Chronic catheterization of the epidural space in rabbits: a model for behavioural and histopathological studies. Examination of meptazinol neurotoxicity.

A technique of epidural catheterization in rabbits is described. Twelve albino rabbits received a totally implanted epidural catheter system. The system was implanted surgically, and the functioning of the system tested for a period of 3 months. X-ray examinations following epidural contrast injections showed a distribution up to Th4 following 1.5 ml and Th8-9 following 1.0 and 1.25 ml. Epidural injection of lidocaine throughout the study period proved the system to be functioning for all 3 months. Another 12 rabbits were included for the neurotoxicological examinations following epidural catheterization, without any injections (three rabbits), epidural injections of saline (four rabbits) and meptazinol (five rabbits) once a day for 14 days. Histopathological examinations showed a fibrous cocoon, at the tip of the catheter, in all rabbits. In the group of rabbits which did not receive any injections, the cocoon was slightly infiltrated with leukocytes and local depression of the spinal cord was observed in one rabbit. In the saline-injected group this infiltration was more pronounced and in one rabbit it extended into the meninges. Three rabbits showed local depression of the spinal cord and local myelopathy of the white matter in the area adjacent to the cocoon. In the group of rabbits receiving meptazinol, three out of five had local depression and myelopathy of the white matter. In this group these findings were more pronounced. In two rabbits the myelopathy extended transversely through the white matter into the grey matter of the spinal cord. The number of pathological changes in the group receiving meptazinol was significantly higher compared to the control and placebo groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Post-surgical pain relief with zero-order intravenous infusions of meptazinol and morphine: a double-blind placebo-controlled evaluation of their effects on ventilation.

A double-blind, placebo-controlled study has been made of the analgesic and respiratory effects of constant rate infusions of meptazinol and morphine in 30 patients after abdominal surgery. Group I received meptazinol, loading dose 50 mg followed by i.v. infusion 0.5 mg.kg-1.h-1, Group II received morphine, loading dose 5 mg and then an infusion of 0.05 mg.kg-1.h-1, and Group III received saline. After recovery from inhalation anaesthesia (without opiates or a local anaesthetic) pain relief and chemoreceptor carbon dioxide tolerance were assessed before and at various times after starting the analgesic infusion. A similar degree of pain relief was found after 10 min in Groups I and II, which lasted until the end of observation period (20 h). Heart rate and systolic and diastolic blood pressures were lower in Group II than in Groups I and III, and respiratory rate fell in Groups I and II. After 6 h arterial carbon dioxide tensions (PaCO2) became significantly higher in Group II than Group III. The maximum percentage fall in mean tidal volume (VT) and expired minute volume (VE) from the preinjection values was significant in Groups I and II. End-tidal carbon-dioxide (PETCO2) and PaCO2 were significantly higher after 20 h of infusion in Group II compared to Group I. The slope of VE/PETCO2 (mean value of S) was increased in Group I and it was significantly reduced in Group II. Analysis of derived variables, such as the CO2 intercept (CO2I) and minute ventilation at 7 kPa (VE7), indicated a shift to the right of the slopes in Groups I and II, initially more so in Group I.(ABSTRACT TRUNCATED AT 250 WORDS)

Meptazinol and morphine in postoperative pain assessed with a new method for onset and duration.

Meptazinol, m-(3-ethyl-1-methyl-hexahydro-1-H-azepin-3-yl) phenol hydrochloride is a centrally active opioid analgesic with a specificity for the mu-1 receptor. It has been reported to lack many of the side effects commonly observed with morphine and morphinelike drugs in man. The objective of this study was to assess the analgesic efficacy and safety of meptazinol (50 mg and 100 mg) relative to morphine (5 mg and 10 mg) when administered intramuscularly for the treatment of postoperative pain. In addition, a new clinical method for measuring onset and duration and a statistical technique for evaluating the study data are presented. One hundred and seventeen patients were evaluated for 6 hours in a randomized double blind, single dose, parallel-groups trial. Estimates of relative potency for hourly pain and relief parameters, and the summary variables sum of pain intensity differences (SPID) and total pain relief (TOTPAR) were performed. The estimate of relative potency of meptazinol to morphine for pain relief was 0.19 at 1/2 hour (i.e. 100 mg of meptazinol was approximately equivalent to 20 mg of morphine). Thereafter, there was a rapid decline of efficacy for meptazinol, with a relative potency estimate of 0.12 at 1 hour and 0.06 at 2 hours. The distribution functions for several time related events were estimated including time to onset, duration and time to remedication. The two drugs had approximately equal onset, but meptazinol had significantly shorter duration. More patients on meptazinol required remedication with a rescue analgesic and at an earlier time than patients on morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia-induced respiratory depression: comparison of meptazinol and morphine in the postoperative period.

Forty-nine patients undergoing elective total hip replacement received either morphine or meptazinol for postoperative analgesia from a patient-controlled analgesia apparatus. Ventilatory rate and volume and arterial oxyhaemoglobin saturation were recorded continuously for the first 24 h following surgery. Episodic hypoxaemia was seen in both groups, associated with disturbances in ventilatory pattern. There was no significant difference in the incidence or severity of observed hypoxia between the groups, or with respect to the class of ventilatory disturbance. Mean linear analogue scores for pain and nausea were significantly (P less than 0.05) greater in the meptazinol group than in the morphine group 8 h after operation, but did not differ significantly at any other time. The mean number of demands for analgesic drugs was similar in the two groups. The meptazinol group had a greater requirement for anti-emetic drugs than the morphine group (P less than 0.05). It was concluded that meptazinol and morphine in equianalgesic doses had similar effects on ventilation in the postoperative period.

Salutary and detrimental effects of the (+)- and (-)enantiomers of meptazinol in anesthetized rats subjected to hemorrhagic shock.

The effects of the two enantiomers of the opioid mixed agonist-antagonist meptazinol on mean arterial pressure (MABP), heart rate (HR), and survival time were investigated in pentobarbitone-anesthetized rats subjected to hemorrhagic shock. Following intravenous administration of (+)meptazinol (0.5 mg kg-1) to shocked animals (MABP, 30.0 +/- 0.2 mm Hg), there was significant and gradual elevation of MABP, which at the time the experiment was terminated did not differ significantly from preshock values. In addition, survival was prolonged by up to 7 days. Paradoxically, similar doses of (-)meptazinol produced further falls in MABP, significantly so at 60 min posttreatment. Likewise, the drug produced a slow progressive and significant decline in HR which culminated in premature death (mean survival time, 74.3 +/- 5.9 min, compared with a control value of 104.4 +/- 8.8 min; p less than 0.05). Our results demonstrate that the two enantiomers of meptazinol have opposing effects on hemorrhagic shock sequelae in the rat. It is surprising, in view of its known opioid antagonistic properties, that (-)meptazinol exerted a detrimental effect.

A double-blind comparison of ibuprofen, placebo and ibuprofen with meptazinol in soft tissue rheumatism.

The administration of ibuprofen potentiates and prolongs the analgesic effect of meptazinol when the two drugs are given simultaneously to mice. A double-blind three-way crossover study of placebo, ibuprofen (1600 mg/day) and ibuprofen (1600 mg/day) plus meptazinol (400 mg/day) was carried out in 45 patients with soft tissue rheumatism to see if the same potentiation could be demonstrated in man. Treatment order was randomized and each regimen was given for 2 weeks preceded by 1 week on paracetamol alone. Assessments were made, on entry and after each treatment period, of pain parameters using visual analogue or verbal rating scales. Patients' overall impression and final preference showed both active treatments to be better than placebo and demonstrated a slight preference for the combination.

Meptazinol and pentazocine: plasma catecholamines and other effects in healthy volunteers.

1. This double-blind, random-order study was designed to compare the clinical effects and the plasma catecholamine responses after i.v. administration of meptazinol at doses 0.7 and 1.4 mg kg-1, pentazocine at doses 0.3 and 0.6 mg kg-1 and saline placebo to six healthy volunteers. 2. Mean arterial pressure was not affected by either drug. Heart rate showed slight drug-related changes. Respiratory rate fell slightly with both drugs, but independently of dose. 3. The critical flicker fusion threshold-test and Maddox wing readings could both clearly differentiate active drugs from placebo. Meptazinol caused more nausea and dysphoria as expressed with visual analogue scales. Both analgesics caused short-lived feelings of euphoria. 4. After pentazocine plasma noradrenaline increased almost two-fold in 10-20 min. The effect of meptazinol was slightly smaller, whereas meptazinol caused a pronounced increase in plasma adrenaline concentrations in two of six subjects. Pentazocine had a smaller, but significant effect on plasma adrenaline. 5. We conclude that the effects of meptazinol in healthy volunteers do not differ markedly from those of pentazocine, although it may cause more nausea and dysphoria. The pronounced increase in plasma adrenaline concentrations in two of six subjects calls for caution in its use in patients with cardiac diseases.

[Meptazinol, a new analgesic. Hemodynamic and respiratory effects]. / Meptazinol, ein neuartiges Analgetikum. Hämodynamische und respiratorische Effekte.

In a prospective, randomized double-blind study the hemodynamic and respiratory effects of i.v. meptazinol, a new synthetic narcotic agonist-antagonist analgesic given in 2 dosages (2 mg/kg and 4 mg/kg), were compared over 15 min to a control group that received 0.9% saline solution as placebo. In a total of 80 patients scheduled for elective aortocoronary bypass surgery, the study was performed before and during general anesthesia and during extracorporeal circulation (ECC). A dose-dependent increase in mean arterial pressure (MAP) and total systemic resistance (TSR) were the predominant hemodynamic effects of meptazinol before and during anaesthesia (Tables 1 and 2). Within the study period no change in heart rate (HR) or cardiac index (CI) could be observed. Directly measured left ventricular parameters revealed a significant increase in left ventricular pressure (LVEDP, and dp/dtmax (Fig. 1). During ECC meptazinol injection was followed by a dose-dependent increase in perfusion pressure, indicating a direct vasoconstrictive effect; no influence on the capacitance system ("venous pooling") could be observed (Fig. 2). In the spontaneously breathing, premedicated patients (morphine hydrochloride 0.15 mg/kg and flunitrazepam 0.03 mg/kg) paO2 increased and paCO2 decreased, especially after injection of the higher dosage of meptazinol; there was no influence on intrapulmonary right-to-left shunting (Qs/Qt).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the effects of maternally administered meptazinol and pethidine on neonatal acid-base status.

A randomized double-blind study compared the effects of equi-analgesic doses of maternally administered meptazinol (1.5 mg/kg) and pethidine (1.5 mg/kg) on neonatal acid-base status. Heel-prick samples were taken for assessment of acid-base status at 10 and 60 min after delivery. Maternal antenatal history, details of labour and neonatal status at delivery were also recorded. Meptazinol produced less neonatal respiratory depression than pethidine: the mean 10 min acid-base data from 16 infants whose mothers received pethidine were indicative of a respiratory acidosis (pH 7.13, SD 0.08, PCO2, 9.11, SD 2.2 kPa; standard bicarbonate 22.3, SD 3.1 mmol/l). This was not evident in the mean acid-base data from 16 infants whose mothers received meptazinol (pH 7.23, SD 0.07; PCO2 6.83, SD 1.6 kPa; standard bicarbonate 20.9, SD 4.2 mmol/l). The mean pH and PCO2 in the two treatment groups were significantly different (P less than 0.002) at 10 min but not at 60 min after delivery.

Studies on performance with aspirin and paracetamol and with the centrally acting analgesics meptazinol and pentazocine.

Effects of aspirin (325 and 650 mg) and paracetamol (500 and 1000 mg), and of the centrally acting analgesics meptazinol (100 and 200 mg) and pentazocine (25 and 50 mg) on visuo-motor coordination and dynamic visual acuity, together with critical flicker fusion, digit symbol substitution, complex reaction time and subjective assessments of mood, were studied from 0.75-2.0 h after ingestion by seven healthy female adults. The study was double-blind and placebo controlled, and triprolidine (10 mg) was used as the active control. No effects of meptazinol and paracetamol on performance were observed. Pentazocine (25 mg) impaired performance on digit symbol substitution (p less than 0.05) and aspirin (650 mg) appeared to have shortened complex reaction time (p less than 0.05). Meptazinol (100 mg) increased the component of mood assessments related to wakefulness (p less than 0.05). Impaired performance with pentazocine may involve opioid receptor activity, while the apparent alerting effect of meptazinol may relate to its cholinergic activity. The possible effect of aspirin on reaction time needs to be confirmed.

Traditional Chinese acupuncture: a potentially useful antiemetic?

Two consecutive studies were undertaken to evaluate the effectiveness of acupuncture as an antiemetic used in addition to premedication with opioids in patients undergoing minor gynaecological operations. In the first study 25 of the 50 patients underwent acupuncture immediately after premedication with 100 mg meptazinol, the rest receiving the drug alone, and in the second 75 patients were allocated randomly to one of three groups: a group receiving 10 mg nalbuphine and acupuncture, a group receiving premedication and dummy acupuncture, and a group receiving premedication alone. Manual needling for five minutes at the P6 acupuncture point (Neiguan) resulted in a significant reduction in perioperative nausea and vomiting in the 50 patients who underwent acupuncture compared with the 75 patients who received no acupuncture. These findings cannot be explained, but it is recommended that the use of acupuncture as an antiemetic should be explored further.

The influence of cyclizine and perphenazine on the emetic effect of meptazinol.

The effectiveness of 50 mg cyclizine and 2.5 mg perphenazine against the emetic sequelae of 100 mg meptazinol were studied in a randomized double-blind placebo-controlled trial. Three groups of 40 women received the opioid, together with an anti-emetic by i.m. injection, as premedication prior to minor gynaecological surgery. Beneficial or noxious effects were noted at standard time intervals and anaesthesia standardized as incremental methohexitone with nitrous oxide/oxygen. In the placebo group, 33 out of 40 subjects experienced either nausea or vomiting at some time after the opioid. Cyclizine, 50 mg, provided significant reduction of emetic tendency in both pre-operative and post-operative phases of the study with 22 out of 40 subjects experiencing nausea or vomiting overall. Perphenazine, 2.5 mg, showed no useful anti-emetic effect. Both anti-emetics increased the soporific effect of premedication at the 90-min interval. Subjects receiving perphenazine experienced significantly more dizziness than those of other groups.

Meptazinol--a cause of respiratory depression in general anaesthesia.

The respiratory effects of meptazinol 1 mg kg-1 have been compared with those of pethidine 0.5 mg kg-1 and 1 mg kg-1 in a double-blind trial in 30 patients undergoing arthroscopic meniscectomy under general anaesthesia. Respiratory depression was seen in all treatment groups. Pethidine 1 mg kg-1 produced respiratory depression which was greater than that produced by meptazinol 1 mg kg-1. The least depressant respiratory effects were seen in the group receiving pethidine 0.5 mg kg-1. We submit that the measurement of tidal volume enhances the assessment of the respiratory effects of analgesic drugs during anaesthesia.

Meptazinol. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy.

Meptazinol is a new opioid-type analgesic with mixed agonist/antagonist properties. It may be given orally, intravenously or intramuscularly. In studies in patients with moderate to severe pain of various aetiologies, usually following surgery or in obstetrics, the characteristics of analgesia with meptazinol were comparable to those seen with equianalgesic doses of pentazocine, pethidine or a combination of dextropropoxyphene and paracetamol. Preoperative use and use as a component of anaesthesia require further investigation before conclusions may be drawn on its effectiveness in these areas. Onset of action, recorded in a few studies, was faster than that with the other analgesics but duration was shorter than that of morphine, buprenorphine and pentazocine. Only a small number of patients with chronic pain have received long term therapy with meptazinol; in such patients there was no need for increased doses as treatment progressed. Respiratory depression has only been observed in patients receiving meptazinol as a premedication or while undergoing anaesthesia. Similarly any haemodynamic changes have been limited to preoperative patients or patients undergoing anaesthesia. Like other agonist/antagonist analgesic drugs, the abuse potential of meptazinol seems relatively low, but only wider clinical use for longer periods can establish this with certainty. The most commonly reported side effects have been gastrointestinal in nature, and although the incidence of central nervous system side effects has been relatively low, drowsiness and dizziness have caused occasional problems. Thus, meptazinol is a relatively potent but safe addition to the analgesics available for treatment of the patient with moderate to severe pain.

Epidural meptazinol for pain relief after lower abdominal surgery.

A preliminary investigation is reported into the use of epidural meptazinol for pain relief in 20 patients after major lower abdominal (gynaecological) surgery. Analgesia was rapid in onset (15 minutes), had a median duration of 124 minutes (interquartile range 85-212 minutes) after a single dose of 30 mg and a median duration of 122.5 minutes (interquartile range 70-127 minutes) after a single dose of 60 mg. Overall pain relief, as judged by the patients themselves, was satisfactory in 19 out of the 20 cases. At 30 minutes and 45 minutes pain relief was significantly better with the 60 mg than the 30 mg dose (p less than 0.02). No drug-related adverse effects were observed during the study.

Intramuscular meptazinol and morphine in postoperative pain.

Meptazinol is an agonist-antagonist opioid analgesic believed to be unique in its selectivity for mu1 (high affinity) receptors and its cholinergic activity. Our objectives were to determine the relative analgesic potency of intramuscular meptazinol and morphine and to compare mood and side effects in 102 patients with cancer who have postoperative pain. Meptazinol (50, 100, and 200 mg) and morphine (4, 8, and 16 mg) were given for moderate to severe pain in a double-blind, randomized but balanced, incomplete block design. Serial multiple assessments of pain, relief, mood, and side effects were made. The most precise estimates of relative analgesic potency indicate that meptazinol is equivalent to 10 mg morphine at 120 mg (95% confidence interval 80 to 170 mg) for peak effect and at 175 mg (95% confidence interval 125 to 270 mg) for total effect. Mean (+/- SE) times to peak effect and to remedication were 0.9 +/- 0.1 and 3.6 +/- 0.2 hours for meptazinol and 1.4 +/- 0.1 and 4.8 +/- 0.4 hours for morphine at equianalgesic peak effects. The percentages of subjects with one or more side effects were 18, 49, and 73 for graded meptazinol doses and 32, 49, and 65 for graded morphine doses. Mean numbers of side effects per subject were 0.3, 1.5, and 3.5 for meptazinol and 0.5, 0.7, and 1.7 for morphine. Profiles of side effects differed. Mood improvement and overall satisfaction were dose related and greater for morphine than for meptazinol. Side effects may limit the use of meptazinol in doses that relieve severe postoperative pain.

Oral meptazinol--United Kingdom experience.

An oral formulation of meptazinol has been developed and marketed in the United Kingdom. The 200 mg tablet has a potency similar to dextropropoxyphene 32.5 mg/paracetamol 325 mg or pentazocine 50 mg. Nausea is the major side effect and constipation and dysphoria are virtually absent. Though a variable first pass metabolism restricts its potential for use in severe pain, oral meptazinol provides effective analgesia in mild or moderate pain.

A study of the effect of meptazinol on fetal heart rate patterns.

A study was carried out in 40 women undergoing labour to investigate the effect of 100 to 150 mg meptazinol intramuscularly, given alone for the relief of labour pain, on fetal heart rate patterns. Patients were monitored continuously using a fetal scalp electrode attached to a fetal monitor, and fetal heart rate patterns recorded on the cardiotocograph. Traces were interpreted for 2 hours preceding and 2 hours after administration of meptazinol using a 12-point scoring system to quantify the variables of baseline rate and variability and the presence or absence of variable or late decelerations. All babies were born live and, except for 1 delivered by emergency caesaraen section under general anaesthesia, none had an Apgar score less than 8 at 1 minute. Analysis of the cardiotocograph traces showed that adverse changes, such as loss of variability, were not significantly associated with the use of meptazinol.