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PubMed1982

Morphine- and methadone-tolerant mice differ in cross-tolerance to other opiates. Heterogeneity in opioid mechanisms indicated.

Mice were rendered tolerant to morphine or 1-methadone by subcutaneous injections for 4 days. The antinociceptive activities of morphine, codeine, l-methadone and d-propoxyphene were determined in tolerant and control mice using the hot-plate test, and the respective ED50's were calculated by the up-and-down procedure of Dixon. An asymmetry in cross-tolerance patterns was found: While morphine-pretreated mice were tolerant to morphine only (with a dose-ratio tolerant: control of 5.2), methadone-pretreated mice were tolerant to all analgesics tested, and more so to morphine 5.2; l-methadone 3.0; codeine 2.7 and d-propoxyphene 1.9). The results are discussed in terms of heterogeneity in opioid receptor mechanisms.

Analgesia↗
PubMed1981

Changes in the activity of nigral neurones induced by morphine and other opiates in rats with an intact brain and after prenigral decerebration.

The effect of morphine and related opiates on the spontaneous activity of nigral neurones was studied in unanaesthetized rats with an intact brain or after prenigral decerebration. Less than 50% of the neurones were influenced by the opiates. In the intact brain, intravenous (i.v.) injection of morphine 2 mg/kg, dextrorphan 1 mg/kg and tilidine 5 mg/kg increased the discharge rate, whereas levorphanol 1 mg/kg, pethidine 20 mg/kg and codeine 10 mg/kg reduced it. Naloxone 0.2 mg/kg i.v. abolished the effects of morphine, levorphanol and codeine; it reduced the effect of pethidine and was ineffective against dextrorphan and tilidine. Intracaudate injections of morphine 10 microgram and pethidine 50 microgram increased the spontaneous activity of some neurones in the ipsilateral substantia nigra and reduced that of others; the increase in activity after morphine was more pronounced than the depression. The effects of intracaudate injections of morphine or pethidine were reduced by i.v. naloxone. After prenigral decerebration, i.v. injections of morphine depressed, and i.v. injections of levorphanol increased the activity of nigral neurones; pethidine i.v. either increased or reduced the spontaneous activity. These effects were reduced or abolished by naloxone. It is concluded that opiates including morphine affect the activity of nigral neurones not only by an action on opiate receptors in the striatum but also by an action on opiate receptors outside the striatum (e.g. in the substantia nigra and, perhaps, by an action unrelated to opiate receptors.

Animals↗
PubMed1987

Effect of drugs on oro-caecal transit time assessed by the lactulose/breath hydrogen method.

The comparative actions of two benzamides; the one metoclopramide, having and the other, BRL 20627, lacking dopamine receptor antagonist properties have been investigated on orocaecal transit time (OCTT) using the lactulose/breath hydrogen method. In addition, the action of codeine, propantheline and domperidone on OCTT has been assessed. Similar quantitative reductions in apparent OCTT were found with metoclopramide and BRL 20627 thus, metoclopramide 20 mg orally and 10 mg i.v. brought about 32.5% and 42% reductions in OCTT. Similar reductions were also found using 20 mg BRL 20627 orally and 10 mg i.v. (31 and 26% respectively). In addition 20 mg domperidone orally was found to cause a 10% reduction. Codeine orally and propantheline i.m. brought about increases in the assessed transit time.

Adult↗
PubMed1991

A case of high opiate tolerance: implications for drug analyses and interpretations.

A case of driving under the influence of extremely high concentrations of codeine and ethylmorphine is reported. A high blood concentration of morphine was also found, which in this case was probably a metabolic product of codeine and ethylmorphine. This illustrates that when morphine is found in blood, the sample should also be analysed for other opiates in order to avoid misinterpretations.

Automobile Driving↗
PubMed1990

Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial.

A double-blind study was performed comparing 5 mg delta-9-tetrahydrocannabinol (THC) p.o., 50 mg codeine p.o., and placebo in a patient with spasticity and pain due to spinal cord injury. The three conditions were applied 18 times each in a randomized and balanced order. Delta-9-THC and codeine both had an analgesic effect in comparison with placebo. Only delta-9-THC showed a significant beneficial effect on spasticity. In the dosage of THC used no altered consciousness occurred.

Adult↗
PubMed1991

Role of adrenoceptors in the potentiation of opioid antinociception by ephedrine and phenylpropanolamine in mice.

Ephedrine and phenylpropanolamine (PPA) (10 mg/kg) pretreatment intraperitoneally (IP) potentiated the antinociceptive effects of subcutaneous (SC) morphine (5 mg/kg) and codeine (60 mg/kg) in mice using the tail-flick method. Prior administration of propranolol (6 mg/kg, SC) 10 min before the sympathomimetics had no effect on this action. Phentolamine (2 mg/kg, SC), on the other hand, abolished the enhancing effects of ephedrine and PPA on opioid antinociception. Prazosin (2 mg/kg, SC) pretreatment did not significantly affect the potentiation of opioid antinociception by ephedrine and PPA, while yohimbine (4 mg/kg, SC) effectively antagonised this enhancing effect. None of the adrenoceptor antagonists had any effect on the tail-flick reaction time on their own in the doses used, and neither did they affect opioid antinociceptive responses. It is concluded that ephedrine and PPA potentiate the antinociceptive effects of morphine and codeine, most probably through an action on alpha 2-adrenoceptors.

Analgesics, Opioid↗
PubMed1990

Etodolac: analgesic effects in musculoskeletal and postoperative pain.

Numerous clinical trials have shown etodolac to be an effective analgesic. The purpose of the present report is to review results of 14 studies that demonstrate the effectiveness of etodolac in a variety of painful conditions. Presented are the results of four postsurgical pain studies, one study of acute gouty arthritis and nine studies of acute musculoskeletal disorders: acute low back pain, acute painful shoulder, tendinitis and bursitis, and acute sports injuries. A single oral dose of etodolac (25, 50, 100, 200, or 400 mg) was compared with aspirin (650 mg) or a combination of acetaminophen (600 mg) plus codeine (60 mg) for the relief of pain up to 12 h following oral, urogenital or orthopedic surgery. In multiple dose studies of acute gouty arthritis and musculoskeletal conditions, etodolac 200 or 300 mg twice a day (b.i.d.) or 200 mg three times a day (t.i.d.) was compared with naproxen 500 mg b.i.d. or t.i.d., diclofenac 50 mg b.i.d. or t.i.d., and piroxicam 20 or 40 mg once a day (o.d.) administered over 5 to 14 days. The efficacy of etodolac was at least equal and in some ways superior to aspirin and acetaminophen plus codeine in the relief of postsurgical pain. In studies of acute gouty arthritis, significant improvement from baseline were seen for all efficacy parameters evaluated for both the etodolac- and naproxen-treated patients. All the present studies of musculoskeletal conditions have shown etodolac to be effective and comparable in analgesic efficacy to naproxen, diclofenac or piroxicam. In summary, etodolac therapy for pain following surgery, in acute gouty arthritis and in acute musculoskeletal conditions resulted in analgesia comparable to that provided by several well-established analgesic or anti-inflammatory agents.

Acetaminophen↗
PubMed1995

Oral ondansetron decreases vomiting after tonsillectomy in children.

Vomiting is a common, unpleasant aftermath of tonsillectomy in children. Intraoperative intravenous ondansetron (OND) reduces vomiting after this operation. Our double-blind, placebo-controlled, randomized investigation studied the effect of the oral form of OND on vomiting after outpatient tonsillectomy in children. We studied 233 healthy children age 2-14 yr undergoing elective tonsillectomy. Subjects were given placebo (PLAC) or OND 0.1 mg.kg-1 rounded off to the nearest 2 mg one hr before surgery. Anaesthesia was induced with either propofol or halothane/N2O. Vecuronium 0.1 mg.kg-1 was administered at the discretion of the anaesthetist. Anaesthesia was maintained with halothane/N2O, 50 micrograms.kg-1 midazolam iv and 1-1.5 mg.kg-1 codeine im. At the end of surgery, residual neuromuscular blockade was reversed with neostigmine and atropine. All episodes of in-hospital emesis were recorded by nursing staff. Rescue antiemetics in the hospital were 1 mg.kg-1 dimenhydrinate iv for vomiting x 2 and 50 micrograms.kg-1 droperidol iv for vomiting x 4. Parents kept a diary of emesis after discharge. Postoperative pain was treated with morphine, codeine and/or acetaminophen. The two groups were similar with respect to demographic data, induction technique and anaesthesia time. Oral OND (n = 109) reduced postoperative emesis from 54% to 39%, P < 0.05. This effect was most dramatic in-hospital, where 10% of the OND-patients and 30% of the PLAC-group vomited, P < 0.05. The OND-subjects required fewer rescue antiemetics, 7% vs 17%, P < 0.05. In conclusion, oral ondansetron decreased the incidence of vomiting after outpatient tonsillectomy in children.

Administration, Oral↗
PubMed1995

Ondansetron is a better prophylactic antiemetic than droperidol for tonsillectomy in children.

Both intravenous ondansetron (OND) and droperidol (DROP) have been observed to reduce vomiting after tonsillectomy in children. This randomized, double-blind investigation compared the effect of OND and DROP on vomiting after outpatient tonsillectomy in 276 healthy children age 2-12 yr. All subjects received a standardized anaesthetic, which consisted of induction with either propofol or halothane/N2O, vecuronium 0.1 mg x kg(-1) on an as needed basis, maintenance with halothane/N2O, midazolam and codeine, and reversal of neuromuscular blockade with neostigmine and atropine on an as needed basis. Subjects were given either OND 150 micrograms x kg(-1) or DROP 50 micrograms x kg(-1)iv after induction of anaesthesia. Rescue antiemetics in the hospital were administered to patients who vomited X 2 and X 4, respectively. Postoperative pain was treated with morphine, codeine and/or acetaminophen. For 24 hr following surgery, emesis was recorded by nursing staff while subjects were in the hospital, and by parents following discharge from hospital. The two groups were similar with respect to demographic data, induction technique and anaesthesia time. The frequency of in-hospital emesis was 16% in the OND-patients and 30% in the DROP-group, P <0.05. The OND-subjects required fewer rescue antiemetics, 5% vs 13%, P <0.05. The overall incidence of emesis was 45% in the OND-group and 57% in the DROP-group, P <0.05. In conclusion, ondansetron was a superior prophylactic antiemetic for tonsillectomy in children when compared to droperidol.

Antiemetics↗
PubMed1997

Peri-operative multimodal pain therapy for caesarean section: analgesia and fitness for discharge.

PURPOSE: To compare, the efficacy of a multi-modal analgesic regimen and single drug therapy with iv PCA morphine alter Caesarean delivery with spinal anaesthesia. METHODS: Forty ASA 1-2 parturients presenting for elective Caesarean section were randomized to receive multimodal pain treatment with intrathecal morphine, incisional bupivacaine and ibuprofen+acetaminophen po until hospital discharge (Group 1) or conventional therapy with iv PCA morphine weaned to acetaminophen+codeine po (Group 2). Both groups received spinal anaesthesia with 1.7 ml hyperbaric bupivacaine 0.75%. Visual analog pain scores at rest (RVAPS) and with movement (DVAPS) were recorded q 2 hr during the first 24 hr, then q 4 hr until discharge. Time to first walking, eating solid food, flatus, bowel movement, voiding and hospital discharge were recorded. RESULTS: Pain scores were lower in Group 1 patients during the first 24 hr after spinal injection RVAPS 0.6 +/- 0.1 in Group 1 vs 2.1 +/- 0.1 in Group 2 (mean +/- SEM), DVAPS 1.9 +/- 0.1 in Group 1 vs 4.1 +/- 0.1 in Group 2 (P < 0.0001). Times to first flatus, 36.1 hr +/- 2.9 vs 20.5 +/- 1.8 (P < 0.05) and to first bowel movement, 74.8 hr +/- 5.6 vs 57.4 +/- 4.7 (P < 0.0001) were longer in Group 2 patients. There was no difference between groups in time to eating solid food, walking or hospital discharge. CONCLUSION: Multi-modal pain therapy resulted in improved early post-operative analgesia during the first 24 hr after Caesarean delivery. Patients receiving iv PCA morphine followed by acetaminophen+codeine po were more likely to develop decreased bowel mobility. All patients, with one exception, achieved discharge criteria (eating solid food, absence of nausea, normal lochia, dry incision and DVAPS < 4) at 48 hr after spinal injection.

Analgesia, Obstetrical↗
PubMed1999

[Therapy with opioids in liver or renal failure].

In patients with renal or hepatic failure, the pharmacokinetics of opioids may be affected in several ways, leading to the necessity to correct the dose. The liver is the major site for biotransformation of most opioids. The major metabolic pathway is oxidation. Exceptions to this are morphine and buprenorphine, which undergo primarily glucuronidation, and remifentanil which is cleared by esther hydrolysis. The hydrophilic metabolites are predominantly excreted by the kidneys and may accumulate in patients with renal insufficiency. Some metabolites such as morphine-6-glucuronide (M6G) or normeperidine are active opioid agonists. With high concentrations they may cause narcotic effects or respiratory depression. In addition, special risks are known for normepridine that has been shown to exert neurotoxic effects with the risk of seizures. Few cases of respiratory depression following the administration of codeine, dihydrocodeine and tramdol have been reported. The elimination half-life of these drugs was prolonged. Lastly, the disposition of methadone, buprenorphine, fentanyl, sufentanyl and remifentanil appears to be unaffected in renal failure. In patients with hepatic cirrhosis it has been shown that oxidation of opioids is reduced, resulting in a decreased drug clearance (meperidine, propoxyphene, pentazocine, tramadol and alfentanil) and increased oral bioavailability due to reduced first-pass metabolism (meperidine, propoxyphene, pentazocine, dihydrocodeine). Although glucuronidation is thought to be less affected in liver cirrhosis, the clearance of morphine was found to be decreased and its oral bioavailability increased. The consequence of reduced drug metabolism is the risk of accumulation in the body, especially with repeated administrations. As for patients with renal failure, special risks are known for meperidine with potential accumulation of normeperidine, which can cause seizures, and for propoxyphene for which several cases of hepatotoxicity have been reported. On the other hand, the analgesic activity of codeine and tilidine depends on transformation into the active metabolites, morphine and nortilidine. In the case of reduced metabolism in chronic liver disease, the analgesic action of these drugs may be compromised. Lastly, the disposition of a few opioids, such as fentanyl, sufentanil, and remifentanil, appears to be unaffected in liver disease.

English Abstract↗
PubMed2006

Combination analgesia in 2005 - a rational approach: focus on paracetamol-tramadol.

A multimodal (or balanced) approach to anaesthesia is a familiar concept that offers important benefits in the management of both acute and chronic pain. Rational combinations of analgesic agents with different mechanisms of action can achieve improved efficacy and/or tolerability and safety compared with equianalgesic doses of the individual drugs. Combining different agents also enhances efficacy in complex pain states that involve multiple causes. Combinations of paracetamol plus a weak opioid agent are widely used. One such combination, paracetamol plus tramadol, exploits the well-established complementary pharmacokinetics and mechanisms of action of these two drugs. This combination has demonstrated genuine synergy in animal studies and also combines paracetamol's rapid onset of efficacy with tramadol's prolonged analgesic effect. Numerous studies have confirmed the efficacy and tolerability of paracetamol plus tramadol in both acute and chronic pain. As a single-dose treatment for acute post-operative pain, this combination delivers rapid and sustained pain relief that is greater than either agent alone. There is also extensive evidence for efficacy in the long-term management of chronic pain conditions, including osteoarthritis, low back pain and fibromyalgia. In the setting of chronic pain, paracetamol plus tramadol has shown sustained efficacy, safety and tolerability for up to 2 years without the development of tolerance. The efficacy of this combination has been demonstrated as well in respect to reduction of pain intensity and, more importantly, with regard to improvement of function and quality of life and the reduction of disability. Comparative trials have shown that paracetamol plus tramadol has comparable efficacy to paracetamol plus codeine, but with reduced somnolence and constipation compared with the codeine combination. The paracetamol plus tramadol combination is also free of organ toxicity associated with selective and non-selective non-steroidal anti-inflammatory drugs. Hence, paracetamol plus tramadol offers an effective and well-tolerated alternative to anti-inflammatory drugs or other paracetamol plus weak opioid combinations.

Acetaminophen↗
PubMed1983

Comparative kinetic studies of the dealkylation reaction and steroid hydroxylations in various oxygen and carbon monoxide:oxygen atmospheres.

The time-course kinetics of the cytochrome P-450-catalyzed dealkylations of the exogenous compounds benzphetamine, ethylmorphine, codeine, and 7-ethoxycoumarin were compared to the hydroxylation of the endogenous compound testosterone. Using liver microsomes from phenobarbital-induced rats, the time course of the demethylations of ethylmorphine, codeine, and especially benzphetamine was characterized by a fast initial phase of enzymatic activity and then a steady decline in the rate throughout the remainder of the reaction. In contrast, under the same experimental conditions, both the dealkylation of 7-ethoxycoumarin and the hydroxylation of testosterone showed no initial fast phase of activity and a constant rate of product formation for most of the remainder of the time course. The difference also held for the carbon monoxide inhibition studies in which the degree inhibition of the demethylation reactions by a variety of CO:O2 mixtures was time dependent, in contrast to the constant, time-independent degree of CO inhibition of the other two reactions. The kinetics of the demethylation reactions could not be explained by enzyme destruction, back reaction, or product adduct formation and were further confirmed by measurements of the rate of O2 utilization and NADPH oxidation. The complexity of the demethylation reaction should be taken into consideration in any detailed studies of the monooxygenation reaction system.

Animals↗
PubMed1979

Morphine derivatives with diminished opiate receptor potency show enhanced central excitatory activity.

Central excitatory potency of morphine administered by cerebroventricular infusion in enhanced in derivatives substituted at the 3-position (phenolic group) and/or 6-position (alcoholic group). Morphine-3-glucuronide is several hundred times more potent than morphine in evoking dose-related hyperactive motor behavior which can progress to lethal convulsions. Excitatory potencies in decreasing order are: (1) 3-glucuronide; (2) 3-SO4; (3) 3-OAc, 6-OAc (heroin); (4) 6-OAc; (5) 3-OAc; (6) 3-OH, 6-OH (morphine); (7) 3-OCH3 (codeine); (8) 3-OCH3, 6-OCH3 (thebaine). Levorphanol, lacking a 6-OH group, is devoid of excitatory actions. In this series of substituted morphines, there is an inverse relationship between opiate receptor binding potency and central excitatory potency, but codeine and thebaine behave anomalously. These findings are compatible with the hypothesis that morphine acts upon a species of receptor which mediates behavioral and EEG excitation and is distinct from the recognized opiate receptor mediating sedation and analgesia.

Animals↗
PubMed1993

The effects of gender on allergen-induced histamine release in ongoing allergic cutaneous reactions.

BACKGROUND: Marked variability in the amount of histamine released in the first hour of ongoing cutaneous reactions has been noted. This variability occurs even among subjects with similar degrees of skin test reactivity to antigen. METHODS: To determine gender effects on mediator release, we retrospectively compared: (1) skin chamber histamine release after a 0 to 1-hour and 1 to 5-hour exposure to antigen; (2) neutrophil accumulation after 5 hours of antigen exposure and skin test reactivity to antigen, histamine, and codeine in 91 male and 60 female subjects. RESULTS: There was no difference in skin test reactivity to antigen, histamine, or codeine between male and female subjects. However, in the group as a whole, male subjects released higher amounts of histamine in the first hour (74 +/- 4 ng/ml) than female subjects (55 +/- 4 ng/ml), (p < 0.01). When subjects were matched for equivalent skin reactivity to antigen, male subjects who were sensitive to 10 PNU/ml and 1 PNU/ml released more histamine (67 +/- 9 ng/ml and 82 +/- 9 ng/ml) than female subjects (51 +/- 7 ng/ml and 55 +/- 7 ng/ml) (p < 0.05 and < 0.01). In the most sensitive subjects, those with skin sensitivity to 0.01 PNU/ml of antigen, there was not a significant difference between the histamine release in the first hour in male (79 +/- 12 ng/ml) or female (69 +/- 9 ng/ml) subjects. No difference was observed between male and female subjects in either neutrophil or histamine accumulation in the 1- to 5-hour period. CONCLUSIONS: Since the first hour release of histamine is secondary to mast cell activation and the 1- to 5-hour histamine release is secondary to basophil activation, we conclude that the gender of the subject influences the degree of in vivo antigen-induced histamine release from mast cells.

Adolescent↗
PubMed1992

A patient with jejunostomy liberated from home intravenous therapy after 14 years; contribution of balance studies.

A patient with a jejunostomy 100 cm from the duodeno-jejunal flexure, following surgery for Crohn's disease, had needed parenteral fluids at home for 14 years because of a negative intestinal balance of sodium. Measurements were made of her oral intake and intestinal output during study periods each of 2 days. Loperamide 4 mg QDS, codeine phosphate 60 mg QDS and both together put her into positive intestinal fluid balance but sodium balance remained negative. Both drugs used together were more effective than either used alone. Ranitidine 300 mg BD made no significant difference to her intestinal output. 1 litre of a glucose-electrolyte solution (120 mmol sodium) sipped during the day resulted in sodium balance, but only with the addition of loperamide and codeine phosphate was positive sodium balance achieved (mean 44 mmol/day). This therapy allowed her to dispense with parenteral fluids which have been stopped for the last year.

Journal Article↗
PubMed1978

Possible effects of normetabolites on the subjective and reinforcing characteristics of opioids in animals and man.

When an opioid capable of forming active metabolites is administered, the total pharmacology is the result of interactions of the opioid and such metabolites, especially normetabolites. Normetabolites may affect the morphine-like characteristics of certain opioids and thus influence their reinforcement in animals and man. Most opioids, when administered in single doses, are positively reinforcing in addicts. Oral administration, as compared with parenteral, facilitates the formation of normetabolites. When chronically administered, many opioids, including acetylmethadol, meperidine, morphine, codeine, propoxyphene, and levorphanol, show evidence of a longer half-life for their normetabolites. Normetabolites may have aversive characteristics and thus impair positive reinforcement of the parent drug in animals and man. For example, addicts do not like chronic oral morphine or chronic oral codeine. Conversely, methadone, the normetabolites of which are inactive, is well accepted during chronic oral administration. Drugs which inhibit N-demethylation will increase the agonist potency of opioids having inactive normetabolites (e.g., methadone) but will decrease the agonist potency of opioids having more potent normetabolites than the parent (e.g., acetylmethadol). The divergent responses of addicts to single doses of opiates as compared with chronic doses indicate that chronic addiction tests in man are needed befored relative abuse liability can be predicted.

Animals↗
PubMed1987

Identification of opiates in urine by capillary column gas chromatography of two different derivatives.

A capillary gas chromatographic method is described for the identification and confirmation of morphine, codeine, ethylmorphine and 6-monoacetylmorphine in urine. The method was useful for forensic purposes, as morphine and 6-monoacetylmorphine could be measured together with the legal drugs codeine and ethylmorphine. The legal non-prescription drug pholcodine could be detected together with the metabolites normorphine and norcodeine. After extraction and evaporation the opiates were derivatized with either N,O-bis(trimethylsilyl)trifluoroacetamide or pentafluoropropionic anhydride, and both types of derivative were chromatographed on a non-polar capillary column with a nitrogen-phosphorus selective detector. The use of two chemically different derivatives was found to be necessary for the unequivocal identification of all opiates of interest, which were not all separated as a single derivative. If a mixture of opiates was subjected to the two different derivatization agents, the derivatives were eluted in a different order. This improved considerably the selectivity of opiate analysis in urine. Particularly difficult samples would require mass spectrometric confirmation.

Buffers↗