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Flupirtine is a novel non-opiate centrally acting analgesic agent with muscle relaxant properties, advocated for use in a number of pain states. Preliminary evidence suggests that flupirtine 100 to 200mg orally or 150mg rectally 3 to 4 times daily (maximum daily dose 600mg) is more effective than placebo in relieving moderate acute pain of various types. For the relief of pain due to surgery, traumatic injury, dental procedures, headache/migraine and abdominal spasms, flupirtine has proved at least as effective as the opiate analgesics codeine, dihydrocodeine and pentazocine, the nonsteroidal anti-inflammatory agents suprofen, diclofenac and ketoprofen, as well as dipyrone and paracetamol (acetaminophen). Although evidence to support a role in the treatment of chronic pain is limited, flupirtine has been found as effective as pentazocine in short term trials of patients with muscular or neuralgiform pain, dysmenorrhoea, soft tissue rheumatism or cancer pain.
The safety profile of flupirtine has not yet been fully established, although initial evidence suggests that adverse reactions, while frequent, are usually minor in nature. The most common reactions are drowsiness, dizziness, dry mouth and various gastrointestinal complaints, In comparison with opiate drugs, flupirtine appears to produce fewer central nervous system effects, no respiratory or cardiovascular depression, and no overt tolerance or physical dependence on prolonged administration.
If these initially favourable results are confirmed in larger long term trials, then flupirtine would appear to represent an effective analgesic for the relief of moderate pain, particularly that of musculoskeletal origin.
Flupirtine is a centrally acting analgesic which, unlike the opiates or more peripherally acting drugs such as diclofenac, appears to modify pain perception via activation of descending mono-aminergic pathways. Flupirtine has demonstrated analgesic activity in a number of animal models: while less potent than morphine, buprenorphine, methadone and dextromoramide, flupirtine was as potent as pentazocine and more potent than pethidine (meperidine), dextropropoxyphene, codeine, phenacetin and paracetamol (acetaminophen). In healthy volunteers, oral flupirtine exhibited an analgesic potency similar to that of pentazocine, with dose-dependent decreases in pain intensity occurring within 30 to 60 minutes and peaking at 1.5 to 2 hours postdose.
Flupirtine displays muscle relaxant activity at doses similar to those producing analgesia, an effect possibly mediated via GABA-ergic mechanisms. The potency of flupirtine is comparable to that of the GABA agonist baclofen and the benzodiazepines diazepam and tetrazepam. Flupirtine additionally possesses anticonvulsant activity, but no appreciable anti-inflammatory or antipyretic activity.
Flupirtine produces a dose-related central nervous system depression, although the degree of sedation noted with usual therapeutic doses is less than that with diazepam, pentazocine or antihistamines, and significant impairment of psychomotor performance has not been observed. Flupirtine does not produce clinically significant respiratory or cardiovascular depression. Preliminary evidence from animal and human studies suggests that flupirtine confers little risk of tolerance or dependence. The sedation and euphoria evoked by high doses of flupirtine is mitigated by dysphoric feelings of tension, anxiety and confusion, suggesting a low abuse potential.
Flupirtine is rapidly absorbed from the gastric mucosa, appearing in the plasma within 15 to 30 minutes and reaching a peak plasma concentration of approximately 0.8 mg/L at 1.6 to 2 hours after an oral 100mg dose. Following a rectal dose of 150mg, a similar peak plasma concentration is reached in 5.7 hours. The oral and rectal bioavailabilities of flupirtine are 90% and 72.5%, respectively, and steady-state plasma concentrations are attained within 2 days. Flupirtine is more than 80% reversibly bound to human albumin in vitro and has an apparent volume of distribution of 154L in healthy volunteers.
Flupirtine undergoes hepatic biotransformation to 2 primary metabolites, one of which has 20 to 30% of the analgesic activity of the parent compound. 18% of an oral dose of flupirtine is excreted in the faeces and 72% in the urine, two-thirds of the latter comprising parent compound and the 2 identified metabolites. The mean plasma elimination half-life of flupirtine ranges from 6.5 to 9.6 hours after oral administration and is 10.7 hours after rectal administration in healthy volunteers; these values are increased in the elderly and those with renal or hepatic disease. High plasma flupirtine concentrations, indicative of drug accumulation, have been recorded in patients with biliary cirrhosis, and may be associated with the development of ataxia.
Flupirtine has been used in a number of studies of patients with moderate postoperative pain. Oral flupirtine 100 to 200mg or rectal flupirtine 150mg, administered up to 4 or 5 times daily for 1 to 4 days, provided superior analgesia to placebo on several subjective rating scales. Equivalent analgesic efficacy was demonstrated vis-a-vis the opiate analgesics codeine, dihydrocodeine, pentazocine and metamizol, the nonsteroidal anti-inflammatory agents suprofen, diclofenac, naproxen and ketoprofen, and the peripherally acting agent, paracetamol. Similar results were found in patients with pain due to trauma, abdominal spasm, headache/migraine and dental procedures. Painful conditions with a large inflammatory component, e.g. wisdom tooth extraction, were less responsive to flupirtine.
The role of flupirtine in the treatment of chronic pain states is less well defined. Although patients with severe pain due to malignancy tended to respond more favourably to flupirtine than to pentazocine over a 1 -week treatment period, information regarding its longer term efficacy in this setting is lacking. Patients with muscular or neuralgiform pain, dysmenorrhoea or soft tissue rheumatism showed similar analgesic responses to flupirtine and pentazocine over 2 to 8 weeks of treatment, and flupirtine was the better tolerated agent. Those patients with inflammatory rheumatism were again less responsive to flupirtine and pentazocine.
In the only long term trial reported to date, in which 191 patients with chronic rheumatic pain were initiated on 12 months’ treatment with oral flupirtine 300 mg/day (mean), complete pain relief was obtained by 18 to 25% of patients.
Adverse reactions to flupirtine have been relatively frequent but generally minor in nature, usually necessitating few withdrawals from clinical trials. Common dose-related adverse effects include drowsiness, dizziness, dry mouth and various gastrointestinal complaints. In comparison with other analgesics, flupirtine has proved to be well tolerated, producing fewer central nervous system effects than the opiates. The respiratory and cardiovascular depression associated with the opiates have not been seen with flupirtine, nor has overt evidence of tolerance or dependence been manifest on long term (⩽ 12 months) flupirtine administration. The tolerability of flupirtine in elderly patients and those with moderate renal impairment appears comparable to that in younger patients and those with normal renal function. However, ataxia in association with elevated plasma flupirtine concentrations has been noted in patients with biliary cirrhosis, and patients with a history of hepatic encephalopathy have experienced symptom recurrence during flupirtine therapy.
Dosage and Administration
Flupirtine is available in 50 and 100mg oral capsules and 75 and 150mg rectal suppositories. The usual adult dose is one 100mg capsule or 150mg suppository 3 to 4 times daily, to a maximum of 6 doses per day. The oral dose may be increased to 200mg 3 times daily for more severe pain. The dose in children (⩾ 6 years.) is 50mg orally or 75mg rectally 3 or 4 times daily, to a maximum of 6 doses per day. The minimum analgesic dose should be used in elderly patients and those with renal disease, hepatic dysfunction or hypoalbuminaemia. The duration of treatment should not exceed 8 days without review by a medical practitioner. Driving or the use of machinery should be avoided during treatment with flupirtine. Patients receiving oral anticoagulant therapy should have coagulation time measured regularly and patients taking paracetamol-containing medications should be monitored for elevated hepatic transaminases if treatment is to continue beyond a few days. Flupirtine is not recommended for patients with biliary cirrhosis or a history of hepatic encephalopathy.
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