Initial Morphine Research Articles

Comparison of serum and lithium‐heparinate plasma for the accurate measurements of endogenous and exogenous morphine concentrations

Comparison of serum and lithium‐heparinate plasma for the accurate measurements of endogenous and exogenous morphine concentrations

Poppy Seed Foods and Opiate Drug Testing-Where Are We Today?

Seeds of the opium poppy plant are legally sold and widely consumed as food. Due to contamination during harvesting, the seeds can contain morphine and other opiate alkaloids. The objective of this study is to review the toxicology of poppy seed foods regarding influence on opiate drug tests. Computer-assisted literature review resulted in 95 identified references. Normal poppy seed consumption is generally regarded as safe. During food processing, the morphine content is considerably reduced (up to 90%). The possibility of false-positive opiate drug tests after poppy food ingestion exists. There are no unambiguous markers available to differentiate poppy food ingestion from heroin or pharmaceutical morphine use. This is also a problem in heroin-assisted maintenance programs. A basic requirement in such substitution programs is the patients' abstinence from any other drugs, including additional illicit heroin. Also a lack of forensic ingestion trials was detected that consider all factors influencing the morphine content in biologic matrices after consumption. Most studies did not control for the losses during food processing, so that the initial morphine dosage was overestimated. The large reduction of the morphine content during past years raises questions about the validity of the "poppy seed defence." However, a threshold of food use that would not lead to positive drug tests with certainty is currently unavailable. Research is needed to prove if the morphine contents in today's foods still pose the possibility of influencing drug tests. Future trials should consider processing-related morphine losses.

Improvement in Psychosocial Outcomes in Chronic Pain Patients Receiving Intrathecal Morphine Infusions

When conventional multimodal analgesic therapy is unsuccessful, more aggressive analgesic treatments are required for patients with intractable chronic pain. Despite extensive clinical experience with implanted morphine pumps, there is still controversy regarding the psychosocial effects of this invasive analgesic therapy. In this prospective study, we evaluated the impact of intrathecal (IT) morphine infusions on pain perception and psychosocial functionality. A secondary objective of this pilot study was to assess the effect of IT morphine infusion on the patient's level of functional activity. Thirty patients with chronic nonmalignant pain that failed to respond to multimodal analgesic regimens were evaluated using the McGill Pain Questionnaire before and at 3-, 12-, and 24-mo intervals after implantation of an IT morphine infusion pump. At each clinic visit, the patient's level of pain was assessed using an 11-point visual analog scale, with 0 = no pain and 10 = worse pain imaginable. The mean initial morphine infusion rate was 0.23 +/- 0.14 mg/day (with a range from 0.09 to 0.75 mg/day) and was subsequently adjusted to maintain their pain score at a value <50% of the initial value. Adverse side effects and complications, as well as activity levels, were recorded at each clinic visit. Both evaluative and affective components of the pain assessment demonstrated a significant improvement over the 24-mo study period. The evaluative component of the McGill Pain Questionnaire improved 66%, the affective component 59%, and the sensory component 32%. The average morphine infusion rate increased to 0.44 +/- 0.29, 0.66 +/- 0.39, and 0.80 +/- 0.45 mg/day at the 3-, 12-, and 24-mo follow-up intervals (P < 0.05). The reduced level of chronic pain leads to improved social, work, and family relationships and quality of life. Among 13 patients of working age, 12 returned to work full time, and among 17 retired patients, 14 had a reduced need for assistance. IT infusion of morphine using an implantable pump was helpful in improving psychosocial function in patients with intractable pain that had failed to respond to standard multimodal analgesic therapy.

Effect of KEPI ( Ppp1r14c) deletion on morphine analgesia and tolerance in mice of different genetic backgrounds: when a knockout is near a relevant quantitative trait locus

We previously identified KEPI as a morphine-regulated gene using subtractive hybridization and differential display PCR. Upon phosphorylation by protein kinase C, KEPI becomes a powerful inhibitor of protein phosphatase 1. To gain insights into KEPI functions, we created KEPI knockout (KO) mice on mixed 129S6×C57BL/6 genetic backgrounds. KEPI maps onto mouse chromosome 10 close to the locus that contains the μ-opioid receptor (Oprm1) and provides a major quantitative trait locus for morphine effects. Analysis of single nucleotide polymorphisms in and near the Oprm1 locus identified a doubly-recombinant mouse with C57BL/6 markers within 1 Mb on either side of the KEPI deletion. This strategy minimized the amount of 129S6 DNA surrounding the transgene and documented the C57BL/6 origin of the Oprm1 gene in this founder and its offspring. Recombinant KEPIKO mice displayed (a) normal analgesic responses and normal locomotion after initial morphine treatments, (b) accelerated development of tolerance to analgesic effects of morphine, (c) elevated activity of protein phosphatase 1 in thalamus, (d) attenuated morphine reward as assessed by conditioned place preference. These data support roles for KEPI action in adaptive responses to repeated administration of morphine that include analgesic tolerance and drug reward.

Education initiative improves the evidence‐based use of metoclopramide following morphine administration in the emergency department

We aimed to evaluate a multifaceted education initiative designed to reduce the prophylactic use of metoclopramide. This was a pre- and post-intervention trial undertaken in a single ED. All ED doctors and nurses were targeted. The intervention comprised a specifically designed, 19-slide 'e-learning module', accessible via the ED intranet, supplemented by in-service training and a range of reminder techniques (posters, emails and drug room flyers). The primary end-point was the proportion of patients administered metoclopramide prophylactically with their initial morphine dose. Data were collected on random samples of patients who received morphine, using explicit medical chart review. Both pre- and post-intervention periods were of 3 month duration. The charts of 146 cases were reviewed in each period. In the post-intervention period: * The proportion of patients administered metoclopramide prophylactically decreased from 22.6% to 4.1% (difference 18.5% [95% CI 10.3-26.7], P < 0.001) * The proportion of patients administered metoclopramide appropriately (for known morphine sensitivity, established nausea and rescue anti-emesis) rose marginally from 28.8% to 32.9% (difference 4.1% [95% CI -7.2-15.4], P = 0.53) * There was a 12.7% decrease in the number of ampoules of metoclopramide issued to the ED without a concurrent rise in the issue of other anti-emetic drugs The education initiative resulted in a significant improvement in the evidence-based use of metoclopramide.

Continuous Morphine Infusion: A Retrospective Study of Efficacy, Safety, and Demographic Variables

Objectives. This study aims to assess the efficacy of intrathecal infusion in different types of pain. A number of different variables were assessed to analyze their effect on therapy and to determine in which patients intrathecal infusion is more effective. Materials and Methods. A retrospective study was conducted with data obtained from 1983 to 2002. During this period, 292 intrathecal morphine tests were performed, with positive results in 205 cases. Eight nonprogrammable intrathecal pumps and 205 programmable pumps were implanted. One hundred and thirty-one programmable pumps were studied in which the drug used was morphine alone. Efficacy and side-effects were analyzed in the overall sample, depending on the type of pain, gender, age (20-40, 40-64, >65), and dose of morphine used (<2, 2-4.9, 5-14.9, >15). Results. All results are expressed as median and interquartile range (p25-p75) because the data had a nonnormal distribution. The patients' mean age was 61years (range 50-70years); there were 61 men (46.6%) and 70 women (53.4%). The most commonly reported pain types were cancer pain (64, 48.9%), neuropathic pain (51, 38.9%), and nociceptive pain (16, 12.2%). Test dose used was 0.4mg/day (0.2-0.7), and mean number of test days was 6days (range 4-9days). The initial morphine dose was 0.50mg (0.30-1.45), mean dose was 2.70mg (1.25-6.20), and the final dose was 4mg (0.0-47). The initial numerical rating scale score of 8 (8,9) decreased to 4 (3-8) and 2 (1-5) at the end of the study. The overall rate of complications was 35.35%. Relief was very good in 29 (50.4%), good in 66 (22.1%), fair in 20 (15.3%), and poor in 16 (12.2%) patients. Univariate analysis. (Morphine): Gender: Male 49/58 (84.48%) vs. Female 43/65 (66.15%), RR 1.27 (1.04-1.57), p=0.02 (chi-squared). No significant differences were found in the other variables studied (age and type of pain). The multivariate analysis (logistic regression analysis) revealed a significant difference with regard to gender, with an odds ratio of 2.78 in favor of male gender. When the efficacy and safety of the infusion was compared to the dose of morphine used, no significant differences were observed, with p=0.65 for efficacy and p=0.69 for safety. Conclusions. Pain relief was obtained with this technique in approximately 70% of patients, with no differences between pain types, but with a significant difference in favor of male gender.

Pharmacokinetics and Pharmacodynamics of Methadone Enantiomers in Hospice Patients With Cancer Pain

Racemic methadone is increasingly used to manage cancer pain. The authors studied 13 terminally ill patients with cancer pain, who underwent switching (rotation) from morphine to methadone. The relationship between initial morphine dose and final methadone dose, the pharmacokinetics of R- and S- methadone, and the degree of pain control and side effects were investigated. Preswitching serum morphine concentrations and second daily plasma concentrations of methadone were measured. The brief pain inventory (BPI) was used to assess pain every second day. "Worst pain" as measured by the BPI improved by >/=20% in 6 of the 13 patients. The mean morphine to methadone conversion ratio was 5.2 with wide interpatient variability (range 1.3 to 11). Average steady-state concentrations were 197 (98 to 379) mug/L and 272 (55 to 378) mug/L for R- and S-methadone, respectively. Mean population pharmacokinetic parameters for a 1-compartment model were 455 L and 338 L for apparent volume of distribution and 53.3 hours and 31.5 hours for half-life for R- and S- methadone, respectively. Bayesian estimates of apparent oral clearance for individual patients were 0.082 (0.052 to 0.112) L/kg/h and 0.117 (0.061 to 0.173) L/kg/h for R- and S- methadone, respectively (mean and 95% confidence interval). The low and variable clearance values generally resulted in slow achievement of steady-state concentrations over several days; inappropriately high plasma methadone levels occurred in 1 patient. Whereas optimal pain control was achieved in 46% of patients, there was no relationship with plasma concentrations of methadone. Best practice for methadone use in this patient group should include monitoring of both pain and methadone concentration.

Transgenerational consequences of adolescent morphine exposure in female rats: effects on anxiety-like behaviors and morphine sensitization in adult offspring

Opiate abuse in adolescent girls has increased in the past decade; however, few animal studies have examined the potential consequences of opiate use occurring at this time. The purpose of the present study was to determine whether exposing female rats to morphine during the peripubertal period can alter the adult behavior of their offspring. Beginning at 30 days of age, female rats were injected subcutaneously (s.c.) twice daily with either morphine sulfate or saline. The initial morphine dose of 2.5 mg/kg was increased by 2.5 mg/kg daily for a total of 20 days. Ten days after the final drug treatment, all subjects were mated. Their subsequent offspring were then tested as adults on the elevated plus maze, in a novel environment or were examined in a morphine locomotor sensitization paradigm. Adult female offspring of dams exposed to morphine during puberty spent less time in the open arms of the elevated plus maze and displayed decreased exploration in a novel environment. Female offspring also demonstrated a more rapid induction of morphine sensitization. Finally, male offspring demonstrated a significant enhancement in the expression of morphine sensitization. Chronic morphine exposure during adolescence can have significant transgenerational effects on adult offspring. Future studies will be needed to determine how these changes are transferred to the offspring and whether these effects are specific to drug exposure that occurs during the peripubertal period.

Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates

To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery. Observational study in a level III referral center. Pharmacokinetic estimates from 14 neonates undergoing ECMO were compared with findings from a previous study in 0- to 3-year-olds after noncardiac major surgery using a nonlinear mixed effect model. A one-compartment linear disposition model with zero-order input (infusion) and first-order elimination was used to describe all data. Clearance in neonates (age <7 days) at the start of ECMO (2.2 l per hour per 70 kg) was lower than that in postoperative neonates (10.5 l per hour per 70 kg) but increased rapidly (maturation half-life 30 and 70 days, respectively) and equaled that of the postoperative group after 14 days. Clearance was affected by size and age only. Exchange transfusion, when used, contributed only 1.1% (CV 46%) of total clearance. Distribution volume increased with age and was 2.5 times (CV 102%) greater in ECMO children than in postoperative children. The between-subject variability values for volume of distribution and clearance were 49.4% and 38.7%. Weight and age information explained 83% of the overall clearance variability and 60% of overall distribution volume variability. Morphine clearance is reduced in infants requiring ECMO, possibly reflecting severity of illness. Clearance maturation on ECMO is rapid and normalizes within 2 weeks. Initial morphine dosing may be guided by age and weight, but clearance and distribution volume changes (and their variability) during prolonged ECMO suggests that morphine therapy should be subsequently guided by clinical monitoring.

Acute and chronic morphine treatments and morphine withdrawal differentially regulate GRK2 and GRK5 gene expression in rat brain

Opioid agonist stimulates activation of G protein-coupled receptor kinase (GRK) and causes desensitization of opioid signaling, which plays an important role in opioid tolerance. The current study investigated the potential regulatory effects of acute and chronic morphine administration and withdrawal on GRK2 and GRK5 gene expression in rat brain. Our results showed that the initial morphine treatment (10 mg/kg) significantly increased GRK mRNA levels in cerebral cortex, hippocampus, and lateral thalamic nuclei. A significant decrease in GRK5 mRNA levels was observed in periaqueductal gray. In strong contrast, repeated administration of morphine for 9 days failed to cause any significant increase in GRK5 mRNA in any of these brain regions. Chronic morphine treatment resulted in 30–70% down-regulation of GRK2 expression in cerebral cortex, hippocampus, thalamus, and locus coeruleus, opposite to what observed with the single morphine administration. Moreover, spontaneous and naloxone-precipitated morphine withdrawal resulted in aberrant increases in GRK2 and GRK5 mRNA levels in these brain regions. Taken together, our study suggests that opioid not only induces rapid negative feedback regulation on opioid signals through activation of GRK but also exerts its impact, via controlling levels of GRK gene expression, on the regulatory machinery itself over a longer period of time in brain.

Quantifiable dose-dependent withdrawal after morphine discontinuation in a rat model

We evaluated the intensity of the withdrawal symptoms after the discontinuation of the morphine infusion in rats. Opiate addiction was induced by progressively increasing intraperitoneal morphine infusion rates. The control group (Group 1) received normal saline. The initial morphine rates were 1, 4, and 16 mg kg −1 h for Groups 2, 3, and 4, respectively. Infusion rates were gradually increased by a factor of 1.4, 2, 2.8, and 4 on the second, third, fourth, and fifth days, respectively. The last rate was used for 48 h and then infusions were disconnected. Weight reduction, food consumption, and water intake were used for evaluation of withdrawal. All morphine groups showed a significant reduction of body weight during the 4 postdiscontinuation days and a decline in food and water intake on the first postdiscontinuation day. All changes were dependent on the morphine infusion concentration. No changes were observed in the control group. We suggest that the rat model used in this study may be utilized for quantification of spontaneous withdrawal.

A comparison of morphine analgesic tolerance in male and female mice

Studies comparing morphine tolerance in males and females are rare, and all studies to date have utilized the rat. To generalize from findings with rats morphine tolerance was investigated in male and female mice using the tail-withdrawal test. Three and 7 days of systemic morphine injections produced significant but unequal rightward shifts in the morphine dose–response curve such that females displayed greater increases in analgesic ED 50 values when compared to males. In a separate experiment, males and females displayed similar reductions in morphine analgesic sensitivity when %MPE (maximum possible effect) and %total (area under the curve) were compared after 3 days of morphine. Differences in initial morphine sensitivity between sexes were not observed in either study. The data demonstrate that, in contrast to rats, female mice undergo greater reductions in morphine analgesia relative to males following chronic morphine, but this sex difference may depend on the method of assessing analgesia. Furthermore, the duration and/or cumulative dose of morphine treatment does not affect the expression of sex differences in morphine tolerance.

Tolerance to Morphine-Induced Antinociception Is Decreased by Chronic Sucrose or Polycose Intake

D’ANCI, K. E. Tolerance to morphine-induced antinociception is decreased by chronic sucrose or Polycose intake. PHARMACOL BIOCHEM BEHAV 63(1) 1–11, 1999.—Chronic intake of palatable fluids alters morphine-induced antinociception. Two experiments were conducted to evaluate how long-term access to palatable fluids alters the development of tolerance to morphine-induced antinociception. In Experiment 1, 40 adult male Long–Evans rats were used. In addition to ad lib chow and water, 10 rats were given a 0.15% saccharin solution, 10 were given a 32% sucrose solution, and 10 were given a 32% Polycose solution to drink for 3 weeks. Ten rats were given chow and water alone, and served as dietary controls. Morphine-induced antinociception was assessed using the radiant-heat tail-flick method (TF). Half of the animals in each dietary condition were given preexposure to 7.5 mg/kg morphine; the other half received saline. All rats were given a TF 30-min postinjection. To determine whether tolerance developed, a cumulative dose paradigm (0.625, 1.25, 2.5, 5.0, 10.0 mg/kg) was employed 1 week after initial morphine injections, and was repeated at weekly intervals for 3 weeks. Antinociception was significantly lower in rats preexposed to morphine relative to rats preexposed to saline. Although all rats displayed decreased antinociception relative to the first morphine injection, rats that drank saccharin showed greater reductions in morphine-induced antinociception relative to rats that drank sucrose or Polycose. Experiment 2 was conducted to determine whether initial pairing of the TF with morphine preexposure produced differences in the development of opioid tolerance. All conditions and procedures were identical to Experiment 1, except that the initial morphine and saline injections were not followed by TF. As in Experiment 1, rats that drank saccharin showed less antinociception than rats that drank sucrose or Polycose. The present results suggest that long-term intake of palatable nutritive solutions curbs tolerance to morphine-induced antinociception, whereas long-term intake of a nonnutritive, sweet saccharin solution does not.

COMPARISON OF REMIFENTANIL AND FENTANYL FOR TONSILLECTOMY SURGERY IN CHILDREN*

S294 INTRODUCTION: Remifentanil HCl is a unique opioid that is metabolized by non-specific plasma and tissue esterases. This results in a half-life of < 10 min and no residual opioid activity after termination of the infusion. This study compares the response to surgical stress as well as the emergence (extubation and purposeful movement) and recovery profiles of remifentanil (remi) and fentanyl(fent) when administered with halothane(hal) or sevoflurane(sevo), in pediatric patients undergoing tonsillectomy with and without adenoidectomy; a population in which rapid and complete recovery, and the ability to regain full control of the airway is desirable. METHODS: With IRB approval and parental consent, six centers enrolled 222 ASA I or II pts ages 2-12 yrs in a double-blind, parallel group, active control study. Pts were randomized to 1 of 4 treatment groups: remi/hal (RH), fent/hal (FH), remi/sevo (RS), and fent/sevo (FS). All were premedicated PO with midazolam. Induction was with hal or sevo in N2 0/02, followed by dexamethasone 0.25 mg/kg, atracurium 0.5 mg/kg and ondansetron 0.1 mg/kg. After assessing the hemodynamic response to intubation, all pts received morphine 50 [micro sign]g/kg IV. Maintenance was achieved with a placebo initial bolus and 0.25 [micro sign]g/kg/min remi infusion in the remi groups or a fent 2 [micro sign]g/kg bolus and placebo infusion in the fent groups. Supplemental boluses of 1 [micro sign]g/kg remi or 1 [micro sign]g/kg fent (max 6 [micro sign]g/kg) were given and the infusion rate increased by 50% as intraoperative responses indicated. Hal 0.3% and sevo 0.8% in N2 0/02 (2:1) were the concomitant anesthetics. The remi and placebo infusions were tapered to 0.05 [micro sign]g/kg/min approx. 10 min prior to the end of surgery when sevo, hal, N2 0 and the infusion were discontinued simultaneously. At the end of surgery neuromuscular blockade was reversed. If criteria for extubation was not achieved within 10 min, the pt was stimulated and if necessary, given naloxone. The need to treat inadequate or excessive anesthetic responses, times to purposeful movement, extubation, recovery and time to meet PACU D/C criteria were compared. In addition, PACU pain scores were assessed. RESULTS: Demographic variables did not differ among the four groups. There was no significant difference in the proportion of subjects receiving medication to treat inadequate or excessive anesthesia among treatment groups. Extubation times (median 9 min. vs. 10 min.) and PACU eligibility discharge times (median 21 min. vs. 22 min.) occurred sooner in children anesthetized with remi vs. fent. The frequency of naloxone use and patient stimulation required for extubation was greater for fent than remi (29% vs. 11%). In the PACU, the time to first postoperative pain medication was significantly shorter (20 min. vs. 27 min.) and PACU pain scores for the first 20 minutes were significantly higher for the remi vs. the fent groups. DISCUSSION: Although remi allows for earlier extubation times than fent, these differences were not clinically appreciable under the conditions of the study. However, compared with remi, subjects receiving fent had a higher frequency of naloxone use and patient stimulation prior to extubation. PACU D/C was not accelerated in this study. This was probably due to the extra need for supplemental analgesics during recovery in the remi group. It may be that in order to achieve a more rapid recovery when remi is used, a larger initial (pre-emptive) morphine dose may need to be given to reduce the need for further analgesics in the PACU. Additionally, since the more rapid extubation was found in the RH (vs. FH) combination, a cost analysis comparing remi and hal vs. sevo in this setting should be conducted. This study was supported by a grant from Glaxo Wellcome, Research Triangle Park, NC.

Morphine, Morphine-6-Glucuronide, and Morphine-3-Glucuronide in Cerebrospinal Fluid and Plasma After Epidural Administration of Morphine

Background and ObjectivesIt has been suggested that the potency of epidural morphine might be explained by spinal metabolism to the active and potent metabolite morphine-6-glucuronide (M6G). The main objective of this study was to describe the early pharmacokinetics of epidurally administered, morphine with special attention to the appearance of the glucuronated metabolites in cerebrospinal fluid (CSF).MethodsMorphine was administered epidurally to eight patients scheduled for major abdominal surgery. The concentrations of morphine and its 6-glucuronide and 3-glucuronide metabolites were monitored in blood and CSF at 10, 30, 60, and 120 minutes and 10 and 24 hours. Postoperative pain was estimated on a visual analog scale, and analgesia requirements (administered by a patient-controlled techique) were recorded.ResultsOnly traces of the metabolites were found in CSF and in only two patients throughout the 24 hours. Both metabolites appeared rapidly (within 30 minutes) in plasma in all patients and were found in plasma throughout the study period. Morphine concentration peaked in CSF within 30 minutes at a very high level; in plasma, it peaked at 10 minutes. No correlation was seen between initial or later concentrations of morphine in CSF and postoperative pain or morphine requirements.ConclusionsNo evidence of spinal metabolism of morphine could be found. Rapid distribution of morphine to CSF and plasma occurred after epidural administration. No value of initial CSF morphine concentrations for prediction of analgesic requirements could be demonstrated.

Intrathecal morphine for analgesia in children undergoing selective dorsal rhizotomy

Selective dorsal root rhizotomy is performed for relief of spasticity in children with cerebral palsy. Postoperative pain relief can be provided by intrathecal morphine administered at the time of the procedure. We sought to define an optimal dose of intrathecal morphine in children undergoing selective rhizotomy, through a randomized, double-blinded prospective trial. After institutional approval and parental written informed consent, 27 patients, ages 3–10 years, were randomized to receive 10, 20, or 30 μg·kg −1 (Groups A, B, and C, respectively) of preservative-free morphine administered intrathecally by the surgeon after dural closure. Postoperatively vital signs, pulse oximetry, and pain intensity scores were recorded hourly for 24 hr. Supplemental intravenous morphine was administered postoperatively according to a predetermined schedule based on pain scores. There was considerable individual variability in the time to initial morphine dosing and cumulative supplemental morphine dose. Time to first supplemental morphine dose was not different between groups. When compared to Groups A and B, cumulative 6-hr supplemental morphine dose wa significantly lower in Group C (38.6 ± 47 μg versus 79.1 ± 74 and 189.6 ± 126 for Groups A and B, respectively). By 12 hr, cumulative supplemental morphine dose was similar in Groups A and C. Group B consistently had a higher supplemental dose requirement than Groups A and C at 6, 12, and 18 hr. By 24 hr, there was no difference in cumulative dose among groups. Postoperative pain scores and the incidence of respiratory events, nausea, vomiting, and pruritus were comparable among groups. These data suggest that intrathecal morphine at 30 μg·kg −1 provides the most intense analgesia at 6 hr following selective dorsal root rhizotomy, but was otherwise comparable to the 10 μg·kg −1 dose.

Age is the best predictor of postoperative morphine requirements

The dose of opioid prescribed for postoperative pain relief has traditionally been based on the weight of the patient. Although a reduction in dose is often suggested for elderly patients over 70 years of age, age-related alterations to dose are generally not considered for younger patients. The records of 1010 patients, under 70 years old, prescribed morphine via patient-controlled analgesia (PCA) after major operations were examined to see what factors might best predict the amount of morphine used in the first 24 h after surgery. Factors included were age, sex, weight, operative site, verbal numeric pain score (at rest and on movement) and a nausea/vomiting score. In a subgroup of 78 of these patients, the effects of intraoperative and recovery room doses of opioid (‘clinical’ loading dose) were analysed. Although the interpatient variability in PCA morphine doses was large (differences of up to 10-fold in each age group), the best predictor of PCA morphine requirement in the first 24 h after surgery (the amount required in the 24 h after the initial loading dose) was the age of the patient. An estimate of these requirements for patients over the age of 20 years can be obtained from the formula: average first 24 h morphine requirement (mg) = 100 − age. PCA allows patients the flexibility to titrate their own opioid dose; if conventional analgesic regimens are to become more effective, they too need to allow for the wide interpatient variation in dose requirements. Although previous studies have noted a correlation between patient age and the amount of opioid needed, this study quantifies this correlation and provides guidelines for opioid dosing. Prescriptions for conventional analgesic regimens should include a dose range centred on values obtained from the above formula to allow for the large interpatient variation in each age group. While initial morphine dose should be guided by patient age and not weight, subsequent doses must still be titrated according to effect.

Relationship between pain severity and serum beta-endorphin levels in postoperative patients.

To examine the relationship among postoperative pain severity, serum beta-endorphin level, and serum morphine level in pediatric patients after posterior spinal fusion with instrumentation. A prospective study. University-based medical center. Ten patients age 13-17 years admitted for posterior spinal fusion with instrumentation. Each subject was administered an initial dose of intravenous morphine 100 micrograms/kg, followed by a constant infusion of 50 micrograms/kg/hour. The primary physician was allowed to titrate the dosage as required to meet the patient's requirement for analgesia. Whole blood was obtained for the analysis of serum morphine and beta-endorphin levels preoperatively, after the initial morphine dose, 24 hours after initiation of the infusion, and before any change in dosage. At each blood sampling time, pain severity ratings were obtained from the subject, nurse, and parent using a 10-point linear scale. No statistical difference between serum beta-endorphin values preoperatively and after the initial dose of morphine was observed; mean values were 68 and 60 pg/ml, respectively. The relationships between serum beta-endorphin level and pain scores were statistically significant only for self (subject) pain scores (p = 0.014, r = 0.30). Mean serum morphine level was 21.9 ng/ml for patients with self pain scores of 4 or less. The clinical usefulness of serum beta-endorphin as a measure of pain severity was not established under the experimental conditions of this study.

Development of Tolerance to Morphine Antinociception in Mice Treated with Nociceptive Stimulants

We have examined whether or not the presence of pain can block the development of tolerance to morphine antinociception in mice. A single injection of formalin or Freund complete adjuvant into the dorsal part of one side of the hind paw resulted in a significant swelling of the treated paw which lasted more than 5 days. In formalin-treated animals that received the initial morphine 2 hr after the stimulant, the development of tolerance to morphine was delayed without affecting morphine antinociception when the effect was measured daily by the tail-pinch (TP) method but not by the tail-flick (TF) method. However, the stimulant suppressed tolerance development even in the TF method unless the daily measurement was undertaken. When morphine injection was started from 5 days after the formalin injection, tolerance developed in a pattern similar to that in the control animals. On the other hand, treatment with Freund adjuvant did not affect the development of tolerance measured by both the TP and TF methods, with or without daily measurement of antinociception. When acetic acid was used as a stimulant, daily morphine was administered before or after the acetic acid injection, in the presence or absence of pain, tolerance developed to the same extent as in the control group, regardless of the time of morphine injection. Thus, our results suggest that the development of tolerance to narcotics may be modified by various factors, such as the type and intensity of nociception; and they also suggest that different results may be produced depending on the test method.

Oxytocin and vasopressin release in discrete brain areas after naloxone in morphine-tolerant and -dependent anesthetized rats: push-pull perfusion study

The effects of naloxone on the release of oxytocin and vasopressin in discrete brain areas were investigated in control and morphine-tolerant/dependent female rats anesthetized with urethane. Two or three consecutive push-pull perfusates were collected for 30-40 min each and the peptide contents measured by radioimmunoassay; naloxone (5 mg/kg, i.v.) was given after the first perfusion. In control rats, naloxone did not increase oxytocin release from any of the regions studied: mediolateral septum, dorsal hippocampus, nucleus of tractus solitarius, or supraoptic nucleus. After naloxone, vasopressin release was approximately doubled in the nucleus of tractus solitarius (p less than 0.05), indicating endogenous opioid inhibition of vasopressin release. Naloxone increased oxytocin concentration in the circulation 3.7-fold (p less than 0.001) but did not affect vasopressin secretion. In rats made morphine tolerant/dependent by intracerebroventricular infusion of morphine for 5 d, oxytocin and vasopressin release in the perfused brain was initially similar to that in control rats, indicating tolerance to any initial morphine effects. In these rats, naloxone increased oxytocin release in the septum threefold relative to control rats (p less than 0.02) but did not alter oxytocin release in hippocampus or nucleus of tractus solitarius. Thus, the oxytocin neurons projecting to septum can develop morphine dependence and may be inhibited acutely by opioids acting via mu-receptors. The results indicate morphine acts selectively on oxytocin neurons projecting to mediolateral septum compared with other central projection areas and compared with centrally projecting vasopressin neurons. In the supraoptic nucleus, naloxone increased oxytocin release 2.3-fold (from 9.2 +/- 3.1 pg/30 min) and increased oxytocin release from axons of these neurons fivefold (from 7.8 +/- 3.2 pg/30 min). Naloxone had no significant effect on vasopressin release from any of the central sites, or on vasopressin secretion into blood, although oxytocin secretion was increased 36-fold (from 17.2 +/- 2.6 pg/ml; p less than 0.001), confirming dependence of magnocellular oxytocin neurons. The central processes of magnocellular supraoptic neurons may be a major source of central oxytocin released during morphine withdrawal.