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Increased allocation of behaviour to substance abuse at the expense of personal and social rewards is a hallmark of addiction that is reflected in several of DSM-5 criteria for diagnosis of substance use disorder. Previous studies focused on refining the self-administration (SA) model to better emulate an addictive state in laboratory animals. Here, we employed concurrent SA of sucrose pellets and morphine as two competing natural and drug rewards, respectively, to validate the feasibility of capturing pathological behavioural allocation in rats. A custom-made three-lever operant chamber was used. With one active and one inactive lever presented, rats were trained to self-administer morphine (0.5 mg/kg/infusion; 2 h/day) under a fixed-ratio 1 (FR-1) schedule until a stable response was achieved. Next, they were trained to self-administer morphine in the presence of a third lever dispensing sucrose pellets (20 mg) under FR-1. Concurrent morphine-sucrose SA sessions (2 h/day) were continued until stable morphine taking behaviour was re-established. In another experiment, rats first established stable sucrose pellet SA (2 h/day, FR-1) and then were trained to take morphine (0.5 mg/kg/infusion; 2 h/day). Subsequently, all rats underwent extinction training, in which morphine was replaced with saline while sucrose pellets were still available upon lever pressing, followed by cue-induced reinstatement of morphine seeking behaviour. Results showed that rats retained morphine SA when sucrose pellets were also available, but they showed binge-like sucrose intake when morphine was removed during the extinction sessions. However, morphine SA did not develop in rats that had previously established sucrose pellet SA. In conclusion, morphine SA developed even in the presence of a potent competing nondrug reward in rats. Adding an effort-based contingent delivery of a natural reward to the standard SA model, this protocol may provide an improved model of drug addiction in laboratory animals., (© 2024 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Opioid use and abuse remain a significant public health problem, particularly in the United States. Indeed, it is estimated that up to 10% of youths (age 12-18) have taken opioids illicitly. A growing body of evidence suggests that this level of widespread opioid exposure can have effects that extend to subsequent generations. Utilizing a well-established rodent model of preconception adolescent opioid exposure in females, we found decreased opioid self-administration coupled with increased cocaine self-administration in adult offspring. This bidirectional effect may be related to negative affect associated with opioid withdrawal, including enhanced stress reactivity. In this study, we tested the hypothesis that the adult offspring of females exposed to morphine during adolescence will demonstrate increased signs of opioid withdrawal when compared to offspring of saline controls. Females were administered increasing doses of morphine (5-25 mg/kg s.c.) or saline (1 ml/kg) from postnatal day 30 (PND30)-PND39. They were then maintained drug free for a minimum of 4 weeks and mated with drug-naïve males on or after PND70. As adults, their male and female offspring (referred to as Mor-F1 or Sal-F1) were administered morphine (10 mg/kg s.c.) twice a day for 5 days. They were then tested for spontaneous withdrawal behaviors for the next 4 days (∼PND70). Levels of corticotropin releasing hormone (Crh) and urocortin 3 (Ucn3) were examined in the amygdala at 48 h and 96 h of withdrawal. Circulating corticosterone was measured at 48 h. Results indicate that Mor-F1 males are heavier than Sal-F1 males with no baseline differences in females. However, Mor-F1 females did not gain weight at the same rate as Sal-F1 females during withdrawal. While there were no differences in somatic withdrawal signs, gene expression data revealed a sex-specific and time-dependent effect on Crh as well as increased Ucn3 and corticosterone in females at 48hrs withdrawal. Overall, these data point to differences in withdrawal and stress reactivity in Mor-F1 animals that may contribute to observed differences in addiction-like behaviors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Enhanced recovery after surgery (ERAS) protocols were first developed in colorectal surgery and sought to standardize patient care. There have been several studies in the head and neck surgical literature looking at outcomes after ERAS protocol, but no studies focusing on narcotic use and length of stay. This study aimed to evaluate narcotic usage and length of stay, in addition to several other outcomes, following the implementation of an ERAS protocol., Methods: A head and neck-specific ERAS protocol was implemented at this tertiary care center beginning July 2017. A retrospective cohort study was performed comparing this cohort to that of a retrospective control group. Outcomes included mean morphine equivalent dose, mean pain score, and percentage of patients prescribed narcotics on discharge. Secondary outcomes included ICU and total length of stay., Results: The mean morphine equivalent dose (MED) administered within 72 hours postoperatively was significantly lower in the ERAS group (17.5 ± 46.0 mg vs. 82.7 ± 116.1 mg, P < .001). Average postoperative pain scores in the first 72 hours were lower in the ERAS group (2.6 ± 1.8 vs. 3.6 ± 1.9; P < .001). The average length of stay was shorter for ERAS patients (7.8 ± 4.8 vs. 9.7 ± 4.7 days, P = .008); however, there was no significant difference in ICU length of stay., Conclusion: Following implementation of an ERAS protocol, patients undergoing head and neck surgery had decreased narcotic use in the immediate postoperative period and at discharge, while also demonstrating improved postoperative analgesia., Level of Evidence: Level 3 Laryngoscope, 130:1227-1232, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

The opioid withdrawal syndrome is defined as a complex phenomenon involving multiple cellular adaptations, which leads to the emergence of aversive physical and affective signs. The m-trifluoromethyl-diphenyl diselenide (m-CF 3 -PhSe) 2 elicits an antidepressant-like effect by modulating the opioid system in different animal models of mood disorders. Notably, repeated exposure to (m-CF 3 -PhSe) 2 developed neither tolerance nor withdrawal signs in mice. The aim of the present study was to investigate whether (m-CF 3 -PhSe) 2 attenuates the physical signs and the depressive-like phenotype during morphine withdrawal through its neuroprotective effects on oxidative stress, the NMDA receptor and the proBDNF/mBDNF signaling in the hippocampus of mice. Adult Swiss mice received saline solution or escalating doses (20-100 mg/kg, sc) of morphine for six days. For the next three days, the animals were treated with canola oil, (m-CF 3 -PhSe) 2 (5 and 10 mg/kg, ig) or methadone (5 mg/kg, sc) whereas morphine injections were discontinued. On day 9, physical withdrawal signs and depressive-like behavior were assessed 30 min after the last administration of (m-CF 3 -PhSe) 2. Although short-term treatment with (m-CF 3 -PhSe) 2 at both doses suppressed the aversive physical and affective signs in morphine withdrawn-mice, the highest dose of (m-CF 3 -PhSe) 2 per se increased the teeth chattering manifestation. The intrinsic antioxidant property of (m-CF 3 -PhSe) 2 modulated oxidative stress, it also restored the NMDA receptor levels in the hippocampus of morphine withdrawn-mice. Besides, (m-CF 3 -PhSe) 2 downregulated the proBDNF/p-75 NTR /JNK pro-apoptotic pathway without affecting the mBDNF/TrkB/ERK/CREB pro-survival signaling in the hippocampus of morphine withdrawn-mice. The results show that (m-CF 3 -PhSe) 2 treatment modulated the hippocampal neurotoxic adaptations and abolished the depressive-like phenotype following morphine withdrawal in mice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The purpose of this randomized controlled trial is to determine whether the quantity of opioid pills prescribed at discharge is associated with the number of opioid pills consumed or unused by patients after primary hip and knee arthroplasty within 30 days after discharge., Methods: A total of 304 opioid-naïve patients were randomized to receive either 30 or 90 5-mg oxycodone immediate-release (OxyIR) pills at discharge. Daily opioid consumption, number of unused pills, and pain scores were calculated for 30 days with a patient-completed medication diary. Statistical analysis involved t-test, rank-sum, chi-squared tests, and multiple linear regression with alpha = 0.05., Results: Of the 304 patients randomized, 161 patients were randomized to receive 30 pills and 143 to receive 90. In the first 30 days after discharge, the median number of unused pills was 15 in the 30 group vs 73 in the 90 group (P < .001). Within 90 days of discharge, 26.7% of the 30 group and 10.5% of the 90 group requested a refill (P < .001), leading to a mean of 777.1 ± 414.2 morphine equivalents vs 1089.7 ± 536.4 prescribed (P < .0001). There was no difference between groups in mean morphine equivalents consumed. Regression analysis demonstrated that being prescribed 90 OxyIR pills was independently associated with taking more OxyIR pills (P = .028). There was no difference in pain scores within the first 30 days and in patient-reported outcome scores at 6 weeks postoperatively., Conclusion: Prescribing fewer OxyIR pills is associated with a significant reduction in unused opioid pills and decreased opioid consumption with no increase in pain scores and no difference in patient-reported outcomes., Level of Evidence: Level I. Randomized controlled trial., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Somatic and motivational symptoms accompanying opiate withdrawal are considered one of the major reasons for relapse to opiate-seeking and opiate-taking behaviors. These symptoms are accompanied by the activation of stress-related processes including hypothalamic-pituitary-adrenal axis activity and noradrenergic (NA) signaling. In particular, the NA system plays an important role in the expression of somatic signs of opiate withdrawal, whereas glucocorticoid (GR) and mineralocorticoid receptors (MR) are activated during opiate abstinence. The purpose of our study was to examine the roles of α 1 -, α 2 -, and β-adrenoceptors (ARs) as well as GR and MR, in the formation and expression of physiological and motivational symptoms of morphine withdrawal. We showed that systemic pretreatment with the selective α 1 -AR antagonist prazosin (0-1 mg/kg), the selective α 2 -AR antagonist RX821002 (0-2 mg/kg), the selective β-adrenergic antagonist, propranolol (0-10 mg/kg), or the selective MR antagonist spironolactone (0-50 mg/kg), but not the selective GR antagonist mifepristone (0-40 mg/kg), decreased somatic symptoms of naloxone-precipitated morphine withdrawal in mice chronically treated with morphine. In contrast, only propranolol pretreatment attenuated the dysphoric affective state accompanying naloxone-precipitated morphine withdrawal as assessed in the conditioned place aversion (N-CPA) paradigm. Together, our results demonstrate the important roles of noradrenergic receptors in the modulation of somatic, but not motivational/affective, symptoms of morphine withdrawal. In addition MR but not GR regulates the expression of only somatic symptoms of morphine withdrawal., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The nucleus accumbens (NAc) is a critical brain reward region that mediates the rewarding effects of drugs of abuse, including those of morphine and other opiates. Drugs of abuse induce widespread alterations in gene transcription and dendritic spine morphology in medium spiny neurons (MSNs) of the NAc that ultimately influence NAc excitability and hence reward-related behavioral responses. Growing evidence indicates that within the NAc small GTPases are common intracellular targets of drugs of abuse where these molecules regulate drug-mediated transcriptional and spine morphogenic effects. The RhoA small GTPase is among the most well-characterized members of the Ras superfamily of small GTPases, and recent work highlights an important role for hippocampal RhoA in morphine-facilitated reward behavior. Despite this, it remains unclear how RhoA pathway signaling in the NAc is affected by withdrawal from morphine. To investigate this question, using subcellular fractionation and subsequent protein profiling we examined the expression of key components of the RhoA pathway in NAc nuclear, cytoplasmic, and synaptosomal compartments during multiple withdrawal periods from repeated morphine administration. Furthermore, using in vivo viral-mediated gene transfer, we determined the consequences of revealed RhoA pathway alterations on NAc MSN dendritic spine morphology. Our findings reveal an important role for RhoA signaling cascades in mediating the effects of long-term morphine withdrawal on NAc MSN dendritic spine elimination., Open Practices: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/., (© 2018 International Society for Neurochemistry.)

Nuclear factor kappa B (NF-κB) in the spinal cord is involved in pro-inflammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65 (p-p65) was increased in the dorsal horn of the lumbar 4-6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphaeroides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawal-induced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawal-induced pain hypersensitivity.

Objective: To compare effectiveness, safety, and patient satisfaction of patient controlled analgesia (PCA) with titrated, intravenous opioid injections for the management of acute traumatic pain in the emergency department (ED)., Methods: The study took place in the ED of a teaching hospital. Patients suffering traumatic injury requiring opioid analgesia, and meeting other inclusion criteria, were consented and randomised to either the study group or control group. The study group were given morphine through the PCA system, whereas the control group were given morphine via the conventional route of nurse titration. Pain levels were measured using a visual analogue scale. Both groups had their vital signs (blood pressure, pulse, oxygen saturations, Glasgow coma score, respiratory rate) and pain scores monitored at 0, 15, 30, 45, 60, 90, and 120 minutes, and any adverse events were noted. Patients were followed up with a questionnaire asking about their experience of pain relief in the department., Results: 86 patients were recruited to the study, 43 in each group. There was no significant difference between the groups in terms of pain relief (p = 0.578) and patient satisfaction (p = 0.263). No severe adverse events were observed, although 20.7% (n = 9) of the PCA group experienced mild sedation compared with 7% (n = 3) of the control group., Conclusions: PCA is at least as effective as titrated intravenous injections for relief of traumatic pain. It has considerable potential for use in the ED.

Study Objective: To demonstrate the effect of preoperative and intraoperative, small-dose intravenous (IV) droperidol on postoperative pain relief in orthopedic patients given general anesthesia with morphine., Design: Randomized, double-blind, prospective study., Setting: University-affiliated hospital., Patients: 84 ASA physical status I and II patients undergoing shoulder rotator-cuff repair with general anesthesia., Interventions: Patients were randomly assigned to one of three groups: Group P (n = 27) wee given droperidol 10 microg/kg IV before skin incision; Group A (n = 30) received droperidol 10 microg/kg IV after skin incision; and Group C (n = 27) served as controls. General anesthesia consisted of sevoflurane and nitrous oxide in oxygen and IV morphine 0.2 mg/kg, which was given before skin incision., Measurements: The degree of postoperative pain as assessed by postoperative pain scores and the number of supplemental analgesics given, and the frequency of postoperative nausea and vomiting, nightmares, and respiratory depression were compared among the three groups. A p-value < 0.05 was considered statistically significant., Main Results: The postoperative pain score distribution was significantly greater in smaller values in Groups P and A than in Group C (p < 0.01). The number of supplemental analgesics given in the first 18 hours postoperatively was significantly smaller in Group P than in Groups A or C (p < 0.05)., Conclusions: Preoperative IV droperidol resulted in improved postoperative pain relief inpatients undergoing shoulder rotator cuff surgery with general anesthesia using IV morphine.

The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotide directed against the alpha subunit of different Gi-proteins (anti-Gialpha1, anti-Gialpha2, anti-Gialpha3) on amnesia induced by morphine was evaluated in the mouse passive avoidance test. The administration of morphine (6 - 10 mg kg(-1) i.p.) immediately after the training session produced amnesia that was prevented by PTX (0.25 microg per mouse i.c.v.) administered 7 days before the passive avoidance test. Anti-Gialpha1 (6.25 microg per mouse i.c.v.) and anti-Gialpha3 (12.5 microg per mouse i.c.v.), administered 18 and 24 h before the training session, prevented the morphine amnesia. By contrast, pretreatment with anti-Gialpha2 (3.12 - 25 microg per mouse i.c.v.) never modified the impairment of memory processes induced by morphine. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest the important role played by Gi1 and Gi3 protein subtypes in the transduction mechanism involved in the impairment of memory processes produced by morphine.

The effect of central and peripheral administration of a nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), on morphine hyperthermia was studied in male Sprague-Dawley rats. The first series of experiments examined the effect of subcutaneous (s.c.) administration of L-NAME on the hyperthermia induced by morphine given s.c. in doses of 4 and 15 mg/kg. L-NAME, at a s.c. dose of 50 mg/kg, per se, had no influence on body temperature (T(b)). Coadministration of L-NAME (50 mg/kg, s.c.) with the higher dose of morphine (15 mg/kg, s.c.) caused a significant suppression of morphine hyperthermia during the first 30 min and then produced hypothermia. In contrast, s.c. injection of L-NAME (50 mg/kg, s.c.) failed to alter the hyperthermic response induced by the lower dose of morphine (4 mg/kg). In the second series of experiments, we investigated the effect of intracerebroventricular (i.c.v.) administration of L-NAME on the hyperthermia induced by morphine given s.c. L-NAME, itself, given i.c.v. at a dose of 1 mg did not evoke any change in T(b). Intracerebroventricular administration of L-NAME (1 mg) blocked the hyperthermia induced by 15 mg/kg morphine during the first 30 min and induced a slight hypothermia but did not alter the hyperthermia induced by 4 mg/kg morphine. The results indicate that either central or peripheral NO synthesis is required for the production of hyperthermia induced by 15 mg/kg of morphine. However, NO synthesis does not seem to be involved in the hyperthermic process induced by 4 mg/kg of morphine.

Objective: A review of the English language literature was performed to determine the sensitivity and specificity of morphine sulfate-augmented hepatobiliary imaging for acute cholecystitis. Twenty publications, involving 914 patients, were reviewed from journals published between 1984 and 1999. The analysis of these patients has resulted in the largest combined review study to date. The sensitivity and specificity of morphine-augmented hepatobiliary imaging were calculated to be 96.1% and 88.6%, respectively. After reading this paper, the nuclear medicine technologist should be able to: (a) discuss the clinical use of morphine augmentation during hepatobiliary imaging; and (b) state the sensitivity and specificity of morphine sulfate-augmented hepatobiliary imaging.

The influence of orphanin FQ/nociceptin (OFQ/N) on the morphine-withdrawal symptom was investigated. Withdrawal syndrome was induced in the morphine-dependent rats by an intraperitoneal (i.p.) injection of 2 mg/kg naloxone hydrochloride--an opioid receptors antagonist. Wet-dog shakes were used as a measure of the abstinence syndrome. Intraventricular injections of OFQ/N (5-20 microg/animal) caused significant inhibition of the withdrawal signs at doses between 15-20 microg, in the morphine-dependent rats. OFQ/N alone did not change behavior of the morphine-dependent animals. The obtained results indicate that OFQ/N can inhibit the morphine withdrawal symptoms induced by naloxone.

Unlabelled: 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., Implications: 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 subjective, psychomotor, and physiological effects of three opioid mu-receptor agonists were studied in healthy volunteers using a cumulative-dosing procedure. Sixteen volunteers with no history of drug abuse received i.v. injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL was injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR: 2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological measures were recorded at various times after each injection and during recovery. MEP tended to produce the most intense effects immediately after drug injection, which dissipated rapidly. MOR produced the mildest effects but was associated with unpleasant side effects during recovery and after the session. HM's effects were stronger than MOR's, and the recovery from HM was slower than with MEP. None of the opioids produced consistent effects that are typically associated with abuse liability. Orderly dose-response functions suggested that our cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects within the same study.

Aim: To assess outcome at 5-6 years in a cohort of very preterm infants (< 34 weeks of gestation) who had been randomly allocated within a controlled clinical trial to receive morphine or non-morphine treatment in the neonatal period., Methods: Assessments were made on 87 children at 5-6 years who had been recruited in the neonatal period to two sequential controlled studies (1989-92). Infants requiring mechanical ventilation had been randomly allocated to receive either morphine (n = 62) or other (n = 33) solutions starting on the first day of life. Each child was seen by a single experienced observer and assessed at 5-6 years using the WPPSI-R, Movement ABC, and the Child Behaviour Checklist. The performance of children exposed to morphine was compared with that of those in the non-morphine group. Blood samples for thyroid stimulating hormone (TSH) measurement were obtained from children whose parents gave consent., Results: There was no significant difference in any of the three test scales between infants in the two groups, but there was a trend towards better performance in all three tests in the morphine group. Assessment of TSH values in a subgroup of the survivors showed no difference in thyroid function between the two groups., Conclusion: Exposure to morphine in the neonatal period to facilitate mechanical ventilation does not seem to have any adverse effects on intelligence, motor function, or behaviour when these children are assessed at 5-6 years of age.

For an evaluation of the survival period in morphine-involved deaths, changes of pulmonary histopathology were investigated in a total of 90 morphine-associated fatalities. Although pulmonary histopathology proved to be heterogeneous, several distinctive histological patterns emerged. While the subgroup with short courses of intoxication ( < 1 h, n = 15) was mostly characterized by slight/moderate alveolar edema (12/15), severe hemorrhages (12/15) and marked acute emphysema (9/15), the phenomena of massive edema (8/15), missing/slight hemorrhages (8/15) and absent/slight emphysema (11/15) dominated in the group with intermediate survival times (1-24 h, n = 15). Intravascular leukocyte accumulations (shock equivalent) occurred in the first group only once, but in the group with the longer survival time in 10 of 15 cases. Delayed deaths ( > 24 h, n = 4) were mainly characterized by purulent bronchitis/pneumonia. Those fatalities (n = 56) that could not be classified by anamnestic data were assessed by histological criteria. In comparison with the evaluation of the survival period by toxicological analyses, concordance was found in 46 cases. Pulmonary histopathology is not a tool for an exact graduation of survival time, but the combination of several key parameters can provide criteria for a differentiation between short ( < 1 h) and longer courses of intoxication.

Partially decorticated rats were tested for their response to nociceptive stimulation in the formalin and tail flick tests, and for the effect of morphine on these responses and on motor activity. Undrugged rats showed vigorous responses to nociceptive stimulation in both tests, and exhibited the typical biphasic time course of pain in the formalin test. Morphine 4 and 8 mg/kg produced dose-dependent analgesia in both tests in sham operated rats, and in rats with lesions that removed all or part of the cortex from the midline to the rhinal fissure (excluding the occipital cortex). In rats with lesions that extended deep into the piriform cortex and damaged the amygdala morphine analgesia was eliminated or attenuated. These and other recent findings suggest that analgesia in the formalin test depends on ascending connections to the forebrain, probably the amygdala.

The purpose of this study was to evaluate the agonist and antagonist properties of pentazocine, an opioid mixed agonist-antagonist analgesic, in relation to prototypic opioid agonist and antagonist drugs in opioid-dependent human subjects. Pentazocine (45 and 60 mg), naloxone (0.1 and 0.2 mg), morphine (20, 40 and 60 mg) and saline placebo were administered intramuscularly to six male volunteers maintained on methadone (30 mg/24 hr p.o.), following a double-blind, randomized block order design. Drugs were administered 20 hr after the last dose of methadone. Subject-reported effects and physiological measures were collected before drug administration and during 4 hr postadministration. Morphine produced significant dose-related increases in subjective measures characteristic of mu agonist effects, decreased pupil diameter and was classified as an opioid agonist. Naloxone precipitated a dose-related opioid withdrawal syndrome which was measurable on several subject-rated measures, and significantly increased pupil diameter. Subjects consistently identified naloxone as an antagonist. Pentazocine precipitated a withdrawal syndrome, but the effects were not dose-dependent, and produced symptoms of confusion and dysphoric changes that were not observed after naloxone administration. Pentazocine was classified as an antagonist by some individuals, and as alcohol or hallucinogen by others. The results of the present study indicate that pentazocine acts in humans as a partial mu agonist with a non-mu component of activity.

A novel, solid-phase radioimmunoassay for morphine and related opiates is described in which radiolabelled morphine, antiserum and polyethylene glycol are premixed before being added to the samples or standards. The mixture can be stored at 2 degrees C and used for several months until decay of the 125I label leads to excessively long counting times. The method was developed using the Roche Abuscreen radioimmunoassay for morphine and has the particular advantages of simplicity (only 2 pipetting steps required instead of 5) and economy (800 assay tubes can be prepared from a 100-tube Abuscreen plus a 50% saving in operator time). The procedure can be applied to other assays providing the polyethylene glycol-precipitated antiserum is stable and that the antibody affinity for the labelled compound is not so high as to prevent displacement of the labelled compound from the antibody binding sites by unlabelled drug.

The urinary codeine-to-morphine ratios in fifteen volunteers administered codeine tablets at intervals were studied by gas chromatography (GC) and compared with one month's GC results for enzyme multiplied immunoassay technique (EMIT)-screened urine specimens in a mass-screening programme for abuse of opiate drugs, particularly heroin. It appears that when M less than 2 and C/M greater than 0 or when M greater than 2 and C/M greater than 0.5, where C and M are codeine and morphine concentrations in micrograms per 10 ml of urine, codeine consumption has to be presumed.

A method for the determination of morphine is post-mortem blood by HPLC with electrochemical detection is described. Blood morphine levels in post-mortem cases are reported and the importance of these in causing death is discussed. These post-mortem levels are compared further with morphine levels in the blood of patients receiving morphine as an analgesic.

Intracerebroventricular administration of methionine-enkephalin or morphine sulfate immediately prior to naloxone administration inhibited the precipitated withdrawal jumping response in mice rendered dependent on morphine by the pellet implantation method. Both methionine-enkephalin and morphine sulfate failed to inhibit withdrawal defecation and rearing behavior. Morphine sulfate was found to be four times as potent as methionine-enkephalin, on molar basis, in inhibiting the abstinence syndrome. These data provide new in vivo pharmacologic evidence for the opiate-like action of methionine-enkephalin.

Demerol and methadone have advantages over morphine. Demerol requires a higher dosage than methadone, but produces less respiratory depression. Therefore, it can be used more freely in cases where respiratory depression is contraindicated. Demerol does not depress the cough reflex, and methadone is preferred for this purpose. Both drugs have a sufficient tendency to produce addiction that the usual narcotic restrictions should be observed.