Is Tramadol 377 Extended-release

[Orville Marquez]

TherapeuticGuidelines Limited was recently selected by the Department of Health and Aged Care as the new publisher of Australian Prescriber. All volumes of the journal including new issues can be accessed in the website australianprescriber.tg.org.au

This review originally cautioned against combining tramadol with mirtazapine because of an increased risk of adverse effects due to serotonin toxicity. Subsequent expert advice suggests that combining tramadol and mirtazapine is very unlikely to cause serotonin toxicity. Although adverse events due to serotonin toxicity are unlikely to occur, there are case reports of adverse events in people using both medications.

Tramadol extended-release (Durotram XR) is a once-daily, biphasic tramadol formulation. The outer layer of the tablet releases 25% of the dose within 2 hours, while the remaining 75% is gradually released from the core over 24 hours.2,3

Tramadol extended-release taken once daily has similar efficacy to that of twice-daily tramadol. There are some differences in its adverse-effect profile, but, like all tramadol formulations, the role of tramadol extended-release is limited by drug interactions and adverse effects (see Safety issues).

The PBS listing allows tramadol to be used for up to 10 days. This approach could be considered for indications such as pain after dental extractions, flare-ups in osteoarthritis and for procedural pain.

Tramadol extended-release is PBS subsidised for up to 10 days. Larger quantities of tramadol extended-release can only be prescribed for severely disabling pain that does not respond to non-opioid medications.

Tramadol extended-release once daily has similar efficacy to that of twice-daily tramadol among people with osteoarthritis of the knee.4 Over 12 weeks, scores on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain scale improved by almost 60% among people taking tramadol extended-release once daily and among people taking twice-daily tramadol. In this study the median optimal dose in both groups was 200 mg/day.4

Neither tramadol extended-release nor tramadol sustained-release should be used in people who require rapid titration of analgesia to control acute pain or when the level of analgesia required is unpredictable. Less flexibility in dosing and the longer duration of effect make it more difficult to adjust the dose to requirements with these formulations compared with immediate-release tramadol.

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

In trials, up to 81% of people taking tramadol extended-release experienced an adverse event.4,8,9 A similar proportion of participants (79%) taking tramadol twice daily experienced an adverse event.4

Between 8% and 21% of participants receiving tramadol extended-release discontinued treatment because of adverse events.4,8,9 Similar numbers of people taking tramadol once daily and tramadol twice daily discontinued because of adverse events.4

As with other opioids, the prevalence of adverse events increases with dosage. In one study, 12% of participants taking 100 mg/day tramadol extended-release discontinued due to adverse events. This rose to 18% in those taking 200 mg/day and to 32% in those taking 300 mg/day. The rate of discontinuation due to adverse events was 7% in the placebo group.8

Dizziness or vertigo is less common in people taking tramadol extended-release once daily than in those taking tramadol sustained-release twice daily (26% vs 37%, p = 0.017).4 However, drowsiness is more common among those taking a once-daily dose than among those taking tramadol twice daily (30% vs 21%, p = 0.047).4 The prevalence of nausea, constipation, headache, vomiting and weakness is similar in both groups, although vomiting was reported to be less severe among people taking once-daily tramadol.4

The recommended starting dose of tramadol extended-release is 100 mg once daily.10 If this is insufficient to control pain, increase the dose to 200 mg after 2 full days of treatment (i.e. on day 3 of therapy).12 This may be done by taking two 100 mg tablets at the same time.

The correct dose is the lowest dose that controls pain for 24 hours without intolerable side effects. After titration, the most common dose is 200 mg once daily.4 However, if this is still insufficient to control pain, the dose can be further increased every 2 days in 100 mg increments up to a maximum of 400 mg daily.10,12 Manage incident pain during the titration period with paracetamol or an NSAID.12

Tramadol extended-release (Durotram XR) is designed to be taken once a day. The sustained-release formulations (Tramal SR, Tramahexal SR, Tramedo SR and Zydol SR) are designed to be taken twice a day.

While tramadol extended-release can be taken with or without food, advise people to take their medication in the same manner each day (i.e. always with food or always without food) to ensure a consistent analgesic effect. Consuming a high-fat meal immediately before taking tramadol extended-release can increase the maximum plasma concentration of tramadol by 54% but does not significantly impact upon the overall extent of absorption.10

An NPS Medicine Update leaflet on tramadol is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with those of other medicines

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Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol hydrochloride extended-release tablets, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride extended-release tablets are essential [see Warnings]. Instruct patients to swallow tramadol hydrochloride extended-release tablets whole to avoid exposure to a potentially fatal dose of tramadol.

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings].

Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings].

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [see WARNINGS]. Tramadol hydrochloride extended-release tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS]. Avoid the use of tramadol hydrochloride extended-release tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol [see WARNINGS].

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Tramadol Extended-Release Tablets requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see WARNINGS, PRECAUTIONS; Drug Interactions].

The molecular weight of tramadol hydrochloride, USP is 299.8. Tramadol hydrochloride, USP is a white crystalline powder that is freely soluble in water and ethanol. Tramadol hydrochloride extended-release tablets, USP are for oral administration and contain 100 mg, 200 mg or 300 mg of tramadol hydrochloride, USP. The tablets are white in color. The inactive ingredients in the tablet are pregelatinized maize starch, hypromellose, mannitol, magnesium stearate, cellulose acetate and polyethylene glycol.

Tramadol hydrochloride extended-release tablets, contain tramadol, an opioid agonist inhibitor of norepinenphrine and serotonin re-uptake. Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to binding to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite (M1) to mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.

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