Introduction

Targin® is an oral opioid analgesic medication used to treat chronic severe pain that is not responding to non-narcotic analgesics.

Mode of action

Targin® is a combination product, containing the strong opioid analgesic oxycodone and the opioid antagonist naloxone. Both active ingredients are in a controlled release dual polymer matrix designed for 12-hourly dosing.

Oxycodone is a full opioid agonist with affinity for mu, kappa and delta opioid receptors centrally and peripherally. When bound to central opioid receptors oxycodone elicits pain relief similar to other drugs in this class, such as morphine. Peripherally, by acting on the smooth muscle of the bowel oxycodone also causes the class side-effect of constipation.

Naloxone also has affinity for central and peripheral opioid receptors. However, in contrast to oxycodone, naloxone acts as a competitive antagonist and can negate the effects of opioid agonists such as morphine and oxycodone.

Although the co-administration of both the agonist and antagonist in the same dosage form initially seems counter intuitive, the variable pharmacokinetic profiles of the two drugs can explain the combination.

The oral bioavailability of oxycodone is 87%. The oxycodone component of Targin® has been shown to be bioequivalent to Oxycontin® and the two products produce comparable pain relief. In contrast, the oral bioavailability of naloxone is very low, less than 3%. This means that when taken orally the naloxone is free to antagonise the effects of oxycodone locally in the gastrointestinal tract, although is removed by extensive first pass metabolism by the liver, rendering systemic effects negligible. Simply, the naloxone is able to reduce the side effects of oxycodone in the gut whilst not reducing the pain relief provided centrally by oxycodone.

Additionally, the combination also overcomes another issue associated with controlled release oxycodone. Unsanctioned use by crushing and injecting controlled release Oxycontin® tablets has been an unwanted social and public health issue, conferring the name “hillbilly heroin” upon controlled release oxycodone. Targin® may be less appealing for illicit use as the naloxone dose becomes available if administered parenterally and negates the pleasurable effects of the oxycodone.

Dosage and administration

Targin® is available in the fixed dose combinations of oxycodone/naloxone of 5/2.5mg, 10/5mg, 20/10mg and 40/20mg. These are respectively bioequivalent in regard to the oxycodone component of Oxycontin-CR® 5mg, 10mg, 20mg and 40mg. In opioid naïve patients doses should be initiated at the same oxycodone strength as for Oxycontin® tablets. For patients requiring to be switched from Oxynorm® or Oxycontin® select the Targin® strength with oxycodone dose equal to the total daily oxycodone dose (immediate and controlled release) divided into two 12-hourly doses.

The tablets are controlled release and must not be crushed, chewed or broken. They must be swallowed whole to prevent the rapid release of oxycodone which could be life threatening. They may only be taken orally.

They should be taken with a sufficient amount of water and may be taken with or without food. The dose should be taken 12-hourly (e.g. 8:00am and 8:00pm) to provide 24-hour pain relief.

Side effects

Targin® produces side effects similar to those of others in the opioid class such as respiratory depression, miosis, nausea and vomiting, dyspepsia, drowsiness and dizziness, headache, orthostatic hypotension, dry mouth, itch and urinary retention.

Compared to morphine, oxycodone causes a lower histamine release so the incidence of urticaria and pruritis is reduced, although still listed as common.

Antiemetics may be used prophylactically and to treat established nausea and vomiting from Targin®, although use should be reviewed within a few days as the nausea lessens with continued use.

Targin® causes less constipation compared with Oxycontin®, although it does not completely eliminate it and laxatives may still be required. Patients should be counselled to increase their fluid and fibre intake and ensure they are engaging in exercise to reduce the risk of constipation. In opioid treated patients a reduction in existing laxative dose may be required when changing to Targin® to prevent diarrhoea.

PBS eligibility

Targin® is available on the PBS as a restricted benefit for chronic severe disabling pain not responding to non-narcotic analgesics.

Authorities for increased maximum quantities and/or repeats will be granted only for:

  1. chronic severe disabling pain associated with proven malignant neoplasia; or
  2. chronic severe disabling pain not responding to non-narcotic analgesics where the total duration of narcotic analgesic treatment is less than 12 months; or
  3. first application for treatment beyond 12 months of chronic severe disabling pain not responding to non-narcotic analgesics where the patient’s pain management has been reviewed through consultation by the patient with another medical practitioner, and the clinical need for continuing narcotic analgesic treatment has been confirmed. The date of the consultation must be no more than 3 months prior to the application for a PBS authority. The full name of the medical practitioner consulted and the date of consultation are to be provided at the time of application; or
  4. subsequent application for treatment of chronic severe disabling pain not responding to non-narcotic analgesics where a PBS authority prescription for treatment beyond 12 months has previously been issued for this patient.

Summary

Targin® is an effective and safe medication for the treatment of chronic pain. It provides comparable pain relief to other controlled release oxycodone formulations but causes less constipation. Targin® comprises an ingenious combination of active ingredients by capitalising on the different pharmacokinetic properties of the drugs. Its development represents an exciting frontier in drug development, providing a reminder of the importance of dosage formulation.

References:

  1. Löwenstein O, Leyendecker P, Hopp M, Schutter U, Rogers PD, Uhl R et al. Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: a randomised controlled trial. Expert Opin Pharmacother 2009; 10: 531–43.
  2. National Prescribing Service. Oxycodone-with-naloxone controlled-release tablets (Targin) for chronic severe pain. NPS RADAR 2011; October.
  3. Rossi S, editor. Australian Medicines Handbook 2013 [online]. Adelaide: Australian Medicines Handbook Pty Ltd; 2013 January.
  4. Simpson K, Leyendecker P, Hopp M, Müller-Lissner S, Löwenstein O, De Andrés J, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Curr Med Res Opin 2008; 24: 3503–12.
  5. Targin® (oxycodone hydrochloride and naloxone hydrochloride dihydrate) Australian approved product information. Sydney: Mundipharma Pty Ltd. Approved 14 May 2010, safety related notification 28 December 2011.
  6. Vondrackova D, Leyendecker P, Meissner W, Hopp M, Szombati I, Hermanns K, et al. Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain. J Pain 2008; 9: 1144–54.

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