Modifiedrelease Delivery Systems

In the case of morphine sulfate, this drug is available in both the immediate- and modified-release forms. As a first-generation modified-release system, the active ingredient is suspended in a wax-like matrix from which it is slowly delivered to the patient. The drug is leeched out of the matrix in a monophasic fashion. The drug has slow onset, which is thought to lower the abuse liability of the active ingredient, morphine (30). However, when the drug is crushed, this slow-release system is compromised, allowing for much more rapid absorption and delivery of the morphine sulfate. In fact, first-generation modified-release forms of morphine have been used as a source of injectable morphine by crushing the tablets up and heating the powder in water. When the resultant solution cools, the waxy matrix residue may be peeled off the surface leaving a potent aqueous morphine solution.

In the case of the second-generation modified-release preparations, a portion of the active ingredient is immediately available to help reach satisfactory blood levels, while the remainder of the drug is released slowly, over time. OxyContin®, a modified-release version of oxycodone, is an example of this system.

In OxyContin, approximately 38% of the dose is released rapidly, whereas the remainder of the drug is delivered over the 12 hours, twice-daily dosing schedule (31). For most patients, this results in rapid onset of analgesic effect and stable blood levels of oxycodone over the 24-hour period. This benefit becomes a liability in those patients who have used oxycodone as a drug of misuse, because by simply crushing the tablet, the clever delivery system is compromised, and the OxyContin becomes essentially an immediate-release product.

Opioid level instability, in the physically dependent patient, may also lead to a situation in which the need to continue opioid analgesics is driven not by dramatic improvement in pain and/or function, but rather by how badly things seem to go upon discontinuation. This information is sometimes gained incidentally by patients when they run out of medication on a weekend or if their prescriber attempts to taper the drug too quickly. In some cases, such as neuropathic pain, the pain problem may be less opioid responsive, requiring higher doses (32). Opioid withdrawal will lead to a hyperadrenergic state that will exacerbate virtually all types of pain (33). The use of a modified-release opioid may result in a transient improvement in pain relief sometimes referred to as the "honeymoon" period. In these cases, once opioid stability is achieved, it may be useful to revisit some of the adjunctive agents that were previously tried, even if they appeared to be ineffective at the time of their initial trial. In fact, in cases of poorly responsive pain, it may be useful to carefully try to discontinue the use of opioids, once these adjunctive measures are in place.

For sometime now, it has been known that some forms of pain may benefit from preemptive approaches to pain management. In 1995, Suzuki reviewed the relationship between injury response and acute and chronic pain in the context of preemptive analgesia (34). More recently, a randomized double-blind study of the involvement of presurgical pain in preemptive analgesia for orthopedic surgery showed a statistically significant difference in effectiveness of preemptive analgesia at the time of surgery for those cases where there was significant pain present prior to surgery as compared to matched controls who were pain-free at the time of surgery (35). Of course, the taking of opioid medications in advance of pain can, in some patients, lead to dose escalation and problematic use of medication. It may be that, in properly chosen patients, the use of appropriate doses of an immediate-release (IR) opioid prior to engaging in a painful procedure or activity may help to improve control of existing chronic pain syndromes in those who already suffer from these conditions. It remains to be seen if preemptive analgesia will reduce the development of chronic pain in those patients who suffer from acute episodes of pain (36).

IR opioids may be indicated in the treatment of moderate to severe acute pain. IR opioids are also indicated in incident or transitory exacerbations of pain with relatively stable and adequately controlled baseline (cancer or noncancer) pain. Prevalence of incident pain varies between 40% and 86% and usually lasts less than one hour (37,38). This appropriate use of IR opioids saves money secondary to decreased hospitalizations, emergency room (ER) visits, and office visits (39).

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