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Opioids are a treatment option for moderate to severe pain in appropriately selected patients who have not responded to non-opioid therapies.1 Extended-release opioid formulations can be especially beneficial for the management of chronic moderate to severe pain because they release opioid over a sustained period, resulting in prolonged duration of action (eight to 24 hours for oral formulations) (see Figure 1).2,3 The potential benefits of extended-release formulations include sustained pain relief, the possibility of lengthening dosing intervals, reduction in euphoric effects compared with immediate-release formulations because of the slower rise in peak plasma morphine levels and lower peak levels, pre-emptive treatment of pain, potential for reduced side effects without the peak-related toxicity of immediate-release formulations, reduced end-of-dose pain and withdrawal symptoms, reduced pill burden, ease of compliance, better sleep and general improvement that come from better functionality, and an improved quality of life.4–7 Extended-release opioid formulations, however, can be especially attractive to opioid abusers because of the relatively large amount of opioid per unit dose compared with that in immediate-release formulations.5 In response to the rising rates of opioid abuse and unintentional deaths from drug overdose, the US Department of Health and Human Services Centers for Disease Control and Prevention has encouraged pharmaceutical manufacturers to modify opioid formulations to make them more difficult to tamper with or to block the effect of the opioid if they are crushed, or dissolved and injected.8 Opioids can be abused by a variety of methods and routes of administration, including simple one- or twostep methods such as swallowing intact or crushed/chewed product or inhaling crushed or solubilized product, and more complex methods such as multistep extraction processes to solubilize an active ingredient to be administered by injection or other routes.5,9,10 A study among US college students indicated that the most frequent routes of administration for non-medical use of prescription opioids were oral (97%) and intranasal (13%).11
Several strategies, which can be employed alone or in combination, have been proposed for the development of opioid formulations that are less attractive to drug abusers while addressing the need for analgesics for patients with moderate to severe pain. These strategies include:
• inclusion of a sequestered opioid antagonist that is released and is bioavailable only upon product tampering (crushing, extraction, and solubilizing);
• physical barriers that resist crushing and/or extraction with common solvents or form a viscous substance on contact with a solvent, making intravenous use difficult;
• inclusion of a sequestered aversive agent that is released only upon tampering; and
• development of inactive prodrugs that require absorption into the gastrointestinal tract for conversion to the active opioid compound.5,7,12