The medical profession recognizes the clinical value of prescribed opioids in treating noncancer pain that is persistent and recalcitrant to other therapies.1 However, the clinical benefit of conventional opioid formulations falls short of the need. Although analgesia from opioids is often limited to a subset of patients who achieve benefit, long-term analgesic efficacy is uncertain, and discontinuation of therapy due to adverse events or inadequate analgesia is common.2
Furthermore, opioids are dangerous when used inappropriately. Statistics reveal a trend toward unintended harm involving opioids:
5.1 million persons in the United States used opioids nonmedically in 2010, and 2 million persons tried nonmedical opioids for the first time.3
Nonmedical prescription opioid use is responsible for more than 305,000 emergency department visits per year.4
Prescribed and diverted opioids were involved in more than 14,800 fatal poisonings in 2008, a nearly fourfold increase from 1999.5
The accurate number of deaths caused by prescription drugs is difficult to confirm because data collected by medical examiners and eventually recorded by the Centers for Disease Control and Prevention (CDC) are inadequate to understand the cause of death in many patients.6 Nevertheless, the rise in the number of unintentional overdose deaths is alarming.
Harm from opioids affects two dissimilar populations: patients who are prescribed opioids, sometimes for a long-term, to treat a pain problem, and nonpatients who use opioids without a prescription. Patients who are prescribed opioids may engage in medical misuse (e.g., overusing, mixing with unauthorized substances, and unlawful sharing with others). Nonmedical use by nonpatients can include experimentation, recreation, or use to self-medicate pain or psychiatric disorders. The spectrum of opioid misuse ranges from patients who use an extra pill in search of greater pain relief to patients and nonpatients who are suffering from the disease of addiction and who go to extreme, even illegal, lengths to obtain opioids (Fig 72-1).7
FIGURE 72-1.
The Spectrum of Opioid Misuse: Patients and Non-Patients. The spectrum of misuse involves two different populations—patients and nonpatients—with behaviors that range from mild to severe. Motivations for nonpatients range from using non-prescribed opioids to self-treat pain, to recreation, to serious substance-use disorders. Although most patients are strictly adherent, some misuse opioids by taking them other than as directed, to self-treat uncontrolled pain, to chemically cope with a psychiatric disorder, or because of addiction.7
Motives for misuse, short of addiction, vary. Based on the self-reports of 80 nondependent, recreational users of opioids, the most common feelings obtained from opioids were to feel relaxed or mellow (80%), happy or pleasant (71%), and calm or less nervous (63%) (Fig 72-2). Most participants (55%) first took an opioid to treat pain; however, 38% first took an opioid for the purpose of getting high (Fig 72-3).8
FIGURE 72-2.
Motives for Misuse: How Would You Describe the Feeling of “High” From Prescription Opioids? Nondependent, recreational opioid users explain the effect(s) they seek in misusing opioids.8
FIGURE 72-3.
Initial Exposure: Why Did You Take an Opioid the First Time? Nondependent, recreational opioid users describe their initial reason(s) for taking an opioid.8 Many opioid misusers chemically or physically alter the formulation (e.g., chewing, crushing, dissolving in alcohol or water) before ingesting in order to defeat controlled-release (CR) formulations and gain access to a full dose at once. Data from the Treatment Episode Data Set (TEDS) through the Substance Abuse and Mental Health Services Administration (SAMHSA) show that most persons admitted for substance-abuse treatment because of opioids took the medication orally (72%).9 Other routes included inhaling (16%), injecting (10%), smoking (2%), and other (1%).
The pharmaceutical industry has responded to the rise in opioid-related harm by developing several formulations that employ technologies to resist or deter misuse and to boost analgesic efficacy. Methods include modifying the route of delivery, combining opioid agonists with opioid antagonists or aversive agents that become active if altered, and targeting intracellular or molecular processes within the body. Most formulations are still in development, and none has yet been proved to deter substance abuse in real-world settings.
First introduced via a buccal fentanyl product to treat breakthrough pain,10 BEMA (BioErodible MucoAdhesive) technology is now being applied to other opioids. The technology is a small, bilayered, bioerodable, polymer film consisting of a backing layer and a muco-adhesive layer which contains the active drug.11 Designed to cling to oral mucosa in less than 5 seconds and dissolve within 15 to 30 minutes; the developers claim the product optimizes delivery across the mucosa.
A formulation now in development combines BEMA technology with buprenorphine, a partial µ (mu) agonist and a κ (kappa) antagonist with a high affinity for µ opioid receptors.12 Buprenorphine (monotherapy or in combination with naloxone) has a long history as an addiction treatment but is often used off-label for pain control and—as a Schedule III medication—is considered to have a lower propensity for misuse than other opioids. A randomized, placebo-controlled, Phase 3 clinical study of BEMA buprenorphine for the management of moderate to severe pain failed to meet the primary efficacy endpoint of pain-intensity difference compared with placebo.13 Investigators cited a large placebo response in new opioid users compared with experienced users and planned a follow-up efficacy study.
A sublingual film formulation of combination buprenorphine/naloxone is currently available for the treatment of opiate dependence and is also expected to be used off-label as a treatment for pain with less presumed misuse and diversion potential. The film is placed under the tongue where it dissolves in approximately 5 minutes.14 Clinical testing has established comparable safety and efficacy to the tablet form of buprenorphine/naloxone medication.14
A transdermal buprenorphine that delivers a systemic dose through a patch that is changed every 7 days is approved for the treatment of moderate to severe pain. The formulation has not been studied for addiction treatment. Patient applies the patch to the upper outer arm, upper chest, upper back, or the side of the chest to receive a steady, continuous dose via an adhesive polymer matrix. Transdermal buprenorphine demonstrated equal analgesia with greater tolerability and fewer side effects compared with sublingual buprenorphine15 and has an efficacy and tolerability profile comparable to twice-daily tramadol.16
A sublingual fentanyl spray is in development for the treatment of breakthrough pain in opioid-tolerant cancer patients. A phase 3, randomized, double-blind, placebo-controlled multicenter study showed a statistically significant difference in the sum of pain intensity scores at 30 minutes, which was the primary endpoint, and at all other time points measured (5, 10, 15, 45, and 60 min).17 Significant pain relief at 5 minutes postdose appears particularly well matched to treat the sudden flares of intense pain that characterize breakthrough pain.18
A completely different approach uses prodrugs or less soluble opioid salts that remain inert until a molecular process occurs in the body, thus releasing the active ingredient. In some formulations, the process occurs within the gastrointestinal (GI) tract, and in others, only when the ingredient enters a cell.
An example of prodrug technology uses a Bio-Activated Molecular Delivery system to release an active opioid at the molecular level only if the drug is ingested with no effects from inhaling, chewing, or injecting.19 An additional feature of the formulation is meant to provide protection against oral overdose in that ingesting multiple pills would not equal a dose-proportional increase in active opioid exposure. A phase 1 human proof-of-concept study using hydromorphone confirmed the dose-proportional release of the opioid.19 The study also demonstrated that the emergency department pharmacokinetic profile is intrinsic to the molecule, in contrast to other opioid products that reformulate opioids with physical matrices that may be circumvented. Further testing of these technologies is due with oxycodone and hydrocodone.
This category of formulations may prove useful for the most difficult-to-help category of medication misusers—those who do not tamper with or alter a pill but instead take an extra pill because of inadequate analgesia. Theoretically, prodrug formulations have potential to mitigate misuse but are expensive to develop.
The first generation of novel opioid formulations was developed to resist or deter misuse when the formulation is altered. These formulations consist of the same opioid molecule contained in available prescription medications reformulated in combination with agents intended to act as physical or chemical barriers. Therefore, these formulations are principally aimed at deterring recreational or other nonmedical users who are attempting to convert a controlled-release (CR) formulation into an immediate-release (IR) formulation.
Based on the regulatory response thus far, the Food and Drug Administration (FDA) appears to view many first-generation formulations as offering little proven protection against opioid misuse. A large drawback is the lack of defense against oral overconsumption when swallowed whole. Thus, the relevance of many first-generation formulations to the needs of patients who are prescribed opioids is uncertain.
Strategies to limit opioid misuse are aimed at reducing the individual’s ability to crush or dissolve the pill in order to snort or inject the full dose. One approach is to house the active pharmaceutical ingredient within a capsule that is tamper resistant. For example, a CR oxycodone formulation in a viscous base that is difficult to crush or chemically alter is currently in development (Fig 72-4).20,21 The liquid matrix resists crushing, chewing, and extracting with liquid solvents and also resists injection because it cannot be drawn into or expressed from needles. At press time, the FDA had not approved the formulation for the market.22
A similar formulation combines IR oxycodone with a tamper-resistant gelling agent that resists extraction of the active ingredient. The formulation, which also contains sodium lauryl sulphate as a nasal irritant to prevent snorting, was approved by the FDA on June 17, 2011, for the treatment of acute and moderate to severe chronic pain.23
An available CR hydromorphone formulation uses patented OROS technology to deliver a steady once-daily dose through push-pull osmotic pressure.24 The bilayer tablet appears to have tamper-resistant qualities, although no such claims are made on the product’s label.
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