Evaluation of tilidine for morphine-like subjective effects and euphoria

Tilidine is an opioid analgesic that has been abused predominantly by the oral route. Studies of parenterally administered tilidine in animals did not clearly indicate a dependence potential of the morphine type. In this study we examined the abuse potential of orally and parenterally administered tilidine in humans. Both orally and intramuscularly given tilidine produced miosis and morphine-like subjective effects in non-dependent subjects. Oral tilidine was 1/8-1/10 as potent and intramuscular tilidine was 1/22 as potent as parenteral morphine in producing morphine-like subjective and miotic effects. Intramuscular tilidine suppressed and did not precipitate signs of abstinence in morphine-dependent subjects. However, intramuscularly given tilidine produced toxic effects not seen with morphine. Meperidine, codeine and d-propoxyphene produced morphine-like subjective and miotic effects, but also produced toxic effects at the highest doses tested. The results suggest that tilidine has a potential to be abused, that this potential is less than that of parenteral morphine and that tilidine is more likely to be abused orally than by the intramuscular route.     

Relative potency of controlled-release oxycodone and controlled-release morphine in a postoperative pain model

Objective: The relative analgesic potency of single doses of oral controlled-release oxycodone and oral controlled-release morphine were compared in a randomized, double-blind trial using a postoperative pain model. Methods: Women (n = 169) with moderate to severe pain following abdominal hysterectomy received single oral doses of controlled-release oxycodone, 20 mg or 40 mg, or controlled-release morphine, 45 mg or 90 mg. Assessments were made at 30 min, 60 min, then hourly after dosing for 12 h or until remedication. Results: The most precise estimates of relative potency showed that controlled-release oxycodone was 1.8 times more potent than controlled-release morphine for total effect (95% confidence limits 1.09–2.42; lambda 0.44) and 2.2 times more potent for peak effect (95% confidence limits 0.96–4.59; lambda 0.71). Controlled-release oxycodone at doses of 20 mg or 40 mg was comparable with controlled-release morphine at doses of 45 mg or 90 mg, respectively, for total and peak analgesic effects. For the two higher doses, time to peak relief was approximately 1 h shorter with controlled-release oxycodone than with controlled-release morphine. Most patients reported onset of analgesia within 1 h with all doses. Side effects were similar with the two opioids. Conclusion: Oral controlled-release oxycodone was twice as potent as oral controlled-release morphine in this single-dose, relative potency assay. When converting patients from oral morphine to oral oxycodone, an initial oral oxycodone dose of one-half the oral morphine dose is recommended. Received: 10 August 1998 / Accepted in revised form: 9 March 1999     

Crossover trials in clinical analgesic assays: studies of buprenorphine and morphine

Analgesic studies of buprenorphine, a thebaine derivative and potent partial narcotic agonist, were carried out in patients with cancer who had postoperative or chronic pain. Intramuscular buprenorphine was compared with intramuscular morphine in a series of sequentially related, twin crossover assays and was found to be about 25 times as potent as morphine. Side effects were essentially morphine-like. In a second assay, the acceptability and analgesic activity of sublingual buprenorphine was studied in a 6-dose, balanced, incomplete block assay, a modification of the twin crossover design employed in the all-intramuscular trial. Sublingual buprenorphine was found to be about 15 times as potent as intramuscular morphine and was well accepted by our patients. The 4-dose twin crossover trial in which doses are adjusted sequentially is more flexible in that a wide range of doses may be studied, but it lacks the ability of the 6-dose design to provide estimates of the curvature of the dose-response slopes of the study drugs. When first-dose-only data were analyzed as parallel group assays, the main difference in results compared with the crossover studies was a decrease in efficiency and sensitivity.     

A spirohydantoin derivative of oxymorphone: an agonist with delayed antagonist activity

We have synthesized a novel derivative of oxymorphone, oxymorphone-6 alpha-spirohydantoin. The derivative was less toxic in mice than the parent compound and it showed a significant anticonvulsive activity. It exerted agonist effects in doses lower than those of morphine and its agonist effects were longer lasting. Furthermore, both oxymorphone and the 6-spirohydantoin showed definite antagonist properties 48 hr later: they prevented analgesic effects of morphine. The antagonist effects of the derivative persisted for a week.     

Opioid agonist-antagonist drugs in acute and chronic pain states.

The agonist-antagonist opioid analgesics are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as codeine and morphine but with a limited effective dose range. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine-like. Meptazinol does not fit into either classification and occupies a separate category. Pentazocine, butorphanol and nalbuphine are weak mu-antagonists and kappa-partial-agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is slightly less potent than morphine, and butorphanol is 3.5 to 7 times as potent. The duration of analgesia is similar to that of morphine (3 to 4 hours). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol (acetaminophen) than the weak opioid analgesics such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation. At usual therapeutic doses nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (though the duration of such effects with butorphanol may be longer). Unlike morphine there appears to be a ceiling to both the respiratory depression and the analgesic action. All of these 3 drugs have a lower abuse potential than the pure agonist opioid analgesics such as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to Controlled Drug restrictions. Buprenorphine is a potent partial agonist at the mu-receptor, and by intramuscular injection is 30 times as potent as morphine. A ceiling to the analgesic effect of buprenorphine has been demonstrated in animals and it is also claimed in humans. However, there are no reliable data available to define the maximal dose of buprenorphine in humans. A practical ceiling exists for sublingual use in that the only available formulation is a 2 micrograms tablet and few patients will accept more than 3 or 4 of these in a single dose. The duration of analgesia is longer than that of morphine, at 6 to 9 hours. There have been suggestions that buprenorphine causes less respiratory depression than morphine, but viewed overall it appears that in equianalgesic doses the 2 drugs have similar respiratory depressant effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study

OBJECTIVE: To compare the analgesic efficacy and safety of oxymorphone extended release (ER) and oxycodone controlled release (CR) in patients with moderate to severe cancer pain. Research design and methods: This randomized, multicenter, double-blind, 2-period crossover study included adult outpatients (>or= 18 years of age) with moderate or severe cancer pain who were first titrated for 3-10 days with open-label oxymorphone or oxycodone to achieve a stable dose that provided and other efficacy parameters were comparable for adequate analgesia with tolerable adverse events and no requirement for more than 2 doses of rescue medication per day. The subsequent double-blind treatment phase was a 7- to 10-day period of oxycodone CR or oxymorphone ER treatment followed by crossing over to the alternate medication for another 7-10 days. During the treatment phase, up to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue. MAIN OUTCOMES AND MEASURES: Assessments included the Brief Pain Inventory, global evaluations, Karnofsky performance status, and clinical laboratory evaluations (serum chemistry profile, complete blood count, urinalysis). Efficacy variables were analyzed using a mixed-effects model with treatment, sequence, and period as fixed effects and subject as a random effect. RESULTS: Forty-seven patients entered the titration/stabilization phase, 44 received at least 1 dose of study drug, 42 completed the first double-blind phase, and 40 completed the second double-blind phase. Mean pain intensity scores the 2 groups. The mean daily dosage of oxycodone CR (91.9 mg) was twice that of oxymorphone ER (45.9 mg), an equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups (approximately 1 tablet of morphine sulfate 15 mg/day). No significant differences in opioid adverse events were observed between the groups. CONCLUSIONS: Adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72 h, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.     

Evidence that morphine is metabolized to hydromorphone but not to oxymorphone

A minor pathway for the biotransformation of morphine to hydromorphone has been identified in humans. Recently, an unsubstantiated claim that morphine is metabolized to hydromorphone and then to oxymorphone was published. The goal of this study was to determine if credible evidence that oxymorphone is a metabolite of either morphine or hydromorphone exists. Urine specimens from pain patients who were treated exclusively with high daily doses of morphine (N = 34) or hydromorphone (N = 26) were analyzed by liquid chromatography-tandem mass spectrometry for oxymorphone, hydromorphone, and morphine (LOD = 25 ng/mL). Specimens were also tested for a variety of other medications. Criteria for inclusion of patients' specimens were as follows: 1. patients were undergoing exclusive dosing with either morphine or hydromorphone; 2. non-prescribed medications were not detected; and 3. urine concentrations of morphine were > 100,000 ng/mL for the high-dose morphine group and > 1,000 ng/mL of hydromorphone for the high-dose hydromorphone group. Consistent with earlier reports, hydromorphone was detected in patients treated with high-dose morphine. The ratio of hydromorphone to morphine ranged from 0.2 to 2.2%. Oxymorphone was not detected in any specimen from high-dose morphine or high-dose hydromorphone patients. The authors conclude, based on these data, that oxymorphone is not a metabolite of morphine or hydromorphone.     

Single- and multiple-dose pharmacokinetic and dose-proportionality study of oxymorphone immediate-release tablets

INTRODUCTION: Oxymorphone hydrochloride (referred to as oxymorphone), a semisynthetic mu-opioid agonist, is known to produce a more rapid onset of action and greater analgesic potency compared with its parent compound, morphine. Until recently, oxymorphone has been available only in suppository and intravenous formulations. This study examined the pharmacokinetics and dose proportionality of a new immediate-release (IR) tablet formulation of oxymorphone and its metabolites (6-OH-oxymorphone and oxymorphone-3-glucuronide) following single- and multiple-dose administration in healthy volunteers. STUDY DESIGN: A randomised, three-way crossover design was employed, with a target sample size of 24 healthy men and women. METHODS: A single dose of oxymorphone IR (5, 10 and 20mg) was administered on day 1. After drug washout on day 2, study participants then received the same dose every 6 hours (22 total doses) on days 3 to 8. Treatment periods were separated by a 7-day washout. Naltrexone hydrochloride was coadministered to prevent opioid-related adverse events. Blood was collected up to 48 hours after day 1 to determine single-dose pharmacokinetics and up to 6 hours after the last dose for determination of pharmacokinetics at steady state. RESULTS: Twenty-three of 24 enrolled subjects (12 men, 11 women) completed the study. Following a single dose of 5, 10 or 20mg, the oxymorphone IR mean area under the plasma concentration versus time curve from time zero to infinity ([AUC(infinity)] 4.5, 9.1 and 20.1 microg . h/L, respectively) and maximum plasma concentration ([C(max)] 1.1, 1.9 and 4.4 microg/L, respectively) confirmed dose proportionality. 6-OH-oxymorphone and oxymorphone-3-glucuronide also increased in an approximate 2-fold fashion. Similar results were observed for AUC and C(max) of oxymorphone and its metabolites at steady state. Steady state was achieved within 3 days of 6-hourly administration. The median t(max) (time to reach C(max)) was 0.5 hours for all single doses of oxymorphone and at steady state, and the terminal elimination half-life (t(1/2)) was approximately 7.3-9.4 hours. Adverse events were generally mild, and no clinically significant changes in laboratory or other safety variables were noted. DISCUSSION: Because successful pain management often requires careful drug titration across a wide therapeutic dose range, it is important that opioid formulations provide predictable increases in drug concentration with increasing dose. The single-dose and steady-state pharmacokinetic profiles of oxymorphone IR tablets were linear and dose proportional across the dose range from 5 to 20mg.     

Evidence that oxymorphone-induced increases in micronuclei occur secondary to hyperthermia.

Oxymorphone is a potent opioid analgesic. Oral administration of oxymorphone to rats at doses >or= 20 mg/kg and mice at 500 mg/kg produced an increase in micronucleated polychromatic erythrocytes (MPCEs). Oxymorphone does not produce chromosome aberrations in vitro, suggesting that the increased MPCEs in vivo may involve indirect mechanisms. Opioids are known to affect thermoregulatory mechanisms. Changes in body temperature can increase the incidence of MPCEs in rodents. Studies were conducted to examine the relationship between increased MPCEs in rats given oxymorphone and changes in body temperature. Single oral doses of oxymorphone associated with increased MPCEs (20 and 40 mg/kg) also produced a marked, rapid increase in body temperature. When animals were pretreated with sodium salicylate, peak body temperature was lower and returned to baseline more quickly than when oxymorphone was given alone. MPCEs were evaluated in rats after administration of oxymorphone (40 mg/kg) alone or following pretreatment with an oral dose of sodium salicylate. Oxymorphone alone produced a statistically significant increase in the incidence of MPCEs (3.6 per 1000 polychromatic erythrocytes vs. 0.4 in controls). The number of MPCEs in animals pretreated with sodium salicylate was similar to controls. Sodium salicylate alone had no effect on the number of MPCEs. Systemic oxymorphone exposure was not affected by sodium salicylate pretreatment; maximum plasma concentration (C(max)) and area-under-the-curve values were similar after administration of oxymorphone alone or following pretreatment with sodium salicylate. These results indicate that the increased incidence of MPCEs following oxymorphone administration is directly related to increased body temperature.     

Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study

SUMMARY

Objective: To compare the analgesic efficacy and safety of oxymorphone extended release (ER) and oxycodone controlled release (CR) in patients with moderate to severe cancer pain.

Research design and methods: This randomized, multicenter, double-blind, 2-period crossover study included adult outpatients (≥ 18?years of age) with moderate or severe cancer pain who were first titrated for 3–10?days with open-label oxymorphone or oxycodone to achieve a stable dose that provided adequate analgesia with tolerable adverse events and no requirement for more than 2 doses of rescue medication per day. The subsequent double-blind treatment phase was a 7- to 10-day period of oxycodone CR or oxymorphone ER treatment followed by crossing over to the alternate medication for another 7–10?days. During the treatment phase, up to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue.

Main outcomes and measures: Assessments included the Brief Pain Inventory, global evaluations, Karnofsky performance status, and clinical laboratory evaluations (serum chemistry profile, complete blood count, urinalysis). Efficacy variables were analyzed using a mixed-effects model with treatment, sequence, and period as fixed effects and subject as a random effect.

Results: Forty-seven patients entered the titration/stabilization phase, 44 received at least 1 dose of study drug, 42 completed the first double-blind phase, and 40 completed the second double-blind phase. Mean pain intensity scores and other efficacy parameters were comparable for the 2 groups. The mean daily dosage of oxycodone CR (91.9?mg) was twice that of oxymorphone ER (45.9?mg), an equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups (approximately 1 tablet of morphine sulfate 15?mg/day). No significant differences in opioid adverse events were observed between the groups.

Conclusions: Adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72?h, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.     

Considerations on the use of oxymorphone in geriatric patients

Background: Pain among the elderly is pervasive, under-treated and can be properly managed by judiciously using analgesics in the armamentarium. For severe pain, opioids generally provide the most effective pain relief, but concerns about safety and tolerability have limited, often unnecessarily, their utilization in the geriatric population. Objective: It is common for geriatric patients to be taking more than one medicine. Oxymorphone might be particularly well suited for use in geriatric patients, in that its metabolism is mainly through non-CYPP450 pathways, thereby posing less risk of interaction with the many drugs that are metabolized by the CYPP450 system. However, oxymorphone is not as familiar to clinicians as morphine or some other opioids. We review here the clinical studies on oxymorphone to outline the key considerations for use of oxymorphone in the geriatric population. Methods: Nine available clinical trials of oxymorphone alone or comparing oxymorphone with placebo or other active agents were analyzed with respect to the safety and tolerability findings. These studies included geriatric patients but were not designed to evaluate oxymorphone exclusively in this population. Results: Based on the results from nine published clinical studies, oxymorphone is an effective opioid analgesic with a safety profile at least comparable to other opioid drugs. At low starting doses and individual titration, oxymorphone should be considered for appropriate geriatric patients, particularly in whom there is concern about interaction with drugs that are metabolized by CYPP450 enzymes.     

The pharmacology of 14-hydroxyazidomorphine

6-Deoxy-6-dihydroazido-14-hydroxyisomorphine (14-hydroxyazidomorphine) was synthesized, its analgesic potency in mice and rats, its antitussive effect in rats and its dependence liability in mice, rats and monkeys were studied. Azidomorphine, the 14-nonhydroxylated parent molecule, morphine, hydromorphone and oxymorphone were used for comparison. 14-Hydroxyazidomorphine proved to be as potent an analgesic as azidomorphine, even more potent as an antitussive, and showed the same low tolerance and dependence capacity. It was 11.6 times less toxic than azidomorphine in mice and 6.5 times less toxic in rats.     

Bioavailability of oral and intramuscular phenobarbital

The absorption of phenobarbital was compared in healthy adult subjects after oral and intramuscular therapeutic doses. Serum levels of phenobarbital were determined for 21 days after dosing by means of radioimmunoassay. Serum levels were similar from both dosage routes, with peak levels occurring at 1-3 hours after dosing and then declining slowly with an elimination half-life of about 90 hours. The overall efficiency of phenobarbital absorption from intramuscular doses was approximately 80 per cent of that from equivalent oral doses. Except in cases where oral dosing is not appropriate, there is no clinical advantage in giving phenobarbital intramuscularly to adult patients.     

Effectiveness and duration of intramuscular antimotion sickness medications.

Motion sickness inhibits gastric motility, making the oral route ineffective for medications. The intramuscular route is an effective alternative. The rotating chair was used to produce the M 111 level of motion sickness on the Graybiel Symptom Scale. The intramuscular medications given 30 minutes before rotation were compared with placebo (saline, 1 mL) for effectiveness and duration in increasing the number of tolerated head movements. Average placebo number of head movements was 294. Promethazine 25 mg increased head movements by 78% (P < .05), with a duration of 12 hours. Scopolamine 0.2 mg increased head movements by 91% (P < .05), with a duration of 4 hours. The effect of caffeine 250 mg and ephedrine 25 mg was not significant. When combined with scopolamine, ephedrine produced an 32% additive effect. Scopolamine 0.08 mg, 0.1 mg, and 0.2 mg and also promethazine 12.5 mg and 25 mg were significant (P < .05). Promethazine appears to be the drug of choice for intramuscular use because of a longer duration and a high level of effectiveness. Scopolamine was of high effectiveness, but had a duration of 4 hours. It was eight times as potent by the intramuscular as by the oral route.     

Transdermal oxymorphone formulation development and methods for evaluating flux and lag times for two skin permeation-enhancing vehicles

Oxymorphone is a candidate for transdermal delivery since it is a very potent analgesic, is not very effective orally, and has a short duration of action. In developing a transdermal delivery system, two criteria that were considered important were achieving adequate flux and minimizing the lag time. Oxymorphone skin permeation rates in vitro were very low unless skin permeation enhancers were included in the vehicle. After an initial screen of 17 formulations, two skin permeation-enhancing formulations were selected for further study. These were myristic acid:propylene glycol:oxymorphone base (A), and decylmethylsulfoxide:ethanol:water:oxymorphone.HCl (B). With either formulation and either human or hairless guinea pig skin, there was little dependence of either in vitro flux or lag time on the section of skin used (stratum corneum, epidermis, epidermis/dermis). There were significant differences between human skin and hairless guinea pig skin when comparing in vitro fluxes with the two formulations. With formulation A, fluxes through hairless guinea pig skin were three-to fivefold greater than through human skin. With B, however, fluxes through human skin were up to fivefold greater than through hairless guinea pig skin. In vitro lag times with A were generally long (approximately 24 h), whereas those with B were much lower (approximately 1 to 10 h). The species dependence of permeation enhancement and the differences in lag time between formulations could be related to differences in the mechanisms of permeation enhancement. In vivo lag times with the fatty acid:propylene glycol vehicle were estimated in hairless guinea pigs based on plasma oxymorphone concentrations. These were much lower than in vitro lag times.     

Comparative analgesic activity of various naturally occurring cannabinoids in mice and rats

The analgesic effectiveness of ⁹-tetrahydrocannabinol (THC), a crude marihuana extract (CME), cannabinol (CBN), cannabidiol (CBD), morphine SO⁴ and aspirin following oral administration was directly compared in mice using the acetic-induced writhing and hot plate tests and the Randall-Selitto paw pressure test in rats. THC and morphine were equipotent in all tests except that morphine was significantly more potent in elevating pain threshold in the uninflamed rat hind paw. In terms of THC content, CME was nearly equipotent in the hot plate and Randall-Selitto tests, but was 3 times more potent in the acetic acid writhing test. On the other hand, CBN, like aspirin, was only effective in reducing writhing frequency in mice (3 times more potent than aspirin) and raising pain threshold of the inflamed hind paw of the rat (equipotent with aspirin). CBD did not display a significantly analgesic effect in any of the test systems used. The results of this investigation seem to suggest that both THC and CME possess narcotic-like analgesic activity similar to morphine, while CBN appears to be a non-narcotic type analgesic like aspirin.     

Intranasal diamorphine as an alternative to intramuscular morphine: pharmacokinetic and pharmacodynamic aspects

Diamorphine is a semisynthetic derivative of morphine that is currently licensed for use in the treatment of moderate to severe acute pain, administered by the intramuscular, intravenous or subcutaneous routes. It is highly water-soluble and has a number of properties that render it suitable for administration via the nasal route. Administration via the intranasal route is well described for other drugs, but has only recently been evaluated in a clinical setting for diamorphine. A well-tolerated and rapidly effective analgesic agent has proven elusive in the paediatric setting. The pharmacokinetic profile of intranasal diamorphine in adults has been systematically studied. It is rapidly and dose-dependently absorbed as a dry powder, with peak plasma concentrations occurring within 5 minutes, and has a similar pharmacokinetic profile to that of intramuscular diamorphine. It is rapidly converted to 6-acetylmorphine (peak concentrations within 5-10 minutes) and thence to morphine (peak concentrations within 1 hour). The pharmacodynamic properties of intranasal diamorphine have also been studied in comparison with intramuscular diamorphine. Intranasal and intramuscular administration of diamorphine resulted in similar physiological responses (including pupil diameter, respiration rate and temperature). Changes in behavioural measures (including euphoria, sedation and dysphoria) were also similar. Intranasal administration of diamorphine, therefore, produces the expected drug effects on the same timescale and of the same magnitude as intramuscular injection. Intranasal diamorphine has been clinically evaluated in a randomised controlled trial versus intramuscular morphine in the setting of acute orthopaedic pain in children with fractures. Intranasal diamorphine provided the same overall degree of pain relief as intramuscular morphine, but with a quicker onset of action. It was found to be well tolerated with an acceptable safety profile. It has also been studied in the setting of patient-controlled analgesia for postoperative pain in adults, with encouraging results. The pharmacokinetic and pharmacodynamic properties of intranasal diamorphine, and particularly the ability to administer it without a needle (and therefore reduce the incidence of transmissible infection), have made this a popular route for abuse amongst opioid addicts. In this setting, however, the intranasal route is not free from adverse events, including deaths. The primary clinical need in the paediatric population is for a well tolerated, effective and expedient analgesic agent that is safe to use; intranasal diamorphine has pharmacokinetic properties that would make it suitable for such a clinical indication and, in clinical evaluations to date, appears to be promising.     

A comparative study of intramuscular buprenorphine and morphine in the treatment of chronic pain of malignant origin.

1 Twenty-seven patients with moderate to severe chronic pain of malignant origin received buprenorphine (0.3 mg) and morphine (10 mg) intramuscularly in a double-blind, single dose within patient study. 2 Efficacy analysis demonstrated no significant differences in the peak analgesic effects or in the time to reach these effects. However, buprenorphine had a significantly longer duration of action than morphine. 3 Sedation was the most frequent unwanted effect with a similar incidence following each treatment. Buprenorphine was associated with a significantly higher incidence, greater severity, earlier onset, and longer duration of dizziness, nausea and vomiting than morphine. 4 Following both treatments there were small but significant decreases in pulse rate, blood pressure, and respiratory rate.     

A comparison of patient-controlled and intramuscular morphine in patients after abdominal surgery

This prospective, randomized study compared the effects of two methods of morphine administration after abdominal surgery in 62 adults. All patients were offered intravenous morphine in the Postanesthesia Care Unit. On the ward, one group (PCA-CI) received a continuous infusion of morphine that could be supplemented by a patient-controlled bolus every 10 minutes. The other group (IM) received intramuscular morphine (0.08-0.12 mg/kg) as often as every 3 hours when requested. During three postoperative interviews, patients were questioned about pain relief (visual analogue scale), adverse opioid effects, and satisfaction with the method of analgesia. Total dose of morphine (mg, mg/kg body weight), time to first oral analgesic medication, length of hospital stay, and cost were calculated following discharge. There was a wide interindividual variation in reported pain intensity and morphine usage in both groups. Comparison of both groups demonstrated no significant differences in analgesia, incidence of adverse opioid effects, 24 and 36 hour morphine dose, time to first oral analgesic medication, operating cost, and length of hospital stay. Patients in the PCA-CI group received a slightly greater dose of morphine in relation to body weight (24 hr, P = 0.03; 36 hr, P = 0.05) and reported a greater degree of satisfaction at each assessment (P = 0.005, P = 0.02, P = 0.01). These data support the greater patient satisfaction associated with patient-controlled analgesia but suggest that the wide range of reported pain scores and morphine requirements makes it difficult to demonstrate, in a small population, superior pain relief from patient-controlled analgesia when nurses are encouraged to administer intramuscular pain medication more effectively.     

Agonist and antagonist properties of buprenorphine, a new antinociceptive agent.

1. Buprenorphine is a highly lipophilic derivative of oripavine. In rodent antinociceptive assays (writhing, tail pressure), buprenorphine had an action which was rapid in onset and of long duration; it was 25-40 times more potent than morphine after parenteral injection and 7-10 times more potent after oral administration. 2. The log dose-response relationship for buprenorphine was curvilinear in mouse and rat tail flick tests with the antinociceptive effect decreasing at higher, non-toxic doses. 3. Tolerance developed to the antinociceptive activity of buprenorphine in mice. 4. No signs of abstinence were observed on naloxone challenge or after abrupt withdrawal in monkeys receiving buprenorphine chronically for one month. 5. Buprenorphine antagonized the antinociceptive actions of morphine in mouse and rat tail flick tests but was an ineffective antagonist in the rat tail pressure test. 6. Buprenorphine precipitated signs of abstinence in morphine-dependent mice and monkeys but not in morphine-dependent rats. 7. Buprenorphine produced Straub tails in mice. This effect was not antagonized when the animals were pretreated with naloxone. However, in the rat tail pressure test high doses of diprenorphine antagonized established antinociceptive effects of buprenorphine. 8. It is concluded that buprenorphine represents a definite advance in the search for a narcotic antagonist analgesic of low physical dependence potential.