Propiram

Abstract

Synopsis

Propiram is an orally administered opioid analgesic with partial morphine-like agonist and weak antagonist properties. Analgesic efficacy of propiram, usually 50 or 100mg, appears comparable to that of standard dosages of other oral opioid drugs [i.e. pentazocine, pethidine (meperidine)] in patients with acute pain of moderate to severe intensity arising from various gynaecological and surgical procedures, and may be superior to codeine in gynaecological and postoperative dental pain. Some evidence of a more rapid onset of action for propiram than for these opioid agents, and a longer duration of action for propiram than for codeine, is encouraging but remains to be substantiated in more extensive clinical use. The tolerability profile of propiram resembles those of others in its class, with drowsiness, nausea and vomiting, and dizziness experienced most frequently in controlled trials. The apparently low propensity of propiram for development of physical dependence and psychotomimetic effects requires confirmation with wider clinical experience.

Available data thus indicate that propiram is an effective, orally administered opioid analgesic suitable for providing relief of acute moderate to severe pain arising from various surgical or gynaecological procedures, and that the drug is likely to become a useful alternative in such conditions where opioid analgesia is appropriate.

Pharmacodynamic Properties

Propiram binds with relatively specific affinity to opioid μ receptors, which modulate supraspinal and spinal analgesia, but is inactive at δ receptors. Binding activity of the R-enantiomer is about 2.5% that of morphine. Thus, propiram exerts its analgesic effect by activating pathways responsible for alteration of pain perception which are mediated via opioid receptors, and involve interaction between opioid, adrenergic and serotonergic systems.

Propiram is a partial agonist, as evidenced by its activity at the μ receptor and by its ability to suppress and precipitate abstinence in morphine-dependent dogs, monkeys and humans. It is active in various animal models of morphine agonism and antagonism. As an agonist in humans, propiram is judged to be 1/7 to.1/10 as potent as morphine. As an antagonist it is approximately 1/200 as potent as nalorphine in humans and 1/1789 as potent as naloxone in dogs.

In standard pain models in animals, the milligram potency of propiram administered orally or subcutaneously was less than that of morphine, butorphanol and buprenorphine, and similar to that of codeine, dextropropoxyphene, and pethidine (meperidine). Experience in patients with pain (see Clinical Use) confirms early findings of analgesic efficacy for propiram 25 to 30mg orally as a single dose in human pain models.

In common with other partial agonist opioid analgesics possessing morphine-like agonist activity, propiram displays potential for development of physical dependence. Propiram is self-administered in humans and monkeys, substitutes for morphine in individuals dependent on low doses of the latter drug, and a mild abstinence syndrome has developed following propiram withdrawal in direct addiction studies in humans (past addicts). In contrast, in volunteers dependent on high dose morphine (240 mg/day), propiram does not serve as a sufficient substitute, and no patients in clinical trials have exhibited signs of physical dependence. This, and the preliminary finding that propiram in therapeutic dosages has shown apparently little tendency to cause psychotomimetic effects, lower its physical dependence and abuse potential relative to pure morphine agonists. However, definitive conclusions regarding these effects await broadscale experience with the drug.

Respiration in humans is depressed by propiram in a dose-related fashion, and the depressant effect of propiram 50mg intramuscularly was similar to that of morphine 10mg in healthy volunteers. Confirmation is required of limited data suggesting there may be little influence of the drug on cardiovascular parameters or on psychomotor function in healthy volunteers.

In rat intestines examined ex vivo, propiram administered subcutaneously or orally inhibited intestinal motility, but to a smaller extent than codeine or pethidine, implying a lesser constipating effect. The drug was at least as effective as parenteral codeine in suppressing cough when injected intravenously in cats and subcutaneously in dogs.

Pharmacokinetic Properties

Absorption of propiram from an oral tablet is virtually complete. Peak plasma propiram concentrations (C_max) of about 0.3 mg/L after a single 50mg dose are attained within 0.5 to 1.5 hours. C_max and area under the plasma concentration-time curve did not change after ingestion of propiram 25mg twice daily for 10 days in 4 healthy volunteers, indicating no drug accumulation after multiple doses.

Tissue concentrations after propiram administration in animals are highest in liver, kidney and spleen, but concentrations in the brain are similar to, or lower than, those in plasma. Propiram is detectable in human milk in quantities 2 to 3 times greater than in maternal plasma. The relatively large volume of distribution (2.3 L/kg after a single 50mg tablet) indicates extensive distribution and metabolism; indeed, propiram is largely biotransformed via the liver to its principal metabolite N-[2-(2-pyridylamino)-propyl]-N-propionyl-5-aminovaleric acid. Of the one-third of the dose retrievable as parent drug, 97% is recovered within 24 hours. Total body clearance of propiram (26.6 L/h) is greater than renal clearance (6.3 L/h), indicating extrarenal (i.e hepatic) mechanisms are important in elimination.

Approximately 80% of orally administered propiram 25 to 100mg is excreted renally and 20% via the faeces. The elimination half-life of propiram is about 5 to 7 hours.

Clinical Use in Pain States

Propiram is an effective analgesic when administered orally. Propiram 125mg orally and 100mg intramuscularly are considered equivalent in potency to morphine 10mg intramuscularly. A doseresponse relationship for analgesia is evident for propiram over the range 50 to 150mg. The analgesic efficacy of orally administered propiram was first studied in the 1970s in patients with mainly acute, but also chronic, moderate to severe pain of various aetiologies including cancer pain, who received the drug for periods usually greater than one week in large uncontrolled trials.

More recently, in patients with moderate pain arising from surgical procedures including cholecystectomy and orthopaedic surgery, propiram 50mg produced similar analgesia as pentazocine 50mg and was at least as effective as codeine 60mg and superior to dextropropoxyphene 65mg, when all agents were administered orally. More severe pain appeared to require higher dosages for all analgesics. There is some evidence for a longer duration of action for propiram than for codeine in these patients. Propiram 50mg as a single oral dose tended to be less effective than aspirin 650mg but was more beneficial and longer-lasting than codeine 60mg or placebo in ameliorating postoperative dental pain in 1 well designed trial.

Single doses of propiram 50mg administered orally have been found to be superior to placebo, similar to pentazocine 50mg and pethidine 100mg, and tended to be more effective than codeine 60mg and dextropropoxyphene 65mg in alleviating acute moderate to severe postoperative gynaecological pain. Propiram displayed a faster onset (≈0.5h) but generally similar duration of action (at least 4 hours) as these agents, although there was some suggestion of longer duration of effect with propiram than with codeine in women with severe pain. Equivalent efficacy was demonstrated for propiram 50 or 100mg and pethidine 100mg when given repeatedly for up to 5 days.

Limited published evidence has shown cancer patients with acute pain to respond to propiram 50 to 200mg, and in a few patients with chronic cancer pain propiram 50 or 100mg for up to 10 days was equivalent to levorphanol 2mg.

Tolerability

The most common adverse effects observed during administration of single doses of propiram 50 to 200mg resemble those associated with other opioid drugs of the agonist-antagonist class: most frequently experienced events in controlled trials have been drowsiness (occurring in 20 to 40% of patients), nausea/vomiting (7 to 22%), dizziness (6 to 13%), sweating (0.7 to 9%) and headache (3 to 5%).

About 45% of all propiram recipients in published and unpublished trials report at least one adverse event. This is in the range of the overall incidence cited for codeine 60mg (25 to 45%), pentazocine 50mg (42%), and aspirin 650mg (35%) in published literature comparing propiram with these agents. Apart from one instance of hallucinations, psychotomimetic effects were not experienced by propiram recipients or, indeed, by patients receiving any of the comparator opioid drugs.

In longer term uncontrolled trials, dry mouth has been reported by as many as 76% of patients and the incidence of constipation has ranged from 66% in hospitalised patients to 27% in outpatients. No changes in laboratory tests have been associated with propiram administration.

Dosage and Administration

The recommended dosage of propiram in patients with acute moderate to severe pain is 50 to 100mg orally, repeated every 4 to 6 hours as necessary.