Meptazinol Hydrochloride
A white or almost white powder. Very soluble in water and in methyl alcohol; freely soluble in alcohol; very slightly soluble in acetone; dissolves in dilute solutions of alkali hydroxides. Store at a temperature not exceeding 25 degrees.
Dependence and Withdrawal
As for Opioid Analgesics.
In assessing the dependence potential of meptazinol, a WHO expert committee noted in 1989 that abrupt discontinuation of chronic meptazinol use precipitated only slight withdrawal signs in animals and that meptazinol did not suppress opioid withdrawal signs and symptoms in humans dependent on morphine. Abuse had not been reported. They considered that the likelihood of abuse was moderate and that international control was not warranted at that time.
Adverse Effects, Treatment, and Precautions
As for Opioid Analgesics in general.
Meptazinol is claimed to have a low incidence of respiratory depression. There have been occasional reports of psychiatric disorders such as hallucinations, confusion, and depression. As meptazinol has both antagonist and agonist properties its effects may be only partially reversed by naloxone, but use of the latter is still recommended in overdosage.
Meptazinol has the potential to precipitate withdrawal symptoms if given to patients who are physically dependent on opioids.
Effects on the respiratory system.
Meptazinol is said to have a relatively low potential for respiratory depression and in healthy subjects was reported to produce substantially less respiratory depression than morphine or pentazocine at usual analgesic doses. However, respiratory depression does occur in anaesthetised patients given meptazinol and the effects on respiration may be similar to those of morphine or pethidine. Compensatory mechanisms may come into play after repeated doses of meptazinol but the intravenous use of meptazinol during anaesthesia should be viewed with as much caution as with any other opioid.
Respiratory arrest occurred after an overdose of 50 meptazinol 200-mg tablets and a quarter of a bottle of whisky. Full recovery eventually followed supportive measures although spontaneous respiration was not re-established by naloxone intravenously to a cumulative total dose of 10 mg.
Interactions
The depressant effects of opioid analgesics are enhanced by other CNS depressants such as alcohol, anaesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Cyclizine may counteract the haemodynamic benefits of opioids. Cimetidine inhibits the metabolism of some opioids, especially pethidine.
The actions of opioids may in turn affect the activities of other drugs. For instance, their gastrointestinal effects may delay absorption as with mexiletine or may be counteractive as with cisapride, metoclopramide, or domperidone. Opioid premedicants such as papaveretum have been reported to reduce serum concentrations of ciprofloxacin.
Alcohol.
Rapid release or dose-dumping of hydromorphone from a modified-release preparation (Palladone; Purdue Frederick, USA) has been associated with the ingestion of alcohol. Health Canada has warned that this interaction may occur with all modified-release formulations of opioid analgesics. Licensed drug information for a modified-release preparation of morphine sulfate (Avinza; Ligand, USA) also warns against such use (see Interactions of Morphine.
Antivirals.
Interactions between opioid analgesics and ritonavir, other HIV-protease inhibitors, or reverse transcriptase inhibitors are complex, and the results of the limited number of studies and reports in vivo have not always borne out predictions about the nature of potential interactions.
Substantial decreases in the area under the plasma concentration-time curve (AUC) and in the plasma concentration have been reported for both methadone and for pethidine when given with ritonavir. In the case of pethidine, however, plasma concentrations of the toxic metabolite norpethidine are greatly increased, and the manufacturers of ritonavir counsel against such combined use. The HIV-protease inhibitors amprenavir and nelfinavir may also reduce methadone concentrations and provoke withdrawal symptoms in dependent patients. Patients requiring methadone may need an increase in the dose of this drug if given with amprenavir, nelfinavir, or ritonavir. Similar interactions with methadone have been noted with the NNRTIs efavirenz and nevirapine and the nucleoside reverse transcriptase inhibitor abacavir; again, a dose increase in methadone may be required. The HIV-protease inhibitors indinavir and saquinavir do not appear to interact with methadone. Ritonavir is predicted to reduce plasma concentrations of morphine.
In contrast, an increase in AUC and in elimination half-life has been reported in subjects given fentanyl with ritonavir. The manufacturers of ritonavir also consider that increased plasma concentrations of dextropropoxyphene and tramadol, with an increased likelihood of opioid toxicity, may occur if either drug is given during ritonavir treatment.
Histamine H2-antagonists.
Histamine H2-antagonists may enhance the effects of some opioid analgesics. Cimetidine was reported to alter the clearance and volume of distribution of pethidine whereas ranitidine did not. Morphine has been considered less likely to interact with cimetidine than pethidine because of differences in metabolism. However, although cimetidine did not affect the disposition of morphine in healthy subjects in a study there have been isolated reports of possible interactions between morphine and H2-antagonists; apnoea, confusion, and muscle twitching have been associated with cimetidine plus morphine, and confusion associated with ranitidine with morphine. There has also been a report of a patient receiving regular analgesia with oral methadone and subcutaneous morphine who became unresponsive 6 days after starting cimetidine for prophylaxis of peptic ulcer; treatment with naloxone was required.
Alcohol.
The FDA received data from pharmacokinetic studies in healthy subjects which showed that significantly higher peak plasma concentrations of hydromorphone were achieved, as a result of dose-dumping, when alcohol was ingested with once-daily hydromorphone extended-release capsules (Palladone; Purdue Frederick, USA); these increases were considered potentially lethal, even in opioid-tolerant patients. Subsequently, this formulation was voluntarily withdrawn by the US manufacturer in July 2005.
Pharmacokinetics
After oral doses of meptazinol peak plasma concentrations have been achieved within 0.5 to 2 hours, but bioavailability is low since it undergoes extensive first-pass metabolism. Systemic availability is improved after rectal doses. Peak plasma concentrations have been achieved 30 minutes after rectal or intramuscular use. Plasma protein binding has averaged only about 27%. Elimination half-lives of about 2 hours have been reported. Meptazinol is extensively metabolised in the liver and is excreted mainly in the urine as the glucuronide conjugate. Less than 10% of a dose has been recovered from the faeces. Meptazinol crosses the placenta.
The elderly.
A lower clearance and longer elimination half-life has been reported for meptazinol in elderly patients, but dosage reduction was not considered warranted on pharmacokinetic grounds. Mean half-lives in elderly and young subjects were 3.39 and 1.94 hours respectively following single oral doses and 2.93 and 2.06 hours respectively after intravenous doses.
Hepatic impairment.
Oral bioavailability of meptazinol appeared to be enhanced in patients with liver disease. After a single oral dose of meptazinol mean peak plasma concentrations were 184 nanograms/mL, 131 nanograms/mL, and 53 nanograms/mL in cirrhotic patients, patients with non-cirrhotic liver disease, and patients with normal liver function, respectively, although there was no evidence of accumulation after chronic dosing. There were no significant differences in plasma clearance after an intravenous dose. Reduced oral doses of meptazinol might be advisable in cirrhotic patients.
Pregnancy.
In women given an intramuscular injection of 100 to 150 mg during labour, meptazinol was found to cross the placenta readily but was rapidly eliminated from the neonate. This contrasted with pethidine which was known to be excreted very slowly from neonates. As in the adult, elimination of meptazinol by the neonate appeared to take place mainly by conjugation with glucuronic acid. A half-life of 3.4 hours, similar to that in adults, has been reported in the neonate, in contrast to 22.7 hours for pethidine in neonates.
Disposition of meptazinol appears not to be significantly affected by pregnancy. Mean half-lives of 1.36 and 1.68 hours were reported in pregnant and non-pregnant women, respectively, compared with 2.06 hours in men.
Uses and Administration
Meptazinol is a mixed opioid agonist and antagonist with partial opioid agonist activity at the ?1 opioid receptor; it also has cholinergic activity. Meptazinol is used in the treatment of moderate to severe pain. It has a shorter duration of action than morphine.
Meptazinol hydrochloride is given by mouth or by intramuscular or intravenous injection; doses are expressed in terms of the base. Meptazinol hydrochloride 115.6 mg is equivalent to about 100 mg of meptazinol. For the short-term treatment of moderate pain meptazinol is given by mouth in a dose of 200 mg every 3 to 6 hours. The intramuscular dose is 75 to 100 mg given every 2 to 4 hours; for obstetric pain a dose of 2 mg/kg (100 to 150 mg) may be used. Meptazinol is also given by slow intravenous injection in doses of 50 to 100 mg every 2 to 4 hours.
Administration.
Epidural route.
Epidural meptazinol 90 mg for postoperative pain was reported to be superior to an intramuscular dose of 90 mg. However, in another study a 30-mg dose was ineffective and associated with an unacceptable incidence of adverse effects. A 60-mg dose was also found to be ineffective because of its short duration of action.
The UK manufacturers state that the injectable formulation is not suitable for epidural or intrathecal use.
Administration in hepatic impairment.
See under Pharmacokinetics for a suggestion that doses may need to be reduced in patients with cirrhosis.