenorphine group at both 26-week and 52-week time points. Performance on these measures was virtually identical between the latter two groups. No serious adverse health effects attributable to buprenorphine were noted.
                Buprenorphine maintenance at 8 mg/d appears to be less than optimally efficacious under the conditions of the present study. Continued research is needed to reconcile these findings with the more positive results reported by other investigative groups. There are no apparent health risks associated with long-term buprenorphine maintenance at this dosage. In this study, we examined the side effects and analgesia of the combination of epidural neostigmine and morphine in patients undergoing orthopedic surgery. Sixty patients undergoing knee surgery were divided into four groups. The intrathecal anesthetic was 15 mg of bupivacaine. The epidural test drug was diluted in saline to a final volume of 10 mL. The control group received saline as the epidural test drug. The morphine group received 0.6 mg of epidural morphine. The neostigmine group (NG) received 60 micro g of epidural neostigmine. The morphine/neostigmine group received 0.6 mg of epidural morphine combined with 60 micro g of epidural neostigmine. The groups were demographically the same and did not differ in intraoperative characteristics. The visual analog scale score at first rescue analgesic and the incidence of adverse effects were similar among groups (P > 0.05). One patient from the NG complained of intraoperative nausea, closely related to spinal hypotension. Postoperatively, two patients from the NG had vomited once. The time (min) to first rescue analgesic was longer in the morphine/neostigmine group ( approximately 11 h) compared with the other groups (P < 0.05). The analgesic consumption (number of analgesic administrations in 24 h) was larger in the control group compared with the other groups (P < 0.05).
                The combination of epidural morphine and epidural neostigmine resulted in postoperative analgesia (11 h) devoid of side effects, being an alternative analgesic technique in the population studied. Opioid and spinal monoaminergic agonists have distinct analgesic properties, which may potentiate each other. Tramadol has both opioid and monoaminergic agonist actions. This initial study compared the analgesic and toxic effects of tramadol and morphine in patients with strong cancer pain.
                Pain control and side-effects with tramadol and morphine were compared in 20 cancer patients hospitalised for the treatment of strong pain. Doses of oral solutions of tramadol or morphine were individually titrated in the double-blind, randomized, cross-over study. Cross-over was after day 4, the day of statistical evaluation.
                The mean pain intensity (+/- SD) on a verbal rating scale (0 = none, 4 = unbearable) was similar with morphine (1.6 +/- 1.2, n = 17) and with tramadol (1.5 +/- 1.3, n = 16) on the fourth day of dosing. The mean daily doses on day 4 were 101 +/- 58 mg of morphine and 375 +/- 135 mg of tramadol, indicating a relative potency of 4:1 with oral dosing. The total number of side-effects per person was lower on the fourth day with tramadol (p < 0.05), as was the severity of nausea (p < 0.05) and constipation decreased with tramadol (p < 0.05). Three patients dropped out of the morphine group due to side-effects and 4 out of the tramadol group due to inadequate analgesia. Overall, 8 patients (40%) preferred morphine, 3 (15%) favoured tramadol and 9 (45%) expressed no distinct choice. Nurses rated pain control better with morphine (p < 0.03), but the tolerability of tramadol was judged superior (p < 0.002).
                In certain cancer patients with strong pain, tramadol achieved good pain control with fewer side-effects than morphine. The non-opioid mode of action may result in a different spectrum of analgesia and side-effects. Longterm studies are required to confirm this study of brief duration. The efficacy of buprenorphine and methadone was compared in the outpatient detoxification of heroin addicts. Forty-five patients were randomized to receive either sublingual buprenorphine or oral methadone under double-dummy and double-blind conditions to study the pharmacology of buprenorphine in a 90-day detoxification protocol. The patients were administered either 2 mg buprenorphine or 30 mg methadone for 3 weeks followed by 4 weeks of dose reductions and 6 weeks of placebo medication. No significant between-group differences were seen on measures of treatment retention, drug use, or symptom report. During the hydromorphone challenge, methadone attenuated opioid effects to a greater extent than did buprenorphine on both physiologic (pupil constriction) and self-report measures. However, this did not result in greater abuse of illicit opioid drugs by subjects taking buprenorphine. The results of this clinical trial indicated that buprenorphine was acceptable to patients and as effective as methadone in the detoxification treatment of heroin addicts. It remains unclear whether epidural administration of hydromorphone results in spinal analgesia or clinical benefit when compared with intravenous administration. Therefore, we undertook this study to determine whether epidural administration of hydromorphone resulted in decreased opioid requirement, improved analgesia, reduced side effects, more rapid return of gastrointestinal function, or shorter duration of hospital stay than intravenous administration.
                Sixteen patients undergoing radical retropubic prostatectomy were randomized in a double-blind manner to receive either intravenous or epidural hydromorphone via patient-controlled analgesia (PCA) for postoperative analgesia. All patients underwent a standardized combined epidural and general anesthetic and all received ketorolac for 72 h postoperatively. To decrease variability, patients were cared for according to a standardized protocol and were deemed ready for discharge according to prospectively defined criteria.
                Patients in the intravenous PCA group required approximately twice as much opioid than the epidural PCA group (P < 0.008), but there were no differences between groups in pain scores or patient satisfaction. Epidural administration resulted in a greater incidence of pruritus (P = 0.02). Gastrointestinal function recovered quickly in all patients with little variation, and there were no differences between groups. All patients were deemed ready for discharge by the third postoperative day, and removal of surgical drains was the last discharge criterion reached in all patients.
                Our results indicate that epidural administration of hydromorphone results in spinally mediated analgesia. However, epidural administration did not provide significant benefits in terms of postoperative analgesia, recovery of gastrointestinal function, or duration of hospitalization. Furthermore, we suggest that radical retropubic prostatectomy no longer be used as a model to assess the effects of analgesic technique on postoperative recovery, because control of discharge criteria revealed that hospital discharge was primarily dependent on removal of surgical drains. In a double-blind, placebo controlled crossover study, the effect of morphine on the affective and sensory pain ratings in different forms of chronic pain was investigated. Six patients suffering from central neurogenic pain, 8 from peripheral neurogenic pain and 6 from idiopathic pain participated in the study. Morphine (0.3 mg/kg bodyweight) and placebo (saline) were administered intravenously. Both the affective and sensory dimensions of pain sensation were assessed by means of the 101-point rating scale. From our results it appeared that morphine reduced the affective but not the sensory dimension of pain sensation in both groups of neurogenic pain patients. In the idiopathic pain group, neither the affective nor the sensory dimension of pain sensation were affected. The observed differences in opioid responsiveness were neither the result of differences in opioid consumption nor of differences in baseline pain levels. nan Two randomized, double-blind, parallel-group single-dose 2 x 2 factorial analgesic studies compared a single-dose or a 2-tablet dose of a combination of 7.5 mg hydrocodone bitartrate with 200 mg ibuprofen with each constituent alone and with a placebo in women with moderate or severe postoperative pain from abdominal or gynecologic surgery. A nurse-observer recorded patient reports of pain intensity and pain relief periodically for 8 hours. In both studies, the combination was significantly superior to placebo for sum of the pain intensity differences (SPID), total pain relief (TOTPAR), peak pain intensity difference (PID) and pain relief, global evaluation, and time to remedication. The combination was likewise significantly superior to both hydrocodone and ibuprofen for most of these summary measures of analgesia. In a factorial analysis, both the hydrocodone and ibuprofen effects were significant for most summary measures of analgesia, whereas results of the interaction contrast were consistent with the concept that the analgesic effect of the combination represents the additive analgesia of its 2 constituents. The ideal oral wound care analgesic for children should be palatable, provide potent analgesia of rapid onset and short duration, and require minimal, yet appropriate, monitoring. With use of a double-blinded crossover design, we compared the efficacy and safety of oral transmucosal fentanyl citrate (OTFC) (approximately 10 micrograms/kg) with the efficacy and safety of oral hydromorphone (60 micrograms/kg) in 14 pediatric inpatients (ages 4 to 17 years) undergoing daily burn wound care in a ward setting. Pulse oximetry, vital signs, side effects, patient pain scores, and observer scores for cooperation, anxiety, and sedation were recorded. Pulse oximetry, vital signs, cooperation, sedation, incidence of nausea or vomiting, and the amount of time it took to resume normal activities were similar in both treatment groups. OTFC resulted in improved pain scores before wound care and improved anxiolysis during wound care, but at other points it was similar in effect to hydromorphone. We conclude that OTFC is a safe and effective analgesic, that it may provide minor improvements in analgesia and anxiolysis compared with hydromorphone, and that it offers a palatable alternative route of opioid administration without intravenous access for wound care procedures in children. In a double-blind study with the use of subjective reports of patients as indices of analgesia, we compared the analgesic effect of oral nalbuphine and acetaminophen and determined the contribution of each to the efficacy of their combination. In this parallel 2 X 2 factorial study, 129 inpatients after surgery were randomly assigned to treatment with a single oral dose of nalbuphine hydrochloride (30 mg), acetaminophen (650 mg), the combination of nalbuphine (30 mg) and acetaminophen (650 mg), or placebo. In the factorial analysis, both the nalbuphine and acetaminophen effects were significant for virtually every measure of total and peak analgesia, whereas the interaction contrast was not significant for any measure of analgesic effect. This indicates that the analgesic effect of the combination represents the additive effect of its constituents and is consistent with the results of studies of combinations of codeine and other opioids with aspirin or acetaminophen. There were few adverse effects other than sedation, which occurred twice as frequently in patients treated with nalbuphine as in those receiving acetaminophen or placebo. Our data suggest that this combination should prove at least as effective as any currently marketed narcotic-containing combination. Since nalbuphine has less dependence liability than narcotics and exhibits a ceiling on respiratory depression, its combination with acetaminophen should also be safer than comparable narcotic combinations. To determine the relative analgesic potency and adverse effect liability of hydrocodone bitartrate 7.5 mg with acetaminophen 500 mg, codeine phosphate 30 mg with acetaminophen 300 mg, and placebo in the treatment of pain following oral surgery.
                Randomized, double-blind, single-dose, placebo-controlled, parallel-group study with self-ratings at 30 minutes and then at hourly intervals from hour 1 to hour 6.
                Private, oral surgery practice sites.
                Three hundred twenty-four outpatients with moderate or severe pain after the surgical removal of impacted third molars were selected. One was lost to follow-up and 32 did not need an analgesic; 232 patients had valid efficacy data.
                Patients were treated with a single oral dose of hydrocodone bitartrate 7.5 mg with acetaminophen 500 mg, codeine phosphate 30 mg with acetaminophen 300 mg, or placebo when they experienced steady, moderate or severe pain that, in their opinion, required an analgesic. Using a self-rating record, subjects rated their pain and its relief for 6 hours after medicating; estimates of peak and total analgesia were derived from these subjective reports.
                This study was a valid analgesic assay. Both active treatments were significantly superior to placebo for all measures of analgesic efficacy. The hydrocodone-acetaminophen combination was significantly superior to the codeine-acetaminophen combination for total pain relief and the number of evaluations with 50% relief. Both active treatments manifested an analgesic effect within 30 minutes; the effect persisted for 5 hours for the codeine combination and 6 hours for the hydrocodone combination. Adverse effects were transient, consistent with the pharmacologic profiles of opioids, and none required treatment.
                A slight advantage in analgesic efficacy was demonstrated in this single-dose study for the hydrocodone-acetaminophen combination. Repeat-dose studies, however, should be conducted to determine the clinical significance of the difference in analgesic effect of these opioid combinations. The use of oxycodone to treat chronic cancer pain has been hampered by its short elimination half-life, which necessitates administration every 4 hours. This study compared the clinical efficacy and safety of a novel oxycodone formulation with that of hydromorphone in the treatment of cancer pain.
                In a double-blind crossover study, 44 patients with stable cancer pain were randomized to controlled-release oxycodone or controlled-release hydromorphone, each given every 12 hours for 7 days. Pain intensity, nausea, and sedation were assessed by patients four times daily, and breakthrough analgesia was recorded.
                Thirty-one patients completed the study (18 women, 13 men; mean age, 56 +/- 3 years) and received a final controlled-release oxycodone dose of 124 +/- 22 mg per day and a final controlled-release hydromorphone dose of 30 +/- 6 mg per day. There were no significant differences between treatments in overall Visual Analogue Scale (VAS) pain intensity (VAS 28 +/- 4 mm vs. 31 +/- 4 mm), categorical pain intensity (1.4 +/- 0.1 vs. 1.5 +/- 0.1), daily rescue analgesic consumption (1.4 +/- 0.3 vs. 1.6 +/- 0.3), sedation scores (24 +/- 4 mm vs. 18 +/- 3 mm), nausea scores (15 +/- 3 mm vs. 13 +/- 3 mm), or patient preference. Two patients experienced hallucinations on controlled-release hydromorphone, but none did while receiving controlled-release oxycodone.
                Controlled-release oxycodone demonstrated excellent pharmacodynamic characteristics, analgesic efficacy, and safety as compared with controlled-release hydromorphone and represents an important new therapeutic option for cancer pain management. The prevalence of heroin and other opioid use has markedly increased among adolescents in the last decade; however, virtually no research has been conducted to identify effective treatments for this population.
                To evaluate the relative efficacy of 2 pharmacotherapies, the partial opioid agonist buprenorphine hydrochloride and the centrally active alpha(2)-adrenergic blocker clonidine hydrochloride, in the detoxification of opioid-dependent adolescents.
                A double-blind, double-dummy, parallel-groups randomized controlled trial conducted in a university-based research clinic from October 2001 to December 2003. Patients were a volunteer sample of 36 adolescents who met DSM-IV criteria for opioid dependence (ages 13-18 years eligible).
                Participants were randomly assigned to a 28-day, outpatient, medication-assisted withdrawal treatment with either buprenorphine or clonidine. Both medications were provided along with thrice weekly behavioral counseling and incentives contingent on opiate abstinence. Postdetoxification, all participants were offered the opportunity for continued treatment with the opiate antagonist, naltrexone hydrochloride.
                Treatment retention, opiate abstinence, and human immunodeficiency virus risk behavior, along with measures of withdrawal and medication effects.
                A significantly greater percentage of adolescents who received buprenorphine were retained in treatment (72%) relative to those who received clonidine (39%) (P<.05). For those in the buprenorphine group, a significantly higher percentage of scheduled urine test results were opiate negative (64% vs 32%; P = .01). Participants in both groups reported relief of withdrawal symptoms and drug-related human immunodeficiency virus risk behavior. Those in the buprenorphine condition generally reported more positive effects of the medication. No evidence of opioid intoxication or psychomotor impairment was observed. Sixty-one percent of participants in the buprenorphine condition and 5% of those in the clonidine group initiated treatment with naltrexone.
                Combining buprenorphine with behavioral interventions is significantly more efficacious in the treatment of opioid-dependent adolescents relative to combining clonidine and behavioral interventions. A number of studies have demonstrated that perioperative intravenous, intrathecal, and epidural clonidine enhance postoperative analgesia. The results of previous studies on the usefulness of oral clonidine on enhancing postoperative analgesia have been mixed. The effect of a single preoperative dose of oral clonidine on postoperative analgesia was assessed in this study.
                Forty-three male patients undergoing radical prostectomy were randomized to receive either 3 microg x kg(-1) clonidine or placebo po 90 min prior to surgery. All patients received isobaric 15 mg bupivacaine and intrathecal 5 microg x kg morphine, followed by a standardized general anesthetic, consisting of thiopental, sufentanil, rocuronium, isoflurane, oxygen and air. Postoperatively, PCA morphine use and visual analogue pain scores were recorded for the first 48 hr. The incidence and severity of side effects such as sedation, nausea, and pruritus were assessed, as well as patient satisfaction. Usage of PCA morphine was compared.
                There was no difference in total morphine requirements between the placebo and oral clonidine groups, nor in six hourly morphine usage (P = 0.96). Second, there was no difference in visual analogue pain scores, or the incidence of side effects. Patient satisfaction was high in both groups and again, no differences between groups was noted.
                Oral clonidine 3 microg x kg(-1) as a premedication does not prolong the effect of intrathecal morphine: there was no difference in PCA morphine requirements (P = 0.96). Clonidine did not effect the incidence or severity of nausea or pruritus. This study was designed to evaluate the effects of oral clonidine premedication on postoperative analgesia by epidural morphine in a prospective, randomized, double-blinded design. Sixty consenting patients, scheduled for total abdominal hysterectomy, were randomly assigned to one of three groups (n = 20 each); the clonidine-morphine group received oral clonidine 5 microg/kg 90 min before arriving in the operating room and epidural morphine 2 mg before induction of general anesthesia, the clonidine-placebo group received oral clonidine 5 microg/kg and no epidural morphine, and the placebo-morphine group received no clonidine and epidural morphine 2 mg. An epidural catheter was placed at the L1-2 or L2-3 interspace, and 1.5% lidocaine was used for surgical anesthesia in all patients. General anesthesia was then induced with propofol, and maintained with a continuous infusion of propofol and 67% nitrous oxide in oxygen during surgery. Four patients were subsequently withdrawn from the study. After surgery, patient-controlled analgesia using IV morphine was used to assess analgesic requirement. Morphine consumptions determined every 6 h after surgery in the clonidine-morphine and placebo-morphine groups were significantly less than the clonidine-placebo group until 12 h after surgery, whereas those of the clonidine-morphine group were significantly less than the placebo-morphine group from 13 to 42 h after surgery. Visual analog (pain) scale (VAS) scores in the clonidine-morphine group were significantly lower than the placebo-morphine group at 48 h at rest, and at 1, 24, 36, and 48 h with movement. Similarly, VAS scores in the clonidine-morphine group were significantly lower than the clonidine-placebo group at 1 and 6 h both at rest and with movement, whereas VAS scores in the clonidine-placebo group were significantly lower than the placebo-morphine group at 24, 36, and 48 h at rest and with movement. The incidence of nausea and pruritus was similar between groups. We conclude that the combination of oral clonidine and epidural morphine produces more potent and longer lasting postoperative analgesia than either drug alone without increasing the incidence of adverse effects after major gynecologic surgeries.
                A small dose of epidural morphine is often used for postoperative analgesia. We found that oral clonidine premedication 5 microg/kg improves the analgesic efficacy of epidural morphine without increasing the incidence of adverse side effects.
The studies were varied in terms of quality and methodology. However, the majority demonstrated that hydromorphone is a potent analgesic, that the effects of hydromorphone appear to be dose-related, and that adverse effects are similar to those of other mu opioid receptor agonists. Since the last version of this review, none of the new relevant studies have provided significant additional information.