Clinical application of extended-release hydromorphone for pain management

Hydromorphone is a semi-synthetic μ-agonist commercially available in oral, rectal and injectable formulations for the control of acute and chronic pain [1]. Hydromorphone is typically used for moderate-to-severe pain, and is an effective alternative to morphine [1]. Like other μ-agonists in the opioid family there is no ceiling effect for hydromorphone, and cross-tolerance with other opioids is incomplete [1,2]. In clinical practice, opioids are used for a variety of persistent painful conditions including, but not limited to, those involving the axial spine, arthritis and neuropathic pain. Opioids are also a central agent for the treatment of severe cancerrelated pain [2]. For both benign and oncologic pain, stable plasma levels of opioid are achieved through use of long-acting sustained-release opioid preparations [3]. While extended-release formulations of oxycodone, morphine, oxymorphone and fentanyl are commercially available in the USA, there is currently no extended-release formulation of hydromorphone [4]. Earlier this decade, Purdue Pharmaceuticals (CT, USA) produced an extended-release formulation of hydromorphone (PalladoneTM) that was withdrawn from the market because of concerns regarding accelerated drug release when used in combination with alcoholic beverages. Since the withdrawal of Palladone, there have been no subsequent attempts to bring to market a sustained-release form of hydromorphone in this country [3]. The osmotic controlled-release oral delivery system (OROS) hydromorphone, a patented drug-release formulation produced by the ALZA Corporation (CA, USA) and marketed in Europe under the trade name JurnistaTM (Janssen Pharmaceutica, NV, Beerse, Belgium), is a potential candidate to fill this niche [3]. OROS® drug delivery The OROS osmotic drug-delivery system has been employed to provide extended release of at least 13 drugs, including prazosin, verapamil, oxybutynin, glipizide and albuterol [5]. OROS provides stable plasma concentrations and uniform dosing regimens, which in turn may lead to better patient acceptance of therapy [3]. In the past 30 years, four different systems have been described: the elementary osmotic pump, the two-layer osmotic push–pull tablet, the advanced longitudinally compressed tablet multilayer formulation and the L-OROS system [5]. Using osmosis, the OROS formulations are reported to provide stable drug release for up to 24 h [6]. While beyond the scope of this article, Rathbone et al. provide an excellent review of the mechanisms underlying this technology [5]. Current formulations of sustained-release hydromorphone using the OROS technology are designed to deliver medication for up to 24 h using an osmotically active bilayer surrounded by a semi-permeable membrane [4]. The intrinsic properties of this semi-permeable membrane regulate the flow of water into the ‘push’ layer of the tablet causing it to expand. As the push layer expands, the drug-containing compartment is compressed, resulting in release of drug through a laser-drilled orifice for precise pharma ceutical delivery to the gastrointestinal tract mucosa, resulting in presumably uniform absorption secondary to uniform release [4]. The semi-permeable membrane that acts as an outer shell is subsequently excreted intact in the feces [4,5]. The osmotic controlled-release oral delivery system (OROS®) is being utilized more frequently for once-daily dosing of a variety of medications. While sustained-release formulations of other opioids are currently available in the USA, at present there is no extended-release hydromorphone product on the market. With regard to OROS hydromorphone, a candidate to fill this niche, there is growing evidence to suggest that stable plasma levels can be achieved with tolerable side effects. Furthermore, the drug-delivery system appears to provide reliable opioid release when dosed with food and alcohol.