, Volume 30, Issue 4, pp 285-312
Date: 15 Oct 2012

Meptazinol

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Summary

Synopsis: Meptazinol1 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.

Pharmacodynamic Studies: The opioid agonist activity of meptazinol has been demonstrated in standard animal tests, with a profile of activity characteristic of agonist/ antagonist analgesic compounds. The analgesic action is believed in part to be due to reaction of the drug with opioid receptors, and partly due to an effect on central cholinergic transmission. In analgesic potency assays in animals, meptazinol was estimated to be 2 to 5 times less potent than morphine and less potent than, or equipotent to, pentazocine. Studies in healthy subjects reported meptazinol 200mg to be significantly better than placebo but less effective than pentazocine 50mg in providing analgesia from experimentally induced pain. This result contrasts with those seen in patients.

The narcotic antagonist properties of meptazinol have been demonstrated in various animal models, including the appearance of withdrawal symptoms in morphine-dependent monkeys and exacerbation of the ongoing abstinence syndrome in those animals previously withdrawn for 12 to 14 hours.

Although animal studies revealed an antiarrhythmic effect for meptazinol, no clinically relevant haemodynamic changes have been recorded in healthy subjects or in patients receiving meptazinol for pain of various origins. During anaesthesia, however, meptazinol has resulted in significant alterations of blood pressure, cardiac output, mean arterial pressure, heart rate and rate/pressure product in some patients. Improved ventricular performance has also been reported in some patients.

The respiratory depressant activity of meptazinol has been looked at in healthy volunteers, pre- and postoperative patients, obstetric patients and neonates, and patients undergoing anaesthesia. Significant decreases in respiratory rate were seen only in those given premedication and in patients undergoing anaesthetic procedures.

Animal and human studies suggest that the abuse potential of meptazinol is relatively low. Withdrawal of meptazinol following long term administration in monkeys resulted in minimal abstinence signs. Injection of nalorphine in these animals produced very slight signs, while naloxone injection resulted in slightly more intense signs of withdrawal. Opioid-dependent patients on a methadone withdrawal programme did not suffer any typical withdrawal symptoms following administration cf meptazinol.

Pharmacokinetic Studies: Only limited data are available on the pharmacokinetics of meptazinol in man. Oral administration in healthy subjects resulted in rapid absorption, with peak plasma concentrations being reached within 0.5 to 2 hours. However, as with other phenolic analgesics, bioavailability was low (8.69%) due to an extensive first-pass conjugation. No consistent accumulation was encountered following multiple dosing. Intramuscular administration produced peak plasma levels within 30 minutes, with 99% of steady-state concentrations being achieved before the third dose. Similarly, rectal administration resulted in peak levels which were considerably higher than after oral administration, within 30 minutes of dosing.

Animal studies have demonstrated high concentrations of meptazinol in the lung, spleen, liver and kidneys with some penetration into the brain, especially after intravenous administration. Values for apparent volume of distribution averaged 4.99 L/kg, which is similar to that for pethidine. Neonatal/maternal plasma concentration ratios have ranged from 0.57 to 0.96. A relatively low level of protein binding (27.1%) compared with butorphanol (80%) and buprenorphine (96%) was reported in young healthy subjects. Meptazinol is thought to be extensively metabolised with less than 5% of unchanged drug being recovered in the urine, the major metabolite being the glucuronide conjugate of the parent drug. Excretion was fairly rapid and took place chiefly via the urine with over 50% of the dose predominantly in the conjugated form being recovered in the first 9 hours. Elimination half-lives averaged 2 hours or less and plasma clearance values averaged 2.2 L/min. Age seemed to have little influence on the kinetics of meptazinol because, although the elimination half-lives in the elderly were extended (3.39h after a single dose and 4.97h after multiple doses), peak plasma concentrations after single and multiple doses were similar.

Therapeutic Trials: A number of open studies have reported meptazinol to be an effective analgesic when given orally (100 to 700mg daily), intravenously (100 to 200mg daily) or intramuscularly (100mg daily) in patients with moderate to severe pain from a variety of causes. Meptazinol given orally has proved to be significantly more effective than placebo in providing relief of pain in a limited number of patients with moderate to severe pain of different origin.

Meptazinol, usually given orally or intramuscularly, has been compared with morphine, pentazocine, pethidine (meperidine), buprenorphine, papaveretum, paracetamol (acetaminophen), a combination of dextropropoxyphene and paracetamol, and one of hyoscine-N-butylbromide and dipyrone. Generally, similar analgesic effects were evident for meptazinol and pethidine, pentazocine or the combination of dextropropoxyphene and paracetamol; in one or two studies a greater degree of analgesia was produced by meptazinol than pethidine or pentazocine. The single studies involving comparisons of meptazinol with papaveretum and paracetamol found no significant difference in the analgesia produced by the 2 drugs. Only buprenorphine has proven significantly more effective than meptazinol in provision of analgesia. The results of studies with morphine would suggest that meptazinol may be as effective in maintaining analgesia. Duration of effect of meptazinol was less than that of morphine, buprenorphine and, in 1 study, pentazocine, but equal to that of pethidine, and a combination of hyoscine butylbromide and dipyrone. However, onset of action (where recorded) showed meptazinol to be significantly faster than morphine, pentazocine and the hyoscine-N-butylbromide/dipyrone combination.

Meptazinol given intramuscularly in doses of 75 to 150mg has proved to be an effective obstetric analgesic and is without serious adverse effects on the neonate. The use of meptazinol in anaesthesia has not been adequately investigated. One trial reported an adequate response when combined with hyoscine as a premedication, whilst the other found an unacceptably high level of side effects when meptazinol was included in the anaesthetic technique.

Side Effects: The most common side effects associated with meptazinol administration are the gastrointestinal effects such as nausea and vomiting. Drowsiness and dizziness may also be a frequent problem, but the incidence of other central nervous system side effects has been comparatively low. Although a slightly higher incidence of adverse effects was seen during obstetric use, the condition of the majority of newborn babies was unaffected by the drug. Significant decreases in respiratory rate were seen only preoperatively and in anaesthetised patients, while no serious haemodynamic changes were reported following meptazinol administration.

Dosage and Administration: Meptazinol is available for oral and parenteral use. Recommended oral doses for adults are 200mg 3- to 6-hourly as required, with a usual dose of 200mg 4-hourly. Intramuscular doses of 75 to 100mg may be repeated every 2 to 4 hours if required. Slightly higher intramuscular doses (100 to 150mg) are used in obstetrics, calculated on a weight basis of approximately 2 mg/kg. Slow intravenous injections of 50 to 100mg may be repeated 2- to 4-hourly as required. The possibility of withdrawal symptoms precipitated by meptazinol should be looked for in patients who have previously taken opioids for long periods.

Various sections of the manuscript reviewed by: F. Camu, Department of Anaesthesiology, Academish Ziekenhuis Vrije Universiteit, Brussels, Belgium; M. Evans, Whitchurch Hospital, Cardiff, Wales; A. Hedges, Department of Clinical Pharmacology, St Bartholomew Hospital Medical College, London, England; M.B.A. Jackson, Louise Margaret Maternity Wing, Cambridge Military Hospital, England; L. Lasagna, Tufts University, Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, USA; M. Levy, Clinical Pharmacology Unit, Hadassah University Hospital, Jerusalem, Israel; D.G. Moyes, University of Witwatersrand Medical School, Johannesburg, South Africa; N.J. Paymaster, Department of Anaesthetics, Clatherbridge Hospital, Bebington, England; M.T. Rosseel, J.F. and C. Heymans Institute, Voor Farmakodynamie en Terapie, Gent, Belgium; P.J. Slatterly, Department of Pharmacology and Clinical Pharmacology, School of Medicine, The University of Auckland, Auckland, New Zealand; G. Stacher, Psychophysiologisches Laboratorium, Universitätsklinik Wien, Vienna, Austria.
‘Meptid’ (Wyeth).