Respiratory Depressant Effects Of Morphine Research Articles

Prolonged ethanol administration prevents the development of tolerance to morphine-induced respiratory depression

BackgroundOpioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol can rapidly reverse tolerance to morphine-induced respiratory depression. However, alcohol consumption by opioid users is likely to occur over prolonged time periods. We have therefore sought to determine the effect of prolonged alcohol consumption on the development of tolerance to opioid respiratory depression. MethodsMice were fed control or ethanol (5%) liquid diet for 16 days. On days 9–16 morphine tolerance was induced by administration of 3 priming injections of morphine followed by subcutaneous implantation of a morphine-filled osmotic mini-pump. Control mice received saline. Respiration was measured by plethysmography and the effect of an acute morphine challenge dose was measured on day 16 to assess the development of morphine tolerance. ResultsProlonged ethanol consumption for 14 days did not alter the respiratory depressant effect of an acute dose of morphine. Control mice treated with prolonged morphine developed tolerance to acute morphine respiratory depression whereas ethanol diet fed mice treated with prolonged morphine showed significant respiratory depression during morphine-pump treatment and remained sensitive to the respiratory depressant effect of the acute challenge dose of morphine. The ethanol consumption did not alter blood or brain levels of morphine, whilst conversely prolonged morphine treatment did not alter blood levels of ethanol. ConclusionsProlonged ethanol consumption prevents the development and maintenance of tolerance to the respiratory depressant effect of morphine. These data suggest that ethanol inhibition of tolerance will greatly increase the risk of fatal heroin overdose in humans.

Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths.

Latex allergy - potentially a painful postoperative problem

A healthy young woman presented for a subtotal hysterectomy on a routine gynaecology list with two relevant anaesthetic problems. During a previous anaesthetic, facial oedema had developed after the application of a facemask and a diagnosis of latex allergy had been made. No other information was known about this incident. Second, she was a Jehovah's Witness. Consequently, all reasonable precautions were implemented. The Trust policy on latex allergy was consulted, the patient placed first on the operating list to minimise the level of latex antigen in the atmosphere and latex-free equipment substituted where necessary. The risks of surgery were discussed with the patient and a latex-free (unprimed) blood salvaging autologous transfusion device was available in the operating theatre with the patient's consent. General anaesthesia was administered and the procedure performed without complication. The total blood loss was approximately 400 ml. As a result of being the first case on the morning list and the inherent organisation required to ensure safety due to the latex allergy and religious beliefs, it was not until near the end of the procedure that potential difficulties with postoperative analgesia became apparent. During the case, nitrous oxide and intravenous morphine had provided good haemodynamic stability. At this stage the possible options for postoperative analgesia were: 1 morphine patient-controlled analgesia (PCA); 2 epidural infusion of a local anaesthetic agent; 3 epidural diamorphine bolus; 4 intrathecal morphine; 5 intramuscular morphine + bilateral ilio-inguinal nerve blocks + nonsteroidal anti-inflammatory drugs. Morphine PCA was the preferred method but, although being of appropriate size, the available latex-free syringes were incompatible with all of the hospital delivery devices. The latter only accepted syringes with latex-containing bungs. Despite the low risk to the patient from this source [1], it was decided not to take this option. Unfortunately, the same problem arose when considering an epidural infusion of a local anaesthetic agent. Options 3 and 4 were rejected because of the uncertain additive respiratory depressant effects of morphine, which had been given intravenously during the procedure. Therefore, analgesia was achieved by performing bilateral ilio-inguinal blocks at the end of the procedure, followed by small (2.0 mg) intravenous increments of morphine given in the recovery room and thereafter, with intramuscular morphine and regular nonsteroidal analgesics. Intramuscular morphine was given according to the hospital algorithm for administration on an hourly as required basis [2]. A satisfactory level of analgesia was achieved with this approach. All hospitals should have in place protocols for the treatment of patients and staff who have allergy to latex. One possible difficulty is the provision of postoperative analgesia. As a result of this case epidural packs stocked within our hospital are now all latex free and the list of latex-free equipment has been adjusted accordingly. It is also possible to obtain latex-free syringes compatible with contemporary PCA syringe drivers. Indeed, as the incidence of latex allergy seems to be increasing, the pain team have set up a PCA system, which is only to be used by patients with latex allergy. However, should this equipment be unavailable, other forms of analgesia such as intrathecal opiates, peripheral nerve blocks or intermittent intramuscular opiates can be used. In addition, with a Jehovah's Witness who consents to the use of autologous blood transfusion, that apparatus must not contain, or be contaminated with, substances containing latex.

Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys

There is evidence that blockade of Ca 2+ channels can modify the analgesia and respiratory depression produced by opioid drugs. The interaction between Ca 2+ channel blockade and drug-induced analgesia and respiratory depression was examined by administration of the L-type Ca 2+ channel blocker diltiazem together with various analgesic drugs. The antinociceptive effects of the drugs were evaluated using a warm-water (50°C) tail-withdrawal assay in rhesus monkeys, and the respiratory depressant effects were evaluated using a pressure-displacement plethysmograph. Pretreatment with diltiazem (10–40 mg/kg, i.m.) 30 min before administration of morphine (0.3 to 10 mg/kg) or heroin (0.03 to 1.0 mg/kg) produced a dose-dependent potentiation of the opioid-induced analgesia. The analgesic potency of morphine and heroin was increased by approximately 0.5 log unit in the presence of 40 mg/kg diltiazem. However, diltiazem failed to alter the analgesic potencies of the μ-opioid receptor agonists, fentanyl, etonitazene, nalbuphine, the κ-opioid receptor agonist, U-50,488 [( trans)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide], or the non-opioid, clonidine. Respiratory frequency, minute volume, and tidal volume were suppressed by morphine, heroin, and fentanyl, but these effects were not modified by pretreatment with diltiazem (40 mg/kg). These results suggest that diltiazem selectively potentiates morphine- and heroin-induced analgesia without modifying the effects of these opioids on respiration.

The pharmacokinetic effects of coadministration of morphine and trovafloxacin in healthy subjects

Background: Morphine and antibiotics are frequently coadministered in the surgical setting. These agents may interact, reducing the efficacy of the antibiotic or increasing the toxicity of morphine. It is therefore important to determine whether antibiotics that might be used for surgical prophylaxis have the potential to change the pharmacokinetics of morphine. It is equally important to learn whether morphine affects the plasma levels of antibiotics and thus may potentially influence their efficacy or tolerability. Methods: This open, randomized, placebo-controlled, three-treatment, three-period cross-over study enrolled 19 healthy volunteers. Oral trovafloxacin (200 mg), a novel fluoroquinolone antibiotic, and intravenous morphine (0.15 mg/kg) were coadministered, and the effects on the pharmacokinetics of each drug and on changes in the pharmacologic action of morphine, estimated from its effects on respiratory rate and level of sedation, were examined. Results: When trovafloxacin was coadministered with morphine, the half-life of trovafloxacin was unchanged; however, the ratio of the area under the serum concentration versus time curve (AUC 0–∞) estimates for trovafloxacin/morphine versus trovafloxacin/placebo was 63.8% (95% confidence interval [CI], 40.7% to 100.3%), indicating a 36% reduction in the bioavailability of trovafloxacin. The ratio of the mean maximum serum concentration (C max) estimates of trovafloxacin for the two treatments was 53.8% (95% CI: 36.1% to 80.1%), indicating a 46% reduction in C max. The time to C max was delayed by 4 hours. With trovafloxacin coadministration, there were no statistically significant changes in either the mean relative bioavailability of morphine or that of its metabolite, 6β-glucuronide-morphine. Coadministration of trovafloxacin did not exacerbate the reduction in respiratory rate or increase the number of side effects associated with morphine administration. Conclusions: Coadministration of trovafloxacin and morphine reduces the bioavailability and maximum serum concentrations of trovafloxacin. However, elimination of oral trovafloxacin is not impaired, suggesting that the efficacy of trovafloxacin could be maintained in many patients who receive concomitant morphine. Morphine plasma levels and pharmacologic effects are not significantly altered by coadministration of trovafloxacin. Despite their similar metabolic pathways, the trovafloxacin/morphine combination neither exacerbates the respiratory depressant effects of morphine nor increases the frequency of side effects when compared with placebo/morphine treatment. These results suggest that the efficacy of trovafloxacin may be maintained when coadministered with morphine. Concurrent administration of trovafloxacin and morphine is unlikely to alter the pharmacologic effects of morphine.

The respiratory depressant effect of morphine

The respiratory response to carbon dioxide was measured in 130 ASA 1 adult male patients from three ethnic groups, European, Nepalese, and Chinese, both before and after premedication with intramuscular morphine sulphate (200 micrograms.kg-1 body weight). Satisfactory results were obtained from 125 patients. Overall, there was no ethnic difference in the effect of morphine on the respiratory response to carbon dioxide, but initially the Chinese group appeared to be more sensitive in their response to carbon dioxide than the Europeans and Nepalese. However, there was a significant correlation between respiratory response to carbon dioxide and pulse rate and on restricting analysis to those patients with a pulse rate equal to or less than 72 beat.min-1, the ethnic difference in carbon dioxide response disappeared. It was concluded that there were no ethnic differences in the respiratory response to carbon dioxide before or after morphine in male Europeans, Nepalese and Chinese but that the respiratory response to carbon dioxide may be influenced by long term physical training.

Antagonism of morphine-induced respiratory depression by novel anticholinesterase agents

This study compared the effects of 3 novel antiAChE agents (derivatives of dimethy-laminoethyl-phenyl carbamate) with that of physostigmine on the respiratory depression induced by morphine in rabbits. Each drug, RA 6, (1 mg i. v., 2 mg s.c.) RA 7 (1 or 2 mg i.V.); RA 15 (0.25 or 0.5 mg i.V.), physostigmine (0.05 or 0.1 mg i.v.) or saline (1 ml), was injected simultaneously with morphine (8 mg i.V.) to groups of 6–10 rabbits. Respiration rate, blood gases and pH were monitored for 3hr. Plasma ChE was measured before and at 15 min intervals after injection. The 4 antiAChE's were given to 40 other rabbits, which were sacrificed at the time of maximal antagonism of the respiratory depressant effect of morphine, in order to measure the activity of AChE in the medulla, cortex and hippocampus. Physostigmine (0.1 mg) only antagonized the increase in paCO 2 induced by morphine at 15 and 30 min. The drugs RA 15 (0.5 mg), RA 6 (2.5mg) and RA 7 (2 mg) almost completely prevented the respiratory depression, without obvious signs of peripheral cholinergic hyperactivity, for at least 3 hr. There was no relationship between the degree of antagonism of the effects of morphine with any drug and that of inhibition of ChE in plasma. In contrast, a highly significant correlation ( P < 0.01) was found between the former and the amount of inhibition of AChE in the medulla. It is suggested that the novel carbamates may have potential therapeutic application in reducing the respiratory depression of opiates, without impairing analgesia.

Pharmacokinetics and Pharmacodynamics of Morphine in Infant Monkeys

We report the pharmacokinetics of morphine administered as intravenous boluses in newborn (less than 7 days) and 3- to 4-month-old macaque monkeys. Morphine was administered in a series of bolus doses until PaCO2 was elevated greater than 50 mm Hg. In newborns less than 7 days of age, a mean dose of 1.4 mg/kg was required (range 0.75-2.8 mg/kg), and in the 3-month-olds, a mean dose of 1.88 mg/kg was required (range 1.5-2.5 mg/kg). The respiratory effects measured by PaCO2 and respiratory rate did not correlate with declining serum or cerebrospinal fluid morphine levels. Both newborn and 3- to 4-month-old macaque monkeys show only mild respiratory depression after intravenous morphine, at serum concentrations as high as 300-400 ng/ml. Infant and young macaque monkeys appear to be less sensitive to the respiratory depressant effect of morphine than humans.

Mini-Dose Intrathecal Morphine for the Relief of Post-Cesarean Section Pain

Thirty-three healthy women at term were scheduled to receive spinal anesthesia with 0.75% bupivacaine in 8.25% dextrose. In a double-blind fashion, all patients also received an intrathecal addendum of 0.5 ml of saline alone or containing either 0.1 or 0.25 mg of preservative-free morphine. Employing a visual analog scale (no pain to worst pain possible) postoperative pain was assessed at 3,6,12,16 and 24 hours postoperatively. Simultaneous determinations of maternal respiratory rate, heart rate, blood pressure, nausea and vomiting, and pruritus were made. Possible respiratory depressant effects of morphine were assessed by determining the responses to progressive hypercapnia. When pain relief was needed within the first 24 postoperative hours, 8 mg of morphine were given SC, followed by CO2 response determinations at 1.5 and 3.0 hours after injection. Neonatal status was determined by Apgar scores at birth and NACS at 2 and 24 hours after birth.

Clinical use of opioid antagonists

The preparation of normorphine and norcodeine by von Braun in 1914 made practical the synthesis of a series of derivatives differing from the parent compounds only by the radical substituted on the nitrogen atom. In 1915, Pohl investigated N-allylnorcodeine on the assumption that the addition of an allyl group conferred respiratory stimulant properties on drugs. Although this tenet proved to be incorrect, Pohl did succeed in showing that N-allylnorcodeine would prevent or abolish the respiratory depressant effects of morphine and diacetylmorphine (diamorphine BP) (Pohl, 1915). These observations suffered a fate similar to that of Humphrey Davey's finding of the potential analgesic effect of nitrous oxide--total neglect. It was not until Unna (1943) described the morphine antagonistic properties of N-allylnormorphine (nalorphine), following its synthesis by Weijland and Erikson two years earlier (Weijland and Erikson, 1942), that interest was aroused. It was also shown (Hart and McCawley, 1944) that the substitution in the opiate molecule of N-methyl by N-allyl produced a compound in which the respiratory depressant effect was eliminated, equivalent analgesic effect was maintained, but the action on the gastrointestinal tract was altered. They also showed that the substituted compound had a marked antagonistic effect upon the parent compound. Although these observations suggested that nalorphine could be valuable in the treatment of opiate intox!cation, this potential was not realized until 1951 by Eckenhoff who described its use in the treatment of opiate overdosage in man (Eckenhoff et al, 1951). The precipitation of abstinence by nalorphine and its production of dysphoric effects in man led Isbell and Fraser (1950) to suggest that it might be an effective analgesic with an abuse potential lower than that of morphine and other opiates. Even though these analgesic effects were described shortly after by Lasagna and Beecher (1954) it was as an opiate antagonist that nalorphine achieved clinical acceptance. The major factors limiting its usefulness, however, were the intense dysphoria that was observed at therapeutic doses (Telford et al, 1961) and the physical dependence that developed after sustained use (Martin and Gorodetsky, 1965). Nevertheless, nalorphine was used for a long period as an antidote for opiate overdose. 'It is a tricky drug to use. Too little will not reverse morphine effects; too

Separation of Opioid Analgesia from Respiratory Depression

Pretreating rats 24 hr earlier with naloxonazine (10 mg/kg i.v.) virtually eliminates the analgesic response observed with morphine at 3.5 mg/kg (i.v.) and significantly reduces the elevation in tail-flick latencies seen with higher morphine doses. Full dose-response curves show a 4-fold shift to the right (P less than .001) following naloxonazine treatment. At 3.5 mg/kg (i.v.), morphine depresses respiratory function, as determined by arterial blood gas (pO2, pCO2 and pH) measurements. Unlike analgesia, prior treatment of rats with naloxonazine does not alter the respiratory depressant actions of morphine. This inability of naloxonazine to antagonize the respiratory depressant actions of morphine is supported by full dose-response curves. Thus, prior treatment of rats with the mu-1-selective antagonist naloxonazine selectively antagonizes analgesia without affecting respiratory depression, implying different receptor mechanisms for the analgesic and respiratory depressant effects of morphine. Further comparisons of the analgesic and respiratory depressant effects of morphine and two opioid peptides, metkephamid and D-Ala2-D-Leu5-enkephalin, strongly suggest the involvement of mu-2 rather than delta mechanisms in opioid respiratory depression.

Benzodiazepine-opiate antagonism — a problem in intensive-care therapy

A 14-year-old previously fit schoolboy was admitted with staphylococcal pneumonia secondary to influenza A infection. His condition deteriorated as he developed adult respiratory distress syndrome (ARDS); during a stormy recovery exceptionally high doses of benzodiazepines and opiates were given in order to suppress voluntary breathing during a successful period of assisted ventilation. It is possible that benzodiazepine-opiate antagonism developed. Subsequent studies in laboratory mice indicate that the respiratory depressant effects of morphine can be antagonized by prior treatment with lorazepam.

The effects of a new opioid analgesic, meptazinol, on the respiration of the conscious rat.

In the conscious rat arterial PCO2 was measured as an index of respiratory status. The opioid analgesic meptazinol (7.5 - 30 mg kg-1) evoked small but significant increases in arterial PCO2 which were attenuated by naloxone. Meptazinol significantly reduced the increase in arterial PCO2 evoked by morphine. The respiratory depression induced by meptazinol, but not that induced by morphine, was enhanced by pretreatment with atropine. The (+)-enantiomer, but not the (-)-enantiomer of meptazinol increased arterial PCO2. In contrast, only the (-)-enantiomer reduced the respiratory depressant effect of morphine. It is proposed that the degree of respiratory depression induced by meptazinol is limited by its opioid antagonist and cholinomimetic properties.

Failure to demonstrate mu-isoreceptors

Attempts have been made to confirm reports that naloxonazine and Mr2034 are able to selectively antagonise morphine-induced analgesia and respiratory depression respectively. In the present studies these antagonists proved to be equi-effective against both the analgesic and respiratory depressant effects of morphine, suggesting that these two actions are mediated by a common receptor.

Physostigmine Antagonizes Morphine-induced Respiratory Depression in Human Subjects

The effect of physostigmine on the respiratory depression induced by morphine was studied in human subjects who received morphine as part of their preanesthetic medication. After pretreatment with droperidol (2.5-5 mg, iv) to prevent nausea, the change in minute ventilation was measured in 16 patients in response to increasing concentrations of inspired CO2 (CO2-response curve) by the rebreathing method. This was repeated 30 min after morphine (0.166 mg/kg, iv) in nine subjects and in seven controls who did not receive morphine and again 5-10 min after physostigmine (13-33 micrograms/kg, iv) in all subjects. All subjects were given N-butylhyoscine hydrobromide (5 mg, iv) to antagonize any peripheral cholinergic effects of physostigmine. Morphine decreased the mean slope of the CO2-response curve from 1.78 +/- 0.18 to 1.12 +/- 0.14 1 X min-1 X mmHg-1 (P less than 0.01) and increased the alveolar PCO2 for a fixed minute ventilation (position of curve) from 45.0 +/- 1.3 to 51.9 +/- 1.5 mmHg (P less than 0.001). Physostigmine restored the mean slope after morphine to control value, i.e., 1.79 +/- 0.231 X min-1 X mmHg-1, and position to 46.2 +/- 1.2 mmHg (P less than 0.001). Physostigmine did not increase the slope or alter the position of the CO2-response curves of subjects given droperidol alone. The authors conclude that physostigmine can reverse the respiratory depressant effect of morphine and restore the sensitivity of the respiratory center of CO2, presumably by raising acetylcholine levels in the brain after these have been reduced by morphine.

Postoperative pain control with intrathecal morphine.

A clinical study of the use of intrathecal morphine in two groups of surgical patients, 32 in all, showed that the morphine provided very powerful and prolonged analgesia with little disturbance of cerebral function. When combined with a spinal block it did not interfere with the action of the spinal anaesthetic. When combined with a relaxant technique of anaesthesia some persistent curarisation was seen. The only complication to emerge from the study was respiratory depression which could be very delayed in its offset. The depression was sufficient to induce carbon dioxide narcosis in two patients. It is suggested that the dose of intrathecal morphine in the very elderly should be very severely restricted as they appeared to be unduly sensitive to the respiratory depressant effect of morphine when given intrathecally.

PHYSOSTIGMINE ANTAGONIZES MORPHINE-INDUCED RESPIRATORY DEPRESSION BUT NOT ANALGESIA IN DOGS AND RABBITS

The ability of physostigmine to antagonize the respiratory depressant effect of morphine was studied in conscious rabbits and ketamine-anaesthetized dogs pretreated with atropine methyl nitrate. Morphine 4 mg kg-1 increased PaCO2 in the rabbit from 3.43 +/- 0.16 to 4.95 +/- 0.28 kPa, decreased arterial pH from 7.45 +/- 0.01 to 7.31 +/- 0.01 and decreased respiratory frequency by 36%. Physostigmine 0.1 mg kg-1 reduced PaCO2 to control values within 10 min and significantly increased arterial pH and respiratory frequency. There was no antagonism of the analgesic effect of morphine. Neostigmine 0.1 mg kg-1 did not reverse the respiratory depressant effect of morphine. In dogs anaesthetized with ketamine, morphine 15 mg kg-1 caused loss of consciousness and marked analgesia, decreased the respiratory frequency by 47%, and increased PaCO2 by 47%. Physostigmine 0.1 mg kg-1 antagonized the effect of morphine on respiration and restored consciousness in the dogs, but did not impair analgesia. It is concluded that physostigmine reverses morphine-induced respiratory depression by prolonging the effect of acetylcholine released from brain-stem neurones. The possibility should be considered of replacing opiate antagonists by physostigmine to reverse postoperative respiratory depression and drowsiness induced by opiates.

Respiratory Depressant Effects of Morphine on the Central Nervous System of the Infant Rat

The dose of morphine hydrochloride (1.5 mg/kg) necessary to achieve 50% depression of the ventilatory rates was identical in both 5- and 30-day-old rats. However, at equivalent blood levels, drug concentrations in the brain stem, cerebral hemispheres, and cerebrospinal fluid of the infant rat were approximately 2-fold greater than those found in the older animal. With increased doses (3 mg/kg), the respiratory rate of the infant rat decreased to 15% of resting values, in association with an increased rate of morphine accumulation in the cerebrospinal fluid. Although older rats showed only a 50% depression of the respiratory rate at doses as high as 6 mg/kg, the LD50 (16 mg/kg) was 73% lower than found for the infant animal. In the usual therapeutic dose range, the infant rat appears to be no more sensitive to the toxic effects of morphine than the older animal.

THE INTERACTION OF MORPHINE AND D-TUBOCURARINE ON RESPIRATION AND GRIP STRENGTH IN MAN.

In healthy male volunteers, morphine in combination with d‐tubocurarine produces a greater decrease in responsiveness to end expiratory carbon dioxide than does morphine alone.We believe this represents a central respiratory depressant effect of morphine plus an additive peripheral effect of d‐tubocurare on the respiratory musculature. In these subjects, morphine caused a significant increase in grip strength while d‐tubocurarine caused a significant decrease in grip strength.