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Clinical guidelines for the use of opioids, including the REMS requirements, and their impact on the management of chronic pain.


CME/CE Activities


  • These videos will evaluate clinical guidelines for the use of opioids, including the FDA Opioid REMS requirements, and their impact on the management of chronic pain. This initiative will also evaluate recommended opioid risk-reduction strategies HCPs can use to detect opioid misuse in a timely manner. Finally, this initiative will identify communication strategies HCPs can use to improve their relationships with their patients to ensure optimal patient outcomes and reduce the risk of opioid misuse and abuse. This content builds on the core principles and objectives of REMS 2013.

    FACULTY: Bernard Abrams, MD; Daniel Doleys, MD, PhD; Bill McCarberg, MD

     

    REMS UPDATE 2017: RISK EVALUATION AND MITIGATION STRATEGY

    CME: 3.0 Credits, AANP: 3.0 Contact Hours

  • This series of three activities will evaluate clinical guidelines for the use of opioids, including the REMS requirements, and their impact on the management of chronic pain. This initiative will also evaluate recommended opioid risk-reduction strategies HCPs can use to detect opioid misuse in a timely manner. Finally, the initiative will identify communication strategies HCPs can use to improve their relationships with their patients to ensure optimal patient outcomes and reduce the risk of opioid misuse and abuse.

    FACULTY: Perry G. Fine, MD, Michael A. Ashburn MD, MPH, MBA, and Charles Argoff, MD

     

    Tools for Assessing Patients and Initiating ER/LA Opioids
    CME: 1.75 Credits, AANP: 1.75 Contact Hour

    Tools for Effective Monitoring of Patients on ER/LA Opioids
    CME: 1.25 Credits, AANP: 1.25 Contact Hour

    Tools for Managing Potential Adverse Events and Avoiding Drug-Drug Interactions
    CME: 0.50 Credits, AANP: 0.50 Contact Hour

  • This monograph will evaluate clinical guidelines for the use of opioids, including the FDA Opioid REMS requirements, and their impact on the management of chronic pain. This series of activities will also evaluate recommended opioid risk-reduction strategies HCPs can use to detect opioid misuse in a timely manner. Finally, the monograph will identify communication strategies HCPs can use to improve their relationships with their patients to ensure optimal patient outcomes and reduce the risk of opioid misuse and abuse.

    FACULTY: Paul A. Sloan, MD, Mellar P. Davis, MD, FCCP and Pamela Gamier RN, BSN, CHPN

     

    Tools for Safe Prescribing in Chronic Pain Management
    CME: 3.00 Credits, AANP: 3.0 Contact Hours


Latest articles

  • Controlled-release of opioids for improved pain management

    The adequate treatment of pain remains one of the major medical challenges. Morphine and other opioid drugs are most commonly used to counteract moderate to severe pain, but they are also increasingly accessed by patients with chronic non-malignant pain. To achieve long-term analgesia, opioid therapy still represents the standard treatment for chronic pain alleviation. This work presents an overview of current strategies aiming at controlled opioid release. Two important, and intrinsically linked, features are discussed in detail: the used formulations (i.e. polymer systems) and the applied drug administration routes. The different administration routes and their associated advantages and limitations are described. Links between the chemical structure of commonly used opioids and suited administration modes and formulations are made. This review can potentially give insight into new opportunities for adequate relief of chronic pain, a societal burden, by means of alternative (non-)opioid analgesics and may serve as inspiration for future developments in this area.

    Introduction

    Chronic pain remains a major societal burden that is associated with a decline of normal daily functioning and quality of life. It is defined as pain that lasts longer than three months and which is not in relation with any somatic damage. At least 30% of chronic pain cases evolve from the inadequate treatment of acute postoperative pain [1] and [2]. To provide sustained analgesia in chronic pain patients, regular administration of drugs is required to ensure that the next dose of an analgesic is given before the effects of the previous dose have dissipated. Unfortunately, despite advances in understanding its etiology and pathophysiology, chronic pain remains inadequately treated to date. In general, the appropriate management of chronic pain [3] aims to improve quality of life and daily function by alleviating not only pain symptoms, but also comorbid conditions.

    This review presents an overview of reported administration routes and polymer systems for the controlled drug delivery of opioids in the management of chronic pain. The remainder of this introduction will focus on the treatment of chronic pain by opioids (Section ‘Treatment of chronic pain’) and extended-release of opioids for long-term analgesia (Section ‘Extended-release of opioids for long term analgesia’). The remainder of this review will provide an overview of the state-of-the-art in controlled opioid release formulations, organized by method of administration, including discussion of the types of polymers to obtain controlled-release (Section ‘Routes of administration’). Each of these sections starts with a general reflection on the basic polymer requirements for obtaining sustained release for the different administration routes.

    Treatment of chronic pain

    The pharmacotherapy of chronic pain includes use of non-opioid analgesics, antidepressants, anticonvulsants, scheduled opioid analgesics, and non-scheduled opioid analgesics. For the treatment of moderate to severe pain, opioid analgesic drugs (see examples in Fig. 1), are most useful [4], and over the past years, opioid drug prescriptions have increased significantly [5], [6], [7], and [8]. Indeed, around 90% of patients suffering of chronic pain have been treated with opioids [4]. The application of opioid analgesics for chronic pain alleviation is, however, more controversial as opioid therapy generates adverse effects like addiction, abuse, respiratory depression, gastrointestinal effects (constipation), and urologic effects [9]. Opioid use for treating chronic pain may be justified only in patients who have not responded to any other therapy, as long term effects of clinical and excessive use of opioid drugs can affect nearly every organ system of the body.

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    Figure 1 Examples of opioid analgesics used for moderate to severe pain treatment.

    Clinically, morphine (Fig. 1) remains the most used analgesic drug to date [10]. In addition, hydrocodone, oxycodone, hydromorphone, oxymorphone and buprenorphine are semi-synthetic opioid agonists synthesized from codeine, which present the characteristic phenanthrene-like nucleus [11]. Oxymorphone has a twofold higher potency in comparison to morphine, a characteristic that is often used to make sure that the patient will not develop any breakthrough pain as it can be the case with morphine due to its lower bioavailability. Buprenorphine, a semisynthetic derivative, is a highly potent (100-fold more active than morphine) partial μ-agonist with a moderate addiction potential. For buprenorphine, there is no contra-indication in case of renal failure or for elderly patients due to its ceiling effect, as no respiratory depression occurs. Its metabolites are not accumulated in the kidneys. Other opioids like methadone, fentanyl and sufentanil are classified as synthetic agonists without the morphinan core included in their structures. Methadone is a highly lipophilic synthetic μ-opioid agonist with a long, but highly variable half-life (from 12 to 120 hours). This particular pharmacokinetic property implies an elevated risk of overdose due to its long duration of action. Fentanyl and sufentanil are lipophilic opioids with a short duration of action, but a much higher potency (100 times and 1000 times, respectively) than morphine. The efficacy can be easily explained by a high lipophilicity, which allows the efficient penetration of the blood brain barrier (BBB). Analogs of fentanyl are widely used in intravenous, epidural and intrathecal continuous infusions, but also in transdermal formulations. Fentanyl has no active metabolites and can safely be used in the case of patients with renal failure. Whereas fentanyl was not successful in recovery of surgically induced immunosuppression, buprenorphine has a more favorable profile, devoid of any intrinsic immunosuppressive activity [12]. Immune responses from all components of the immune system, including both the humoral and cell-mediated components, appear to be suppressed by morphine and other opioid-like substances.

    All opioids described above allow pain relief by binding to and activating the μ-opioid receptors in the central nervous central (CNS). Even though the plasmatic drug concentration cannot predict the analgesic effect, it was demonstrated that high doses provide greater analgesia. Effective plasmatic opioid concentration is dependent on many factors such as the opioid drug, the route of administration, the patient and the medical conditions.

    Extended-release of opioids for long term analgesia

    Prescription opioids are available as short-acting opioid (SAO) and long-acting opioid (LAO) formulations depending on their clinical utility. SAOs have a duration of action from 3 to 6 hours, and they are characterized by a high fluctuation in plasma opioid concentrations. Although they are particularly suitable for the treatment of acute, unstable or intermittent pain, SAOs can also be used around-the-clock, in the case of more persistent or chronic pain, for which a regular administration every 3–6 hours is needed. Indeed, opioids have a high first pass elimination effect in the liver resulting in metabolites, obtained after hydrolysis, oxidation, dealkylation or conjugation of the drug, which undergo renal excretion. Morphine, for example, undergoes a metabolic phase II conjugation process called glucuronidation that makes molecules more hydrophilic to enhance renal excretion, leaving only 30% available to exert a biological effect. The metabolites morphin-3-glucuronide (highly toxic and causes seizure) and morphine-6-glucuronide (potent metabolite with analgesic effects like morphine) are both renally excreted. Therefore, older patients with renal failure are preferentially not treated with long term administration of morphine. As a consequence of this metabolic inactivation, and to provide consistent analgesia, opioid administration requires frequent dosing to maintain effective plasmatic drug levels. Otherwise, blood concentrations of opioids can oscillate, resulting in inconsistent pain relief. To provide such a consistent pain relief, it is necessary to develop proper drug delivery systems that can ensure constant opioid blood levels [13] and [14].

    For the treatment of chronic pain, LAOs are intended for a slow release of opioids and a long duration of action [15], [16], and [17]. Compared to SAOs, they are dosed less frequently (i.e. one to three times per day) [18]. The beneficial effects of LAOs in chronic pain management, to improve efficacy, quality of life, and reduced toxicity, make them more robust in comparison with the impact of SAOs [19] and [20].

    LAOs formulations use different types of, mostly polymeric, controlled-release delivery systems that have been called extended-release, sustained release, delayed release, prolonged action, long action and slow release. However, there is no specific definition for each term due to the fact they are inconsistently used in literature, for example, by companies that marketed them. The ‘extended-release’ (ER) profile is characterized by a release profile in which the active molecule released in such a way that blood levels are maintained within the therapeutic window, but below toxic concentrations, over a period up to 35 hours or even longer (see blue curve in Fig. 2). The therapeutic window includes a concentration range between the minimum therapeutic concentration represented by a gray line and the red line, which represents the start of toxic concentrations; the red dotted line is representative of a minimum concentration beyond which the risk of side effect appearance is increased. These sustained release formulations were designed to deliver a first therapeutic dose, to immediately provide a therapeutic drug plasma concentration, followed by a constant and slow drug release to maintain the therapeutic dose required in the blood.

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    Figure 2 Schematic representation of opioid plasma concentrations in function of the administration route (IR: immediate-release and ER: extended-release).

    The different extended-release drug formulations (vide infra) are designed based on the route of administration for which they are developed, but also on the physicochemical, pharmacokinetic and pharmacodynamic properties of the drug. For example, opioids with short half-life such as morphine, oxycodone or hydromorphone are excellent candidates for administration via controlled-release formulations. Ideally, the extended-release drug formulation should release the drug following a zero-order release profile kinetic (blue curve in Fig. 2). Polymeric materials are of utmost importance for the development of such controlled drug release systems [21], [22], [23], [24], and [25]. To achieve improved drug release profiles and pharmacological responses, new formulations are continuously being designed using polymers as carriers for the drugs. In this way, one can improve the bioavailability of drugs by different factors such as the physicochemical properties of the drug, the dosage, the frequency and the route of administration. A wide variety of drug delivery platforms have been reported based on polymeric carriers that embed or covalently link the active pharmaceutical ingredient. Due to the large diversity of such drugs, the challenge remains in the design of polymers that afford the desired extended-release profile for a specific drug. Furthermore, the type of polymer that can be used is strongly dependent on the mode of administration.

    Overall, pain management guidelines advise the use of extended-release (ER) formulations, rather than immediate-release (IR) formulation because they provide sustained analgesia [26] and [27]. For patients suffering from moderate to severe chronic pain, ER formulations represent a viable option for around-the-clock analgesia, allowing a simpler dosing schedule (‘less clock-watching’), but also a more consistent and durable pain relief. An important additional consideration is that slow release formulations can also be utilized to prevent abuse of medically subscribed opioids.

    Routes of administration

    Opioid analgesics can be administered using a variety of routes (e.g. oral, sublingual and buccal, intranasal, rectal, intravenous, subcutaneous). The route of administration and the formulation of the analgesic are dependent on its pharmacokinetic and pharmacodynamic properties. The availability of more concentrated dosage forms and controlled-release opioid preparations for oral and transdermal opioid formulations are among the most recent innovations in opioid analgesia treatment [28]. However, the wide variety of opioid drug delivery systems for chronic pain management can be confusing, but in some cases there are clear indications to opt for one specific formulation [29]. To determine which drug delivery system is most suited, different parameters need to be considered (e.g. the patient's ability to use a specific device, the efficiency to deliver acceptable concentrations of opioid, and the potential complications associated to the system). The financial cost of certain formulations and devices is also an important parameter for patients who need to purchase their own medications.

    Oral administration

    Oral opioid administration is the most common, the easiest and the least invasive delivery system [30]. For patients who are able to take oral medications, this way of administration is the first choice [31]. Indeed, no major complications (except known opioid side effects) are associated with oral administration. The major drawback is based on the biotransformation of opioids in the liver, due to first-pass metabolization of the drug prior to entering the systemic circulation. Consequently, the dose of morphine taken orally, for example, needs to be three times higher than the intravenous or intramuscular dose of morphine. To provide longer-lasting analgesia, several oral formulations are available for slow opioid release (Table 1) [30].

    Table 1 Analgesics, extended-release formulations for oral administration, and delivery systems.

    Analgesic Dosage form Drug delivery system
    Morphine Capsules ER beads SODAS
    Morphine Capsules ER pellets
    Morphine Tablets ER Contin™
    Oxycodone Tablets ER AcroContin™
    Oxycodone Capsules ER DETERx™
    Oxycodone Capsules ER ORADUR®
    Hydromorphone Capsules ER
    Hydromorphone Tablets ER OROS®, Push-Pull™
    Oxymorphone Tablet ER TIMERx™
    Methadone Tablet ER
    Hydrocodone Tablet ER OraGuard™

    For oral administration it is important to design a drug release formulation to release the drug at the desired place, that is, in the stomach or in the intestines, which depends on the stability and uptake mechanism of the drug. If the drug is unstable at the low pH (1–4) of the stomach, formulations can be coated with an enteric coating, which contains carboxylic acid groups that are protonated and insoluble at the low pH of the stomach, and will dissolve in the higher pH (7–9) range of the intestines. Both water-soluble and water-insoluble polymer excipients and coatings can be used for oral administration leading to controlled drug release by (slow) dissolution of the polymer or by diffusion of the drug through the polymer matrix. Importantly, water-soluble polymers should not contain low molar mass polymer fractions as these lower molar mass chains may be absorbed into the body. Degradability of the polymer is not required for oral administration. It is important to note that even though specific formulations for oral ER are developed, this route of administration remains limited by the formulation's residence time in the gastrointestinal tract, which is commonly 5–10 hours. A very recent development has overcome this limitation based on an elastic polymer formulation that unfolds in the stomach and slowly degrades over the course of several days or potentially weeks [32]. Different polymeric systems are used as a matrix to coat the active drug in long-acting formulations [21]. Opioid ER formulations are available as capsules or tablets in different doses. The difference between each formulation is related to the pharmacokinetics of the delivery system, which determine the dose and the dosing interval. These specific formulations will be discussed in the following paragraphs, organized based on the released opioid (Table 1).

    Extended-release morphine capsules that use SODAS® (Spheroidal Oral Drug Absorption System) technology [33] are available for sustained drug release over 24 hours (Fig. 3) [34]. This formulation consists of a gelatin capsule that contains both immediate-release (IR) and extended-release (ER) beads of morphine in a ratio of 9:1 (w/w), which allow to reach a therapeutic level of morphine within 30 minutes (IR beads) while maintaining the plasmatic concentration for 24 hours (ER beads). This technology is based on spherical beads with a diameter of 1–2 mm, containing the drug and the excipient (Fig. 3, in gray), coated with a layer of release rate-controlling polymers such as a statistical copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride, sold under the tradename Eudragit [35] (Evonik Industries) and also sometimes referred to as an ammonio-methacrylate copolymer (Fig. 3, in blue). The beads are prepared by coating of a sugar/starch core with morphine and fumaric acid as excipient followed by the sustained release polymer coating. This coating is not present for the immediate-release beads. After administration and dissolution of the gelatin capsules, these coated beads are exposed to the gastric fluid and water enters the beads to dissolve the morphine and fumaric acid. The latter is present both as osmotic agent to ‘drag’ the water into the beads and to control the pH, making the release rate independent of the pH of the GI fluid. Even though the polymer coating layer is insoluble in the GI fluid it controls the morphine release rate by providing a diffusion barrier.

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    Figure 3 Representation of ER capsule using SODAS® technology.

    Other sustained release (SR) pellet systems of morphine have been marketed under the brand name Kadian [36] and based on the same SODAS technology. However, the gelatin capsules of Kadian only contain one type of beads that provide both immediate and sustained release [37]. The coating used in this system is formed by an insoluble ethylcellulose layer containing two different pore forming agents, namely polyethylene glycol (PEG with a molar mass of 6000/mol) and a copolymer of ethyl acrylate and methacrylic acid (Eudragit, Evonik Industries, also known as methacrylic acid copolymer (type C)). Once the capsule is administered, the gelatin capsule dissolves and releases the pellets into the GI fluid. In the acidic medium of the stomach only the PEG is dissolved forming small pores into the ethylcellulose layer leading to immediate-release of a small fraction of the morphine. The carboxylic acid groups of the ethyl acrylate methacrylic acid copolymer are protonated at this low pH making it insoluble during passage through the GI tract, the pH increases in the intestine leading to the dissolution of the methacrylic acid copolymer resulting in the formation of bigger pores. As such, the drug can continue to diffuse from the beads, providing a constant therapeutic concentration of drug over 24 hours.

    In contrast to the previous two sustained release formulation based on rather complex capsules, the Oramorph sustained release formulation [38] is a relatively simple tablet form based on mixing the drug with a hydrophilic polymer excipient, hydroxypropylmethylcellulose [39]. After mixing and compression, the final tablets are obtained. Once the tablet enters the GI tract, the fluid penetrates the tablet, allowing swelling of the polymer, and formation of a viscous gel. The resulting gel network controls the rate of water diffusion into the matrix but also the drug diffusion out of the system. Additionally, a second drug delivery mechanism can occur due to the erosion of the outer part of the matrix. With this device a therapeutic plasmatic concentration can be maintained for a period of 8 to 12 hours. A more advanced controlled-release morphine tablet that is based on the Contin™ delivery system [40] has also been commercialized. Here, the controlled-release process is regulated by the interactions between hydrophilic and hydrophobic polymers to fine-tune the diffusion of the drug and, thus, its release rate. In this formulation, morphine is mixed with a hydrophilic polymer matrix formed by a mixture of hydrophilic hydroxypropylmethylcellulose and hydrophobic hydroxyethylcellulose. The mixture is hydrated with water or alcohol and then fixed with a hydrophobic aliphatic alcohol, for example, cetostearyl alcohol which is a mixture of stearyl alcohol and cetyl alcohol. This hydrophobic component controls the GI liquid penetration rate. The final tablet form is achieved by adding tableting aids after compression of uniform granules. The partition coefficient of morphine between the hydrophilic and the hydrophobic parts controls the drug release from the tablet. Once the tablet comes in contact with the GI liquid, a swelling of the hydrophilic matrix occurs, giving a viscous gel. The kinetics of the drug release are directly linked to the swelling of the hydrophilic polymer matrix, which is controlled by the rate of fluid penetration through the hydrophobic part. Consequently, the general rate of drug release is regulated by variation of the ratio between the hydrophilic and the hydrophobic polymers. Using this system, morphine can be administered as a twice daily formulation.

    Oxycodone controlled-release [41] tablets have been designed using the AcroContin™ delivery system [42]. The formulation is based on the same dual polymer matrix as used in Contin™, vide supra. This delivery system provides both the immediate and the extended-release of the drug, which cannot be achieved using the Contin™ system alone. Instead of using a neutral hydrophilic polymer, AcroContin™ uses a cationically charged ethyl acrylate, methyl methacrylate trimethylammnoniumethyl methacrylate chloride copolymer to control the drug diffusion. Again the system is fixed with hydrophobic aliphatic alcohols to control the GI liquid penetration rate within the tablet. This formulation shows both immediate and sustained release. The immediate-release comes from the dissolution and the diffusion of the drug that is located at the surface of the tablet. The extended-release is achieved through the same strategy as the Contin™ system, the active component is released from particles embedded into the matrix. This formulation provides a first dose release of 40% over the first hour, followed by an extended-release for up to 12 hours.

    Sustained release of oxycodone has also been developed in a more tamper-proof ER formulation, using the DETERx™ technology [43]. Indeed, opioid abuse after prescription has been discouraged through the development of new drug delivery systems [44] and [45]. The DETERx™ formulation is specifically designed to retain its time-release mechanism even after common methods of tampering (i.e. physical and/or chemical modifications). The formulation consists of small spherical beads containing oxycodone, a fatty acid, and waxy excipients that are charged into a capsule. Embedding the drug in a hydrophobic environment leads to diffusion-controlled slow release. This formulation of oxycodone is unique in that it is an abuse-deterrent formulation designed to allow sprinkle-dosing on food or easy passage through nasogastric and gastrostomy tubes. The intended time-release profile is maintained by either of these two convenient methods of administration [46] and [47].

    Similarly, to facilitate tamper-free drug delivery, another extended-release formulation of oxycodone was developed using the ORADUR® system [48] and [49]. This technology combines extended-release properties with an improved tamper resistance, limiting potential abusers to self-administer the drug by crushing, snorting, injection or inhalation. The capsule is filled with a high viscosity liquid carrier material and the drug. Herein, this specific formulation the viscous carrier consists of sucrose acetate isobutyrate and a cellulose acetate butyrate as polymeric thickener, to form a hydrophobic viscous fluid that is transformed in a matrix with elastic properties when it is in contact with an aqueous medium (e.g. GI fluid) leading to slow diffusion controlled-release.

    The first hydromorphone ER formulation (under the brand name Palladone™) was based on a biphasic drug release, combining both IR and ER over 24 hours [39]. The formulation used a controlled-release melt extrusion technology. The drug is blended with a hydrophobic matrix composed of a copolymer of ethyl acrylate, methyl methacrylate and trimethylammoniumethyl methacrylate chloride, stearyl alcohol and ethylcellulose. The matrix controls both the rate of water permeation within the pellet and the diffusion of the drug from each pellet. The therapeutic concentration in the blood is sustained over 24 hours. Unfortunately, the consumption of alcohol was found not to be compatible with such capsules. It results in the disruption of the system, releasing a fatal dose of hydromorphone. Due to the high risk of overdose, the food drug administration decided to block all marketing and sales.

    Nonetheless, another hydromorphone ER tablet form has successfully been developed [50] and [51]. This formulation uses the osmotic extended-release oral delivery system (OROS®) Push-Pull™ technology [52]. It is the only available ER form of this analgesic (Fig. 4) [53]. The OROS® system is suitable for poorly water soluble compounds. The OROS® Push-Pull™ technology consists of a drug layer consisting of the drug, polyethylene glycol and polyvinylpyrrollidone and an osmotic push layer consisting of polyethylene glycol, sodium chloride and hydroxypropylcellulose that is coated by a semipermeable shell membrane consisting of cellulose acetate and polyethylene glycol [54]. Once in the GI tract, the fluid flows through the membrane at a controlled rate, allowing the push layer to expand and eject the suspended drug from the drug layer out of the tablet through the delivery orifice. This formulation provides a sustained release over 24 hours [53].

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    Figure 4 Illustration of OROS® Push-Pull™ drug delivery tablet.

    Interestingly, extended-release oxymorphone tablets were developed based on a delivery system called TIMERx™ [55]. This technology is based on a hydrophilic natural polymer based matrix that consists of xanthan gum, locust bean gum and dextrose. These polysaccharides form a coat layer around the drug core. This layer regulates the rate of drug release by controlling the GI fluid permeation into the tablet and the solubilization/diffusion of the drug through the tablet. Contact of the hydrophilic layer with water forms a viscous gel that controls the release of the drug from the tablet, as previously discussed for the Contin™ technology. TIMERx™ drug delivery provides sustained analgesia for 12 hours (Fig. 5) [39].

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    Figure 5 Structure and mechanism of the TIMERx™ drug delivery tablet.

    Hydrocodone ER formulations were developed for the first time as a single-agent drug using the OraGuard™ drug delivery technology [56]. The OraGuard™ tamper deterrent and alcohol resistant platform was designed to protect drugs against mechanical crushing and prevent dose dumping when the drug is taken with alcohol [57]. Hydrocodone is comminuted with a high polymer load and coated with a polymeric membrane that controls the drug release even when the tablet is crushed. This formulation is still in clinical trials (Phase III) and no details on the polymers used have been disclosed [58].

    Liquid formulations are also available for patients such as children or elderly patients. The introduction of biocompatible polymers [59], [60], and [61] is an alternative for the design and the production of modified release formulations. Among adequate polymeric materials used for drug microencapsulation, significant efforts have been devoted to the development of hydrophobic ethyl cellulose as the drug carrier. It has been widely used in liquid oral pharmaceutical formulations, and is generally regarded as a non-toxic, nonirritant, safe and stable material. For example, ethyl cellulose pseudolatex particles are able to encapsulate morphine [62] and used for the development of a stable final pharmaceutical form with diffusion-controlled slow release. Using 1% of carbopol as the thickener in the suspension's final formula, 81% of the initial dose of morphine is released over 8 hours [63].

    Oral controlled-release opioid formulations enhance a better pain relief due to the extended therapeutic blood concentration and the improvement in dosing intervals. A reduction of blood drug level fluctuation decreases the appearance of adverse effects (Fig. 1). The differences between all oral ER opioid drugs are the cost, the formulation, including the drug release system, and the excipients. Actually, no data support the higher efficacy of one drug compared to another one. Selection of the first treatment relies mainly on the clinician, who usually prescribes one preferred drug. This preference is sometimes in function of past opioid responses of the patient. Taking into consideration all the parameters such as pain tolerance, drug metabolism and the management of side effects, all treatments have specific benefits and drawbacks.

    Transdermal administration

    Patches

    Transdermal drug delivery systems are an interesting alternative to oral delivery technologies because they offer several advantages over other existing analgesic administration methods [64]. Indeed, this strategy is non-invasive, simple, safe and effective for pain management [65]. Additionally, compared to other parenteral routes, practical drawbacks related to the use of needles and the required venous access, are avoided. Similar to other parenteral routes, transdermal drug delivery also by-passes first-pass hepatic metabolism and circumvents gastrointestinal tract-to-blood passage, common to the use of oral analgesics. In addition, it can also provide release profiles during long periods of time, providing an improvement in patient compliance.

    The major challenge for transdermal delivery is the limited number of molecules that can be formulated for this type of administration, as passive diffusion of the drug through the stratum corneum is required [66]. These analgesics have to present certain characteristics, which include a low molecular weight (less than 500 Da), appropriate partition coefficients and a high potency (i.e. with low dosage, typically less than milligram doses per day) [67]. Delivery of hydrophilic drugs using transdermal delivery is difficult and has not been exploited to date for opiates. There are also some general considerations for designing polymer based transdermal patches. These polymers should not be water-soluble to avoid dissolution and potential interactions with the skin. Furthermore, they need to be soft and tacky to have good adherence and contact with the skin. This means that the polymer should have a low glass transition temperature, at least below body temperature, but preferably even lower to facilitate sufficient chain mobility for diffusion of the drugs.

    Transdermal delivery systems are, according to the penetration mechanism through the skin, subcategorized in three generations, only two of which were used in opioid applications. The first generation of systems gave way to many of today's patches by judicious selection of drugs that can cross the skin at therapeutic concentrations by passive transport. The second generation was developed to increase the skin permeability of small-molecule delivery using alternative driving forces for the transport (using for example the iontophoretic transdermal system, vide infra), while the third generation enabled the delivery of small-molecules, macromolecules, virus-based and vaccines through the skin's stratum corneum by more invasive systems (such as microneedles and microdermabrasion) [64].

    Transdermal delivery systems were applied to the management of chronic pain. Among all molecules which are available to treat chronic pain, only two (fentanyl and buprenorphine) have been used in this type of system due to their high potency, high lipophilicity and low molecular weight. Indeed, due to the very fast metabolization of fentanyl by enzymes in the small intestine and the liver, transdermal delivery technologies are highly suited to provide fast and efficient pain relief.

    First generation: reservoir and matrix patches

    Fentanyl is a suitable analgesic for transdermal administration thanks to its physicochemical characteristics. It has a low molecular weight (286 Da), high lipophilicity (LogP = 717), and optimal skin flux (around 1000 times higher than morphine) [66].

    Different transdermal fentanyl delivery systems [68], patches that contain a drug reservoir or a drug-infused matrix, rely on skin penetration by passive diffusion (Fig. 6).

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    Figure 6 Schematic representation of reservoir and matrix patches; adapted from [65].

    The fentanyl-containing reservoir patch represented the first opioid transdermal delivery system available in this form and proved effective and convenient for providing pain relief. This delivery system contains a reservoir of fentanyl with a sufficient dose for a three day treatment [69]. It consists of a backing layer, formed by a polyester film that protects the patch from the environment, a liquid drug reservoir with dehydrated alcohol gelled with hydroxyethylcellulose, a membrane, constituted of an ethylene-vinyl acetate copolymer, which controls the rate of release of fentanyl from the reservoir, and a silicone adhesive layer to adhere the patch to the skin surface. The fentanyl release occurs from the reservoir, at constant rate until the reservoir is emptied. The rate of fentanyl diffusion across the skin layers is determined by the properties of the ethylene-vinyl acetate copolymer membrane. The addition of alcohol (0.1 mL/10 cm2) into the formulation also helps to increase the permeability of fentanyl through the skin. After the initial application of the fentanyl transdermal system, the skin gradually absorbs fentanyl, resulting in an increase of plasma concentrations. A maximum dose that remains relatively constant is achieved in 12–24 hours, with only some small fluctuations, and an efficacy over 72-hour [70]. After patch removal, fentanyl serum concentrations decline gradually, dropping to 50% in approximately 20–27 hours. The bioavailability of transdermally administered fentanyl has been calculated to be approximately 90% [71]. This percentage depends on the skin permeability and the body clearance of each patient. The reservoir patch presented a risk of drug leakage (incidental or intentional by cutting), and this was clearly considered as an important concern.

    To address this concern about the reservoir system, a second transdermal patch generation was developed. Herein, the drug is directly dissolved into the matrix, a semi-solid formulation of a polyacrylate adhesive. Fentanyl matrix patches with a lower drug load were found to be superior to and as safe as established standard oral and transdermal opioid treatments [72]. Afterwards, a second type of matrix patch was developed. In such systems the drug is dispersed in a semi-solid formulation within the adhesive itself. The matrix is constituted by fentanyl-containing dipropylene glycol droplets dispersed in a silicone matrix formulation. This formulation modifies both the drug release profile by extending it, and the drug loading which can be reduced by 35–50%, compared to other matrix patches. The rate-controlling membrane ensures that fentanyl concentrations are maintained at a constant level throughout a 72-hour application of the patch. It was shown that the two fentanyl transdermal delivery systems (reservoir and matrix patches), described before, have equivalent properties in terms of tolerability and bioavailability of the drug [70].

    The fentanyl patches present limited side effects that can, generally, be easily treated. The most important adverse effects reported are dermatological reactions, such as skin occlusion or local irritation [69]. A rotation of skin sites can prevent these mild side effects. For patients suffering of chronic pain, transdermal delivery systems are well tolerated due to the administration of stable opioid doses. Some sort of ‘breakthrough’ pain coverage is still advised by, for example, an immediate-release oral dose of morphine.

    Buprenorphine is also available as a matrix patch. It provides consistent blood drug concentration over a 7-days dosing interval [73]. A comparison between transdermal fentanyl and transdermal buprenorphine patches was reported, showing the equal efficacy [74]. The best treatment seems to switch between the two opioid formulations to increase tolerance and acceptability by suppressing side effects.

    Iontophoretic transdermal system (ITS)

    The first generation of patches (vide supra) functions through passive transdermal diffusion, eventually resulting in a slow absorption of the drug from the skin depot. One drawback of this approach consists of the prolonged action after removal of the patch.

    To provide a more precise control over the delivery of the analgesic drug, an alternative system that improves the permeation of the drug through the stratum corneum by using an active transport was developed. The iontophoresis patch technology was designed for the management of moderate to severe pain in a clinical setting (Fig. 7) [75] and [76].

    gr7

    Figure 7 Iontophoresis patch technology adapted from [77]. The system is composed of a plastic top containing the battery and electronics, the plastic bottom contains two hydrogel reservoirs and a skin adhesive. The hydrogel located at the anode contains the opioid (blue dots). The other hydrogel, located at the cathode, contains only pharmacologically inactive compounds (yellow dots).

    The iontophoretic system is based on a low intensity electric current that drives the active transport of analgesic drugs through the skin and into the systemic circulation. This device uses the skin to complete the circuit between the anode and the cathode, allowing transport of ionized active molecules present in a reservoir. More precisely, the driving force for the displacement of ionized molecules, is based on the electrostatic-repulsion of similar charges. Drug delivery by an iontophoretic system is however influenced by several parameters including the skin surface which is in contact with the electrode, the current intensity as well as the duration, but also the chemical properties of the molecule. Generally, the best efficiency of this delivery system is obtained for lipophilic compounds with a low molecular weight and positive charge [75]. As a consequence, the number of opioids that can be used for this delivery system is limited [66]. Nonetheless, fentanyl is suitable for iontophoretic transdermal delivery, reaching blood drug concentrations comparable to those obtained by intravenous infusion [78] and [79]. In contrast, morphine is not ideal for use in iontophoretic patches [80] and [81], due to its low lipophilicity that prevents skin penetration. The general requirements for the polymer are similar as described for the first generation patches.

    The iontophoresis patch is a patient-controlled analgesia (PCA) system. Patients could self-administer analgesic doses by pressing one button depending on their need for pain relief. For example in the case of fentanyl, a pre-programmed dose delivers 40 μg of drug over 10 min, with a maximum of six doses per hour. This type of administration offers several advantages compare to passive transdermal systems, such as an increase of opioid absorption rate, a rapid decrease in plasmatic concentrations and a more precise control of dosages.

    Several limitations inherent to this transdermal drug delivery system need to be noted as well. First, the impossibility to modify the delivered dose during the treatment can become problematic in case of patients with considerable opioid needs for a suitable pain relief. The other limitation is associated to the patient-controlled analgesia (PCA) concept, wherein patient involvement is crucial. The patient needs to be a suitable candidate for pain self-management, since he/she needs to be able to follow the instructions for operating the system. Finally, the most significant drawback of this technology consists however of the associated price which has limited its broad applicability. Iontophoretic transdermal system marked an evolution in pain management system with an improvement in terms of safety and convenience, as compared with existing patient controlled-analgesia, through the use of a pre-programmed and disposable drug delivery systems [82].

    Topical administration

    Topical opioid treatments give access to local analgesia with attenuated or eliminated systemic adverse effects. Results from case studies and pilot clinical studies on local morphine treatment for painful skin ulcers, however, have not shown to be fully convincing with respect to efficacy and tolerability [83], [84], and [85]. A major drawback is the required repeated replacement of the wound dressing, which is very painful for the patient and bears a risk of destroying any regenerated epithelia. Therefore, the interval of the changes should be extended as much as possible and new formulations were still needed.

    Various studies dealing with local applications of opioids for the treatment of painful skin ulcers have been reported [86]. Most of them show an analgesic effect post administration without side effects that are normally observed after systemic administration. Indeed, the potential advantages of such a delivery system include the possibility to optimize opioid concentration at the site of pain and decreased systemic opioid levels. For topical formulations, a morphine solution is generally mixed with a hydrogel containing 2.3% carboxymethylcellulose polymer with 20% propylene glycol, but other formulations have been used as well [85], [87], [88], and [89]. Unfortunately, this gel-based morphine formulation does not adhere very well to a moist wound surface.

    To improve adhesion, a novel topical preparation of morphine was formulated using poloxamer 407 (P407), a thermoreversible gel also known as Pluronic (F127) [90]. The temperature-controlled self-assembly of poloxamer into micellar structures can yield hydrogels at sufficiently high polymer concentrations [91]. Poloxamer 407 is a triblock copolymer consisting, by weight, of approximately 70% polyethylene oxide as outer blocks and 30% polypropylene oxide as middle block with an average total molecular weight of 12.5 kDa. P407 gels show adequate bioadhesive properties. The formulation of 0.5% (w/w) morphine–HCl in a 22% (w/w) P407 hydrogel was developed [90]. The observed release follows zero-order kinetics and is controlled by drug diffusion from the gel matrix. Morphine–HCl was released at a rate of 150 μg/cm2/h. These results are in favor of the use of P407 gel as a topical sustained release formulation for the treatment of painful ulcers [92], although absorption of these relatively low molar mass polymers may be a concern.

    Parenteral administration

    Due to limitations in bioavailability and the formulation challenges associated with some of these pharmaceuticals, parenteral drug delivery is an administration route of paramount importance. This includes intravenous, subcutaneous and intramuscular injection. Indeed, parenteral administration of opioids is needed in patients with gastrointestinal tract disorders, when the opioid need is high or in cases where toxicities associated with intermittent dosing schedules emerge. Morphine sulfate is the most commonly used parenteral opioid and it can be administered as a bolus or continuous infusion. Continuous parenteral administration of opioids is usually cumbersome and expensive, it needs availability of vascular or subcutaneous catheters, infusion pumps, and it requires trained nursing and pharmacy personnel.

    Subcutaneous administration route

    Subcutaneous administration of opioids can be highly useful for patients that do not have indwelling intravenous access and require parenteral opioid administration [93]. Here, the infusion rates of fluid that can be administrated have been found to be around two to four milliliters per hours (without generation of pain at the administration site), which represents the limiting factor [94]. The main advantage in favor of subcutaneous over intravenous analgesic administration is that there is no need for vascular access. Indeed, the administration sites can easily be changed and problems associated with indwelling intravenous catheters are avoided. For local treatments, parenteral administration of drugs is often associated with poor retention of the pharmaceutical product at the site of delivery. In case of systemic delivery, short half-lives can be problematic. To compensate for these drawbacks, parenteral drug administration is typically done at high concentrations or at high dosing frequencies. However, high concentrations of the drug can result in adverse side effects.

    To increase the efficacy of parenteral administration one can make use of delivery vehicles. In this method, the administered drug is encapsulated within a material that releases the therapeutic agent in a controlled manner that optimizes the dosage for a specified period of time. Hence, polymer implants can be used. Advances in polymer chemistry have resulted in the development of polymeric delivery devices that reliably release therapeutic compounds in a controlled and continuous fashion. In this way a highly biocompatible, non-biodegradable, polymeric device which releases hydromorphone at a constant rate over four weeks was developed. This device could improve compliance, minimize the risks of drug diversion, and provide a low cost alternative for patients with pain who could benefit from chronic parenteral opioid infusion [95]. In this formulation hydromorphone is embedded in a controlled-release matrix, namely an ethylene-vinyl acetate (EVA) copolymer. In the study reported by Lesser et al., the implant had a cylindrical geometry and measured approximately 0.27 cm in height and 1.05 cm in diameter. Variations in the thickness and diameter of these devices, as well as in the number of devices implanted, provides flexibility in the amount of hydromorphone released per hour, the duration of hydromorphone release, and the magnitude of plasma hydromorphone levels. To avoid the potentially deadly ‘burst effect’ with this type of devices, a poly(methyl methacrylate) coating has been used. Placing an uncoated cylindrical channel through the center of the coated polymer limits the available surface area for drug release, and allows hydromorphone to be released with near zero-order kinetics for approximately 4 weeks in preclinical in vitro and in vivo models. These implants could substantially reduce the need for pumps, storage or refrigeration, frequent medical or nursing evaluations and multiple daily opioid doses.

    There are several potential disadvantages linked to the use of these opioid delivery devices. Placement and removal of these polymer disks requires a minor surgical procedure. They are inserted through a small skin incision and advanced into the subcutaneous tissues. It should be mentioned that this may be avoided by developing thin tubular implants with a diameter up to 2 mm that can be simply injected as is done for the contraceptive implant Implanon™. These implanted hydromorphone polymers were developed to meet stable dosing needs of patients in pain. Acute exacerbations in pain intensity will require supplemental oral or parenteral opioids. Finally, this polymeric drug delivery system may not be appropriate for patients requiring high doses of parenterally administered opioids. As noted above, the dose of hydromorphone delivered per hour can be modified by changing the height of the implant and more than one polymer implant can be placed subcutaneously, as was tested in rabbits to increase the delivery rate and dosing even further.

    Clinically, subcutaneous administration of opioids is not preferred for patients with very high opioid requirements, who may be best served with another method of opioid delivery or a combination of methods to provide adequate analgesia.

    Continuous infusion

    The subcutaneous administration of analgesics is often used in combination with a pump-based PCA system. This provides a better control over analgesia by the patient, as compared to the continuous infusion system alone. The subcutaneous administration of hydromorphone using a PCA system gives a bioavailability of around 80% [96]. Steady-state plasma hydromorphone concentrations were reached within 24 hours in a study performed by Moulin and coworkers. When compared to the intravenous route, subcutaneous PCA administrations avoid the need for vascular access, and present the possibility to easily change the administration site. Alternatively, the analgesic drug can be bound to an ionic polymer such as hyaluronic acid or poly-γ-glutamic acid. The polymer can be anionic, and the drug cationic, or vice versa. The polymer-drug matrix can be injected either subcutaneously, intramuscularly or intraperitoneally. The matrix is degraded over time via the enzymatic machinery of the body, thereby releasing the drug [97].

    Intravenous route

    The intravenous administration is prescribed for patients whose pain relief cannot be controlled by less invasive systems. For patients who need opioid infusion for pain control, nursing support is required, which generates serious costs. Depending on the frequency and duration of the treatment, different devices can be used, such as a Port-a-Cath® or other types of indwelling central or peripheral catheters [98]. Any indwelling intravenous catheter can become a source of infection. Many opioids are commercially available at various concentrations for intravenous solutions, such as morphine, hydromorphone, fentanyl and sufentanil. Due to the above mentioned drawbacks, intravenous administration is only used in extreme cases, when more common routes are not appropriate, for example in advanced cancer, or in palliative care.

    Perispinal route

    The majority of patients, who suffer of chronic pain, can be adequately treated by opioid administration using one of the many systems discussed above. However, in some cases the pain relief remains troublesome despite large administered opioid doses. Patients can for example suffer from unmanageable adverse effects such as nausea or oversedation. As last resort, opioids can be administered as local anesthetics using the perispinal route [99] and [100]. Perispinal opioid administration involves the direct application of a small opioid dose close to the spinal opioid receptors. The main advantage of this administration system is the suppression of undesirable effects by decrease of the total opioid dose.

    This way of administration requires the implantation of a permanent catheter, associated to an external infusion pump, into the epidural or intrathecal space [101]. Different perispinal approaches including intrathecal injection, continuous intrathecal infusion, epidural bolus, and continuous epidural infusion are available for opioid drug delivery [98].

    The choice between epidural versus intrathecal application or external versus implantable pumps to deliver the opioid is based on several factors such as the type and pain location, the duration of treatment, the patient preference, etc. The opioid dose required for epidural administration is around 10 times superior to intrathecal administration [102]. Intrathecal opioid delivery allows higher opioid dose administration due to a focused opioid application at the receptor site, generating decreased drug-related adverse effects. Regarding treatment duration, a therapy exceeding 6 months requires the placement of an intrathecal catheter to limit refills of the pump.

    Different types of side effects are associated to perispinal opioid delivery. The surgical and procedural complications include bleeding and/or infections [103]. Some complications can originate from a system malfunctioning, including kinking, obstruction, disconnection, tearing or migration of the catheter, all of which can have an influence on the rate of opioid delivery. Finally, pharmacological side effects such as overdoses can be avoided by means of precise formulation. Generally, except constipation which is the most common adverse effect encountered in opioid treatment, perispinal opioid administration does not generate any supplementary side effects for patients who are already tolerant to opioids.

    Clearly, this route of administration needs nursing care and a clinical environment, making this delivery system highly expensive.

    Conclusions and perspectives

    Chronic pain therapy is a complex pathology with extensive consequences for the patient and society. The main challenge with chronic pain therapy is the need for a multidisciplinary and multipharmaceutical approach, which makes advances in daily treatment difficult to optimize and follow up. Integration in chronic pain schemes of newer drugs such as glutamate antagonists, vanilloid receptor agonists, acetylcholine and norepinephrine modulators, adenosine receptor agonists, anti-inflammatory drugs will be as important as the administration routes of these drugs.

    Adequate pain relief can significantly improve the quality of life of these patients and attenuate this societal burden. Chronic pain management guidelines recommend the use of long-acting, extended-release analgesics because they provide prolonged, and more consistent plasma concentrations of drug compared with short-acting compounds. But before exposing patients to an extended-release formulation of opioids, they must fulfill certain criteria. The most important of all is that the patients must be opioid tolerant; meaning that they must consume more than 60 mg of morphine (or an equivalent) per day for more than seven days.

    To manage chronic pain, several opioid delivery systems are available. Selection of the most efficient, cost-effective and user-friendly method needs careful consideration. This means that the patient's ability to use a specific type of delivery system, the efficiency of the system, the potential complications associated, and the cost must be regarded.

    Oral administration of opioids is efficient and acceptable for most of patients suffering of chronic pain. Indeed, a large set of oral opioid drug formulations is available. Obviously, the main advantage is the ease of administration. Additionally, various polymer systems have been applied successfully resulting in sustained release providing longer and gradual pain relief. The major disadvantage for oral therapy is the first-pass effect and the organ-dependent metabolism, resulting in the necessity of higher dosage forms compared to other types of administration. Minor and less frequent disadvantages occur in patients with dysphagia or neurological impaired persons that cannot swallow.

    Alternatively, the transdermal route is useful for highly lipophilic opioid such as fentanyl and buprenorphine, whereby the drug is formulated into a polymer reservoir coated with an adhesive polymer or the drug can directly be formulated with the adhesive polymer. Fentanyl and buprenorphine are equally effective, but the latter drug is less addictive. Transdermal patches have a medium risk for adverse effects and are even approved in children older than 2 years. No mg/kg dosing is however used as over- and under-dosing can occur due to age-related and developmental changes in pharmacokinetics. Transdermal formulations are often preferred by patients compared to oral controlled-release options [104]. The advantages of transdermal therapy in elderly people include a non-invasive long term administration mode that is independent from intestinal absorption and circumvents first-pass effects. A slow attainment of the peak-plasma concentration also results in improved therapy compliance. Some disadvantages include skin irritation and the limitation of the drug types that can be used with this formulation. The dose is also limited by 240 mg/h, without any possibility for dose adjustments outside the hospital. The second generation of transdermal administration, the iontophoretic delivery system, has a better control of dosage, gives a rapid absorption rate and allows fast clearance. It is important to note that the associated cost of this technique represented a major drawback for its broad applicability.

    Even though topical opioid therapy is not fully established, it can give analgesia without common opioid side effects. By applying the drug locally, the total opioid dose can be reduced. The only drawback is related to the repeated replacement of wound dressing, as the regeneration of epithelia can be damaged. The intravenous opioid administration system is useful for patients whose pain cannot be controlled by less invasive ways. The intravenous opioid infusions can be administered by continuous infusion, or using a patient-controlled analgesic device. The delivery can be accomplished by central venous access, vein puncture or implantation of a Port-a-Cath® in the subclavian vein during surgery. The latter is commonly used in cases of chemotherapy. The major disadvantages are the risk of infection, the cost and the need of educated personnel, limiting the patient's freedom. Finally, for a limited number of patients, for who adequate analgesia by systemic administration fails, because of side effects like nausea, sedation and constipation, spinal or epidural dosing via catheters needs to be considered. The dose is directly injected at the spinal cord, giving a better analgesia and a reduction of side effects, which allow a decrease of the total opioid dose. Because this mode of administration is invasive and accompanied by a significant risk of infection, it is restricted to the palliative care.

    In the future polymer implants can also be employed in pain therapy. The cylindrical geometry and variations in thickness and diameter can change the rate of release and total dosing. It is reliable, controlled, gives a better compliance, and there is less need for a pump or a daily intake of drugs. The disadvantage is that it requires a minor surgical intervention, which may be overcome in the future by developing thin tubular implants that can be directly injected. Such a device might present a possible burst-release effect of the drug, with a risk to lose the implant in the body due to migration. For the latter, it should be noted that on-demand drug delivery systems have already been developed and may be applied for opioid delivery in future developments [105], [106], and [107].

    In the field of drug delivery, nanotechnology aims to formulate therapeutic agents in biocompatible nanocarriers (roughly 10 to 200 nanometer size range), such as nanoparticles [108], nanocapsules, micelles and liposomes, nanotubes and dendrimers. The major advantage of these formulations is their extended blood circulation time, in combination with enhanced cellular uptake especially by non-healthy, cancerous, tissue, also known as the enhance permeation and retention effect [109]. Furthermore, functionalization of the nanocarriers with targeting ligands allows direct drug delivery to the site of action, improving the bioavailability of the drug [110]. In this way, these nanosystems help to prevent the possible undesired exposure of the drug to off-target tissues. Although nanotechnology for drug delivery is extensively used for therapeutics in cancer and inflammation applications, in the literature only few examples have already been reported for opioid administration. One example consists of an extended-release morphine suspension, that uses DepoFoam® technology [111]. It is a single dose liposomal formulation of morphine, which is administered by epidural injection [112]. This formulation is applied following important surgery, it decreases the need of repeated systemically administered analgesics, and provides an efficient pain relief for up to 48 hours after injection. This technology disperses lipid-based particles that form multivesicular liposomes containing multiple internal aqueous chambers [113]. The drug is encapsulated in the water-filled particles affording a milk-like solution ready to be injected. This example of a ‘nanotherapeutic’ exemplifies further innovations based on nanotechnologies [114].

    Clearly, if a new technology could arise that realizes a stable continuous opioid release system that lasts longer than the state-of-the-art 72 hour patches; it would represent a tremendous advancement in chronic pain therapy. It could improve the patient's quality of life and compliance by a less timely bound intake of drugs. Continued research remains of paramount important to tune the optimized administration format for each patient with chronic pain.

    Acknowledgements

    We thank the Research Foundation-Flanders (FWO Vlaanderen) for the financial support. This work is also supported by the Scientific Research Network (WOG) ‘Supramolecular Chemistry and Materials’ of the Research Foundation-Flanders.

    References

    Footnotes

    1 Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, Brussels B-1050, Belgium

    2 Department of Anaesthesiology and Perioperative Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, B-1090 Brussels, Belgium

    3 Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281, 9000 Ghent, Belgium

    4 Supramolecular Chemistry Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281, 9000 Ghent, Belgium

    Corresponding authors:

  • The Opioid Epidemic in the United States

    There is an epidemic of opioid abuse. This article discusses the history of opioid use. Abusers of opioids are at great risk of harm. There have been increasing legislative efforts to curb this abuse and we present a review of the current state of these laws. Naloxone has made a profound impact in the care of these patients if they present for medical care early enough. This paper discusses naloxone pharmacodynamics, its use in the medical setting, and how its use is now being expanded to include nontraditional providers with take home naloxone programs.

    Keywords: Opioids, Opioid epidemic, Heroin, Prescription drugs, Overdose, Legal liability.

    Key points

    • There is an epidemic of opioid abuse in the United States.
    • The risk of heroin abuse has been appreciated for more than a century with it now being considered to have no justifiable medical use.
    • Opioids commonly prescribed to treat painful conditions have had a dramatic increase in the rate of abuse, addiction, overdose, and death.
    • The increase in complications corresponds with a dramatic increase in the rate of opioid prescriptions that resulted from pressures placed on practitioners to avoid undertreatment of pain.
    • Naloxone is a competitive opioid antagonist that is used to reverse the adverse effects of opioid intoxication. It is increasingly being prescribed for emergent outpatient administration.

    Pain is a more terrible lord of mankind than even death itself. —Dr Albert Schweitzer, 1931.

    Introduction

    The United States is currently experiencing an epidemic of opioid abuse. This article discusses the history of opioid use for pain management and how epidemiologic data demonstrate a convincing degree of association between the increasing rate of opioid prescriptions and the increasing rate of adverse effects, aberrant use, and unintentional death from opioids. There is a clear but not complete overlap between prescription opioid abuse and heroin use. Regardless of drug of choice, abusers of opioids are at great risk of harm. There have been increasing legislative efforts to curb this abuse and we present a review of the current state of these laws. Naloxone, an opioid antagonist, has made a profound impact in the care of opioid overdose patients who present for medical care early enough. This paper discusses naloxone pharmacodynamics, its use in the medical setting and how its use is now being expanded to include nontraditional providers with take home naloxone (THN) programs.

    Opioid is the term used to describe a substance that is able to bind the opioid receptors. The more specific term, opiate, refers to a class of agents that are directly derived from naturally occurring opium. The opiate class includes morphine and codeine. The term narcotic is less informative, has a negative connotation, and tends to be reserved for law enforcement and the lay public when referring to an opioid that is used illicitly.

    The use of opiates dates back to the Sumerians of Mesopotamia who first cultivated the opium poppy around 3400 bc. The plant was known as Hul gil or “joy plant.”1 Opium use, both recreationally and for the treatment of various medical ailments, spread along routes of trade and conquest. Its use was abandoned in most of Europe during the Medieval Inquisition. Philippus von Hohenheim (1493–1541), known as Paracelsus and sometimes called the “father” of toxicology, is credited with the reintroduction and promotion of laudanum, a tincture of opium, for medical treatment in Europe.2 Thomas Sydenham (1624–1689) further popularized the medical use of laudanum and related products. Friedrich Sertürner (1783–1855) first isolated morphine in 1804.3 In an effort to find a nonaddictive alternative to morphine, Charles R. A. Wright first synthesized diacetylmorphine, or heroin, in 1874. Bayer Pharmaceutical Products later marketed heroin as an analgesic and cough suppressant.4 It was also touted a medication to help those addicted to morphine.5

    In modern times, there have been multiple swings in prevailing attitudes regarding the use of opioids for analgesia. For example, the first edition of the classic text, Cope’s Early Diagnosis of the Acute Abdomen, in 1921 directed the provider to withhold opioid analgesics until a diagnosis was certain in patients with undifferentiated abdominal pain. This practice persisted to some degree until recent times, despite numerous studies that demonstrated that the use of opioid analgesics does not interfere with the diagnostic process in these patients.6, 7, 8, and 9 The use of opioids for acute traumatic injuries or other acute painful conditions is less controversial.

    Opioid use for patients with chronic pain owing to cancer has long been a mainstay of therapy. The goal of this therapy is to maintain pain relief to tolerable levels to allow for improved quality of life. The risk of addiction or overdose is ethically justified through application of the principle of double effect. This principle dates back to St. Thomas Aquinas (1225–1274) and states that it is moral to perform an action in the pursuit of a good outcome with the knowledge that a foreseeable harm may occur. The action must fulfill the following conditions: the action cannot of itself be morally wrong, the good outcome cannot be directly caused by the harm, the potential harm cannot be the intention of the action, and the harm cannot be disproportionate to the good outcome.10 and 11

    Chronic pain has been estimated by the World Health Organization to be present in up to 22% of patients attending primary care clinics.12 Through most of the 20th century, physicians avoided the use of opioids in treating chronic noncancer pain. This practice was owing to fear of addiction, overdose, and lack of effectiveness. The concern over addiction started to wane in 1980 with the publication of a 1-paragraph letter in which the authors stated there were only 4 instances of addiction in review of more than 11,000 cases of patients receiving at least one opioid prescription.13 In 1986, Portenoy and Foley14 published a retrospective review showing addiction in only 2 of 38 patients treated with chronic opioid therapy. Both patients had a history of prior drug abuse. After this, there was a campaign of editorials proclaiming the safety of chronic opioid therapy for noncancer pain.15 and 16

    The drumbeat to eradicate pain continued despite no quality efforts to research the effects of opioid use in chronic pain. The term “oligoanalgesia” was coined in 1989 and worked to shift the blame onto the provider if the patient experienced pain.17 James Campbell18 introduced the concept of pain as the fifth vital sign in his 1995 Presidential Address to the American Pain Society. Numerous medical societies and organizations adopted policies of pain control that championed the use of opioids.19 and 20 The Veterans Health Administration adopted “Pain: the 5th vital sign” as the name of its 1999 pain management initiative that mandated evaluation and treatment of pain at all clinical encounters.21 The Joint Commission on Accreditation of Healthcare Organizations (now known as The Joint Commission) began assessing pain management as a requirement for accreditation in 2000.22 The balance shifted toward treatment of pain with less regard given for contributing to development of abuse and risk of opioid overdose.

    Despite the increase in opioid addiction and deaths that contemporaneously occurred with the dramatic increase in prescriptions for opioid pain medications, there has been a very slow response in the medical community. Numeric pain scores remain a part of the vital signs collected at clinical encounters, regardless of the reason for the encounter and often without consideration of the score given in a broader context. Within the past few years there has been some increased momentum to control the opioid epidemic.23 and 24 This paper looks at some of the responses to the epidemic including the implementation of prescription drug monitoring programs (PDMPs) and the use of THN. To effectively manage this problem, there will need to be increased research into pain, pain management, and opioid abuse.

    Epidemiology

    Opioid Prescription Epidemic

    The first decade of the new millennium saw a significant increase in the availability, use, and abuse of prescription opioid medications and the development of an unprecedented drug overdose epidemic. This situation slowly garnered the attention of medical organizations, news media and individual practitioners. As described previously, this phenomenon is complex and multifactorial in etiology, owing in part to increased emphasis on treating pain, a push toward the philosophy that opioid pain medications are “safe,” insufficient or ineffective oversight, and a marked growth in nationwide consumption and demand in the United States. As general medical use became more commonplace, so too did nonmedical use. This parallel relationship led to an estimated 25 million Americans engaging in the nonmedical use of prescription opioids from 2002 to 2011.25 The general epidemic seems to have peaked around 2010, the eleventh consecutive year that saw an increase in the number of prescription opioid-related deaths with 16,651 fatalities.26 Put into perspective, in that year, opioid analgesics contributed to more than twice as many deaths as heroin and cocaine combined.27 In 2009, deaths attributed to drug overdose surpassed mortality from motor vehicle collisions for the very first time.25 More than three-quarters of these drug overdose deaths are unintentional.26 Although medication overdoses frequently involve multiple classes of drugs, 4903 of 16,651 opioid deaths (29.4%) in 2010 involved solely the ingestion of opioids, a proportion nearly 3 times higher than fatal single-class ingestions of any other psychotropic or central nervous system medicine.28

    Morbidity and Economic Burden

    Prescription opioid-associated deaths notwithstanding, there are other considerable health consequences associated with these medications, and the morbidity associated with prescription drug overuse has also increased in recent years. Prescription opioids are associated with chronic constipation and narcotic bowel syndrome,29 falls and orthopedic injuries in the elderly,30 neonatal abstinence syndrome, and transition to intravenous (IV) drug use with further associated health risks such as infectious complications and human immunodeficiency virus and hepatitis C virus exposure.

    The resource costs associated with opioid abuse are considerable. Over the past decade, there has been a general increase in the number of emergency department visits and inpatient hospitalizations related to prescription drug use.31 and 32 From 2004 to 2011, the number of emergency department visits related to opioid abuse or misuse increased by 183%. In 2011, there were 420,040 emergency department visits for prescription opioid abuse.31 The increase in patient volume alone is yet another affliction on an already overtaxed health care system, but the financial cost is substantial as well. It is estimated that the abuse and misuse of prescription opioids are responsible for somewhere between $53 to $72 billion in cumulative costs annually.33 and 34 These figures account for insurance payments and fraud, lost productivity, criminal justice costs, drug abuse treatment, and general medical complications.

    Demographics: Who Is at Risk?

    Chronic nonmedical use of opioids is almost twice as high in men, although women have higher rates of being prescribed types drugs that are prone to abuse. Men also have a higher rate of death related to opioids compared with women. Use of emergency departments for abuse or misuse of opioids seems to be similar across the sexes.35 About 13% of high school seniors report having used prescription opioids for nonmedical purposes at some time in their life.36 For adults, the rate of nonmedical use of opioids is highest among 18 to 25 year olds and decreases with increasing age.37 Despite that trend, death rates from opioid overdoses are highest in 45 to 54 year olds.35 Overdose death rates of non-Hispanic whites and Native Americans have been 3 times as high as Hispanic whites and African Americans.32

    Certain socioeconomic and clinical factors have also seemed to play a role in differential opioid prescribing, misuse, and poor outcomes. Patients who have lower educational attainment, are eligible to receive Medicaid, or have history of previous substance abuse and/or psychiatric disease all tend to be prescribed more opioids and at higher doses.38 Perhaps predictably, the rate of opioid overdose death is higher in Medicaid-eligible populations, and also in those with previous substance abuse or psychiatric histories.39 and 40 It has been shown previously that patients with psychiatric conditions are at risk for opioid overuse and abuse.41

    Which Prescription Opioids Are Most Common?

    Hydrocodone has been the most frequently reported drug exposure for cases called into United States poison centers.42 According to data analyzed from 2009 involving 13 states in the Drug Abuse Warning Network Medical Examiner System, oxycodone, closely followed by methadone, were the 2 most frequently implicated drugs in fatal overdoses. Methadone has been associated in the most single-drug deaths, twice as many as any other opioid.43 From 1999 to 2009, the rate of overdose death from methadone increased by 5-fold. Methadone is not a medicine prescribed frequently from the emergency department, but patients may be taking it as a replacement therapy or for chronic pain management, so exceptional caution should be exercised with patients on chronic therapy, or those who admit to recreational use.

    Providers should also take caution with patients who are taking other types of prescription medications, especially psychiatric or central nervous systems agents, when considering prescribing an opioid. Opioid analgesics are by far the most commonly involved medications for pharmaceutical overdose deaths, followed distantly by benzodiazepines and antidepressants. However, overdose deaths are frequently owing to coingestions, and opioids are often implicated in many deaths from other medications. For instance, opioids have been identified in the majority of overdose deaths involving benzodiazepines (77.2%), antiepileptics/anti-Parkinsonian medication (65.5%), antipsychotic and neuroleptic drugs (58.0%), antidepressants (57.6%), other analgesics, antipyretics, and antirheumatics (56.5%), and other psychotropic drugs (54.2%).28

    Limitations of Data

    One shortcoming of the data used for reporting the amount of prescription opioid abuse is that the true incidence is likely underreported. Much of the research is culled from numerous sources, encompassing a patchwork-like pattern that involves self-reporting, criminal databases, poison control center data, autopsy or death certificate results, pharmacy data, and hospital billing coding. All of these sources have limitations.

    As with any other illegal activity, self-reporting is likely limited to the degree to which any individual may be forthcoming. Overdoses of prescription opioid medications are coingested frequently with other medications, street drugs, and alcohol.28 Furthermore, deaths can be multifactorial, and unless there is a known ingestion or autopsy performed, suspected cause of death by the certifying physician may be incorrect. Another problem underlying the reliance on data from death certificates is that a specific drug is not reported in almost a quarter of all reports.44 Fluctuating criminal justice priorities and state/regional variance in reporting, rates of abuse, or prescribing of opioids affect the generalizability of information available from those sources. A majority of the opioid prescribing and abuse has been dominant in the Southeast and Western United States,45 and although no area of the country has been immune, research studies that focus exclusively on particular regions may not capture the full picture. Complete representative data from the entire country are lacking.

    According to data from the Researched Abuse, Diversion, and Addiction-Related Surveillance system, prescriptions for opioid analgesics increased substantially from 2002 through 2010 in the United States, but then decreased slightly from 2011 through 2013. Similarly, the diversion and abuse of prescription opioid medications also increased between 2002 and 2010 and plateaued or decreased between 2011 and 2013.46 Furthermore, data analyzed by the Centers for Disease Control and Prevention from 28 states indicated that the death rate from prescription opioids in their study population decreased from 6.0 per 100,000 in 2010 to 5.6 per 100,000 in 2012.47 Comparable patterns were seen in the Researched Abuse, Diversion, and Addiction-Related Surveillance data.

    Although the longevity of these changes is yet to be determined, it is nevertheless encouraging and may be representative of a general trend toward recognition of the problem and improvement of care on a nationwide scale. Multiple factors likely contribute. Most states now have active and functional PDMPs48 and local, state and federal efforts aimed at reducing questionable practices such as doctor shopping and so-called pill mills have likely had an impact. Introduction of abuse-deterrent formulations of opioids, such as the transition of oxycodone in 2010, have been shown to decrease the popularity of their misuse.49 Unfortunately, these recent downtrends have also been accompanied by a marked increase of heroin use, and therefore, for some, one drug may have been supplanted or supplemented with another.

    Heroin epidemic

    Unlike the slight decrease that has recently been seen with prescription opioid–related deaths, there has been a noticeable growth in the abuse of heroin and the number of heroin-related deaths since 2010. From 1999 to 2010, deaths from prescription opioids essentially quadrupled whereas deaths from heroin increased by less than 50%. However, in the span of the next 3 years, the heroin overdose death rate nearly tripled from 1.0 per 100,000 in 2010 to 2.7 per 100,000 (8257 total deaths) in 2013. Heroin overdose death rates increased in both genders, all age groups, all geographic regions, and all ethnicities except Native Americans.47, 50, and 51

    Demographics: Who Is at Risk?

    In 2013, there were an estimated 517,000 people who were dependent on or abusers of heroin, which included 169,000 new users.52 A well-identified trend is that the overall demographic of heroin users has changed over time. Primarily affecting urban minorities in the 1980s and 1990s, heroin abuse has become more prevalent in suburban and rural areas.53 New heroin users over the past decade are also now predominantly Caucasian (90.3%), and although heroin use was previously much more common in men, it is now similar between the sexes. Heroin overdose deaths remain nearly 4 times more frequent in men.54 People with annual household income less than $20,000, the uninsured and Medicaid recipients are also at increased risk for dependence and overdose.55

    Heroin use has become more commonly accepted among individuals who engage in nonmedical prescription opioid use. The odds of heroin use in prescription opioid abusers from 2008 to 2011 were double what they were in 2002 to 2005. Prescription opioids also seem to have served as a “gateway” for this new breed of heroin user. Among new heroin initiates from 2009 to 2011, 86.1% reported abusing prescription opioids before their first use of heroin.56 A major factor that has been attributed to the recent increase in overall heroin use is the introduction of a higher volume and lower cost product into the drug marketplace.57 Research on this transition is limited, but evidence suggests that many users adopt heroin because it is cheaper and easier to obtain than similarly potent or injectable prescription opioids.54 As mentioned, this overall trend seems to have coincided with reformulation of common medications previously associated with abuse, such as the introduction of abuse-deterrent extended-release oxycodone hydrochloride,46 and an uptick in the regulation and monitoring of prescription drugs.

    It would seem to make intuitive sense then that the recent decline in opioid-related deaths is simply the result of a shift to heroin use. However, in 1 study across multiple states from 2010 to 2012, decrease in opioid pain reliever deaths were not found to be associated with increased heroin death rates. In other words, independent of whether a state had an increase, decrease or no change in opioid deaths, all of the included states had an increase in heroin deaths during that time.47 This illustrates that although populations that utilize either type of drug are known to overlap to a certain extent, usage, demographic patterns, and factors contributing to these deaths remain partially independent. Overall, there seems to be a rapidly worsening problem with heroin, superimposed on a continued problem with nonmedical use of prescription opioids.

    Limitations of Data

    Data for heroin abuse are fraught with the same limitations as prescription opioids; however, some heroin overdose deaths may also be underreported owing to death certificate reporting. Because heroin is metabolized to morphine, listing of that metabolite on an autopsy report or death certificate may lead to misclassification of an opioid pain medication death rather than from heroin itself. This has been demonstrated in several states.44

    Furthermore, there have been 2 major reported outbreaks of overdoses related to fentanyl being sold as heroin or being mixed with heroin in 2005 to 2007 and 2013 to 2014. This caused a number of overdose deaths, even among veteran heroin users, because of the relative potency of fentanyl or its analogs and its surreptitious introduction into the marketplace. Between the 2 spikes there were more than 1700 fatalities, although this number is likely underestimated. Fentanyl may not be tested for by medical examiners at autopsy. Adulteration of heroin with fentanyl was initially most prevalent in the Northeast and Midwest, but became much more widespread during the more recent outbreak.58

    Opioid antagonist agents

    Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that is frequently administered to reverse the adverse effects of opioid intoxication (ie, opioid-induced central nervous system and ventilatory depression). It has a high affinity for the mu (μ)-opioid receptor and effectively reverses the effects of both exogenous and endogenous opioids.59, 60, and 61 Unlike opioid antagonists that were used before its availability (eg, nalorphin and levallorphan), naloxone is a pure antagonist that is devoid of any opioid receptor agonism.62 Naloxone has no pharmacologic or adverse effects regardless of dose when administered in the absence of opioid agonist.59 and 63 However, in the opioid-dependent population, excessive dosing of naloxone may precipitate acute opioid withdrawal syndrome (OWS). Abstinence-related OWS typically has limited clinical consequence (eg, piloerection, vomiting, diarrhea, dysphoria).64 In contrast, clinical effects of pharmaceutically precipitated OWS can result in significant morbidity including acute agitation, delirium, seizure, acute respiratory distress syndrome, and cardiac dysrhythmias.64, 65, and 66

    A patient’s history of opioid use is often not available when caring for patients in the emergency department with signs and symptoms of acute opioid intoxication. Several case reports have shown that the standard recommended initial dose of naloxone (0.4 mg) can precipitate acute OWS in opioid-dependent patients.65 and 67 To minimize the risk of precipitating acute OWS, several resources advocate for the use of low-dose naloxone (0.04 mg IV with titration every 2–3 minutes).64, 68, 69, and 70 Two commonly used emergency medicine textbooks adopted similar dose recommendation.71 and 72 Outside of the standard dose of 0.4 mg, which was established from anesthesiology research from the 1960s, there is limited clinical evidence to support the use of low-dose naloxone.62, 73, and 74 A recent small case series (n = 15) demonstrated that low-dose naloxone with titration reversed methadone-induced ventilatory depression with a median total dose administration of 0.08 mg IV.68 There is insufficient evidence to advocate the use of low-dose naloxone as the standard of care. However, the use of low-dose naloxone may be a prudent approach to minimize potential harm to patients in the emergency department while reversing opioid-induced ventilatory depression.

    Hypoxic end-organ injury owing to ventilatory depression, irrespective of the type or dose of opioid, is responsible for opioid overdose deaths. Opioid-induced central nervous system depression alone is usually of limited clinical consequence. Therefore, the indication for naloxone administration should be to reverse the opioid-induced ventilatory depression. Diagnostic use of naloxone to determine acute opioid intoxication in patients in the emergency department with central nervous system depression alone provides limited clinical benefit and should be avoided. In apneic patients, assisted manual ventilation (via bag–valve–mask) should be initiated until naloxone is available. It has been demonstrated in animal studies that an increase in partial pressure of CO2 (Pco2) potentiated the catecholaminergic response to naloxone-assisted reversal of opioid intoxication, which may increase the risk of OWS.75 and 76 Therefore, normalizing Pco2 via assisted manual ventilation may decrease the risk of precipitating OWS.64

    Naloxone can be administered by several different routes: IV, intraosseous, intramuscular, subcutaneous, intranasal, inhalational (nebulized), and, less commonly, via intralingual injection. The onset of action of naloxone can range widely, from 30 seconds (intralingual) to 6 minutes (intramuscular), depending on the route of administration. The duration of action of naloxone is approximately 20 to 90 minutes.64 and 69 The duration depends on the type and dose of the opioid agonist, as well as the dose and route of naloxone administration.64 The short duration of action of naloxone compared with many opioid agonists (eg, methadone) can lead to recrudescence of opioid intoxication, requiring repeat administration of naloxone or a continuous infusion (two-thirds of the response dose per hour).77 Patients in the emergency department who received naloxone for the opioid-induced ventilatory depression should be observed in the emergency department for possible recurrence of intoxication. The observation period of 2 hours may be adequate for the majority of acute opioid intoxication as the opioid receptor antagonism effect of naloxone is short lived.78 Based on several case reports of delayed recurrence of opioid intoxication in a setting of long-acting opioid exposure, a longer observation of 4 hours has been suggested.64, 79, 80, and 81

    The reversal of buprenorphine-induced ventilatory depression, unlike other opioids, has been shown to be delayed and to require large doses of naloxone (>2 mg IV).82 and 83 This has been attributed to the slow association and dissociation rate between buprenorphine and opioid receptors, which limits the competitive antagonism of naloxone by reducing its ability to displace buprenorphine from opioid receptors.64, 82, and 83 Administration of naloxone doses of greater than 4 mg have resulted in an inverse dose–response relationship with a decrease in the reversal of ventilatory depression.82 and 83 Caution should be exercised when caring for patients in the emergency department with suspected buprenorphine-induced ventilatory depression because their response to naloxone may be inconsistent and/or delayed compared with other opioid overdoses.

    Take Home Naloxone

    Distribution of naloxone to opiate users at high risk for overdose is gaining momentum in the United States. The first THN programs in the United States started in Chicago in the mid 1990s as an extension of harm reduction practices for IV drug users.84 Robust programs are now in place in many other cities and states.85, 86, 87, and 88 The World Health Organization placed naloxone on its Model List of Essential Medicines in 2012 and released a manual titled “Community Management of Opioid Overdose” in 2014.89 From 2010 to 2014, there was an increase in the number of local sites that dispense naloxone from 188 to 644. Despite this increase, in 2013 there were 20 states that had no local dispensing sites.90

    Detractors of THN programs cite multiple reasons why they should not exist. There is concern that providing this rescue medication encourages the use of opioids. This view is based in drug control rather than public health policy. Similar arguments have been made regarding provision of condoms and needle exchange programs. The practice of “flat lining” was purported to be the practice of 1 person using a high dose of opioid with another person standing by with naloxone in case of overdose. There was also concern that naloxone may be used as a weapon against other opioid abusers.91 A survey of opioid addicts enrolled in a methadone program revealed that 6% of the respondents felt that having naloxone available might lead to them increasing their heroin dosages.92 Despite these concerns, these issues do not seem to be present in the many successful THN programs that exist today.

    Another argument is that laypersons do not have the medical knowledge to administer this medication appropriately. The use of lifesaving medications and devices by laypersons is not a novel concept. Epinephrine autoinjectors have been given to patients with anaphylaxis for more than 30 years. Patients with hereditary angioedema are now being given icatibant for self-administration at the onset of life-threatening symptoms.93 Training for both of these medications often involves caregivers or family, and they may sometimes be administered by a third party in a life-threatening situation. Automated external defibrillator availability is widespread and their use by people with no or minimal training is encouraged.

    Other concerns regarding layperson administration of naloxone include the short duration of action of this antidote. People who are treated successfully may be given the false sense that they are no longer at risk from the current overdose. The risk is greatest when the overdose was with long-acting opioids, especially methadone. THN programs stress the importance that administration of naloxone by a layperson should be followed by prompt medical attention. Often patients who are given naloxone by medical providers leave once they experience the unpleasant symptoms of withdrawal that this may precipitate. In a review of 552 refusals of care after prehospital administration of naloxone, no patient was found to have died within 48 hours.94

    The assertion that THN programs saves lives is less clear. The data are mostly anecdotal.85 and 95 One analysis of the Massachusetts’s Overdose Education and Nasal Naloxone Distribution program showed an association of fewer opioid overdose fatalities in communities where Overdose Education and Nasal Naloxone Distribution was implemented.87 The N-ALIVE trial is an ongoing study assessing the impact of distribution of naloxone to a high-risk population.96 The population being studied is prisoners at the time of release. There is an increased rate of opioid overdose in the weeks after release owing to reduced tolerance after a period of prolonged abstinence. This study plans to randomize 56,000 participants to either receiving a supply of naloxone or standard care (no naloxone).

    THN programs have used multiple delivery systems for the administration of naloxone to overdose patients. Currently, naloxone is approved by the US Food and Drug Administration for IV, intramuscular, and subcutaneous administration. The recommended route is IV, but this recommendation is for medical providers and not laypersons. Naloxone kits that come as a syringe with a separate ampule of medication require the person administering the medication to successfully draw up and then inject the medication. Owing to concern over needle stick injuries, some Emergency Medical Services (EMS) systems have moved to intranasal delivery despite its lack of US Food and Drug Administration approval. Using an approved medical device called the mucosal atomization device (MAD Nasal, Wolfe Tory Medical, Inc), naloxone can be administered without risk of needle stick to the provider. Some THN programs have also adopted intranasal delivery devices. Recently, the only manufacturer of naloxone that makes it in a dose appropriate for intranasal delivery doubled the price of the medication to $40.97

    In 2014, the US Food and Drug Administration approved a handheld naloxone autoinjector (EVZIO; kaléo, Inc, Richmond, VA, USA) that uses technology that was first successfully used for an epinephrine autoinjector made by the same company. One benefit of the autoinjector is that it eliminates the need for assembly of parts to administer the medication. Cost of this product may limit its widespread adoption. In a recent interview, it was announced that the wholesale cost of the kit, which includes a trainer device and 2 naloxone autoinjectors, is $575.98 Third-party payers who are able to negotiate bulk discounts may easily absorb this cost. Community and small municipal programs may be unable to afford this when compared with alternative delivery mechanisms.

    When naloxone from a THN program is administered, it is often done so by a person other than the overdose victim.99 and 100 This is owing to the nature of the overdose and the fact that most overdoses occur in the presence of other people, who are often opioid users themselves. Training family members and other people likely to witness an overdose in the administration of naloxone may be beneficial.101 There may also be additional benefit in training these groups in cardiopulmonary resuscitation.102 Overall, there is a growing body of evidence that naloxone can be safely and effectively administered to victims of opioid overdose.

    Opioid antagonists and public health laws: barriers and solutions

    Legislative responses to increasing opioid use in the United States initially focused on taxing the commercial trade of the product. Later, the Harrison Narcotics Tax Act passed by the US Congress of 1915 not only regulated the taxation and trade of opioids, but also regulated their medical use. The Controlled Substances Act of 1970 is the current federal legislative basis for most opioid regulation. Under this act, drugs are classified based on their abuse potential and medical use into 5 schedules. Schedule 1 drugs have a high abuse potential and no accepted medical use. Schedule 5 drugs have the least abuse potential.103

    In light of the current epidemic of opioid abuse, state legislatures have implemented a patchwork of laws in an effort to overcome barriers to the dispensing and use of naloxone for narcotic overdoses.104 and 105 Generally, there are 2 main varieties of laws that have been promulgated to combat the current epidemic: laws that increase access and use of naloxone and laws that promote reporting of overdoses.

    First, there are laws that provide greater access and use of naloxone. They do this by allowing physicians to engage in third-party prescribing (prescriptions for patients not examined), prescribing by standing order and broadening the personnel who can prescribe antagonists (eg, pharmacists).104, 105, 106, 107, and 108 Other laws have been created to encourage distribution and use of opioid antagonists by limiting the civil and criminal liability of prescribing physicians and laypersons administering the reversal agents.104 and 105

    The second type of laws addresses the reluctance of overdose witnesses to call EMS for fear of criminal prosecution.64, 109, 110, and 111 This is owing to the fact that witnesses to overdoses are often themselves engaging in the criminal use of controlled substances, are in possession of such substances, or are afraid of arrest for other reasons (eg, possession of illegal drugs or outstanding warrants).109, 110, and 112 To combat this, many states have enacted Good Samaritan laws that provide limited criminal immunity to bystanders who report an overdose.

    Laws Encouraging Access to Naloxone by Limiting Liability

    In 2001, New Mexico became the first jurisdiction to create a law to specifically provide liability protection for providers who dispensed and lay rescuers who administered naloxone.113 Currently, New Mexico and several other states have an Opioid Antagonist Administration Training Program that provides naloxone to certified lay rescuers.105

    As of July 2015, 40 states and the District of Columbia of have made changes to their laws to allow the prescribing of naloxone with varying limits to civil and criminal liability (Table 1).104 Some of these laws provide for both civil and criminal liability protections to varying degrees for both prescribers and lay rescuers, whereas others only protect either providers or rescuers but not both. Some states have enacted laws that protect providers from disciplinary action by the state medical board. Interestingly, despite a flurry of legislation that would seem to indicate prosecution of prescriber and layperson rescuers was a major issue, but in reality prosecution is extremely rare.105

    Table 1 Opioid antagonist liability protection and third-party prescribing laws as of July 2015 source: Data from The Network for Public Health Law. Legal intervention to reduce overdose mortality: naloxone access and overdose Good Samaritan laws. 2015. Available at: https://www.networkforphl.org/_asset/qz5pvn/network-naloxone-10-4.pdf. Accessed September 2, 2015.

    Civil Liability or Disciplinary Protection for Prescribers Criminal Liability Protection for Prescribers Civil Liability Protection for Lay Rescuers Criminal Liability Protection for Lay Rescuers Third-party Prescription Allowed
    AL, AR, CA, CO, CT, DE, FL, GA, ID, IN, LA, MA, MD, ME, MI, MN, MS, NC, ND, NH, NJ, NM, NV, OH, PA, SC, TN, TX, UT, VA, VT, WA, WI, WV AL, AR, CA, CO, CT, DE, FL, GA, ID, IL, LA, MN, MS, NC, ND, NE, NH, NJ, NM, NV, OH, PA, SC, TX, VT, WA, WI, WV AL, AR, CA, CO, CT, DC, FL, GA, ID, IL, IN, KY, LA, MD, MI, MN, MS, NC, ND, NH, NJ, NM, NV, NY, OH, OR, PA, RI, SC, TX, UT, VA, VT, WA, WI, WV AL, AR, CA, CO, CT, DC, GA, ID, IL, KY, LA, MA, MD, MN, MS, NC, ND, NE, NH, NJ, NM, NV, NY, OH, PA, RI, SC, TX, VA, VT, WA, WI, WV AL, AR, CA, CO, FL, GA, ID, IL, IN, KY, LA, MA, MD, ME, MI, MS, NC, ND, NE, NH, NJ, NV, NY, OH, OK, OR, PA, SC, TN, TX, UT, VA, VT, WA, WI, WV

    Laws to Promote Prescribing of Opioid Antagonists

    To increase the distribution of opioid antagonists, many states have enacted laws to facilitate the prescription of this medication. Usually a provider cannot prescribe medication to a patient unless the provider has examined that patient personally.105 and 106 Strategies to circumvent this issue have included third-party prescriptions, standing orders, and collaborative practice agreements.105, 106, 107, and 108 Third-party prescriptions allow physicians to prescribe medication for patients they have neither seen nor examined. For example, under the Massachusetts law, an “opioid antagonist may lawfully be prescribed and dispensed to a person at risk of experiencing an opiate-related overdose or a family member, friend or other person in a position to assist a person at risk of experiencing an opiate-related overdose.”114 Similar strategies have been adopted to combat sexually transmitted diseases using Expedited Partner Therapy.

    Many jurisdictions have created similar legislation specifically for opioid antagonists third-party prescriptions (see Table 1).106 In other jurisdictions, standing orders signed by a physician allow other providers to dispense opioid antagonists through established protocols.106 and 108 Another way of facilitating dispensing of naloxone is through the use of collaborative practice agreements that allow for pharmacists to prescribe opioid antagonists on behalf of and in conjunction with licensed physicians.106 and 107 New Mexico, a state that has led the way in legislative solutions for the opioid epidemic, recently was the first state to give pharmacists the authority to dispense opioid antagonists independently.106

    These legislative efforts demonstrate attempts to increase opioid antagonist availability through standing orders, pharmacist prescribing, and third-party prescriptions. An even better way to distribute antagonists to the public might be to simply provide the medication as an over-the-counter drug. However, for naloxone to be approved by the US Food and Drug Administration for over-the-counter use, some entity would have to fund clinical trials and then the application process. This process would take years and would likely be cost prohibitive.105 and 106

    Good Samaritan Laws: Providing Immunity to Bystanders Who Report Overdose

    Opioid overdose is commonly witnessed by individuals who also use opioids.85, 90, and 112 In 1 survey study of 329 drug users, 34% stated that they had experienced an unintentional overdose and 64% stated that they had witnessed an overdose.90 and 115 Another study surveyed 1184 drug abusers, of which 797 (67.3%) had witnessed a nonfatal or fatal overdose.90 Of these, 278 (23.5%) had seen an overdose within the previous 6 months.110

    Despite bystanders’ familiarity with potentially deadly overdoses, they often do not call EMS. Survey data estimate that only 10% to 60% of bystander witnesses actually call EMS when drug overdoses occur.85, 109, 110, and 112 The primary reason that bystanders do not call is fear of arrest and criminal prosecution.109 and 110 In a survey of 301 bystanders who delayed or did not call for help during an overdose, 152 (52%) stated that they feared police response and potential arrest.64, 109, and 110 Although prior surveys of police officers indicate that they are unlikely to arrest an overdose victim or bystander, the fear of legal action remains a significant barrier to calling for assistance.110 and 111 Although uncommon, the legal risk to the bystander is not completely absent.105, 112, 116, and 117

    To address this fear of arrest and to encourage bystanders to call for EMS, many states have passed laws that create limited criminal immunity for bystanders who report an overdose.64, 104, 105, and 109 As of July 15, 2015, 31 states and the District of Columbia have passed Good Samaritan laws (Table 2).104 Most of these laws provide protection from criminal charges regarding possessing a controlled substance, whereas others also provide protection from possession of drug paraphernalia.

    Table 2 State Good Samaritan laws as of July 2015 source: Data from The Network for Public Health Law. Legal intervention to reduce overdose mortality: naloxone access and overdose Good Samaritan laws. 2015. Available at: https://www.networkforphl.org/_asset/qz5pvn/network-naloxone-10-4.pdf. Accessed September 2, 2015.

    No Charge for Controlled Substance Possession No Charge for Drug Paraphernalia Protection from Other Crimes Reporting Overdose Can Mitigate Prosecution of a Crime
    AK, AL, AR, CA, CO, CT, DC, DE, FL, GA, HI, IL, KY, LA, MA, MD, MN, MS, NC, NH, NJ, NM, NV, NY, OR, PA, RI, TN, VA, VT, WA, WI, WV AL, CA, CO, CT, DC, DE, GA, HI, KY, MD, MN, MS, NC, NJ, NV, NY, OR, PA, RI, TN, VA, WI AL, AR, CA, CO, DC, DE, GA, HI, IL, LA, MD, MN, MS, NC, NJ, NV, NY, OR, PA, RI, TN, VA, VT, VW AK, DC, FL, HI, IL, IN, MA, MD, MN, NM, NV, NY, RI, TN, UT, VT, WA, WV

    Safe opioid prescribing practice in the emergency department

    As many as 42% of all emergency department visits are owing to pain-related conditions.118 Between 2001 and 2010, there has been a 49% increase in the percentage of total emergency department visits where an opioid was prescribed for pain.119 In 2010 alone, enough morphine milligram equivalents were prescribed by all specialties nationwide to provide every adult American with enough to take 5 mg every 4 hours for a month.32 Although primary care providers and dentists prescribe the majority of opioids in the United States, emergency medicine ranks among the top 5 specialties (for ages 0–39 years) for opioid prescribing in the ambulatory setting.120 Some data suggest that there is an increased rate of diversion and abuse of opioids that are prescribed from emergency departments, especially by young people.36 The primary challenge for emergency department providers in the current opioid abuse epidemic is how to balance the need to provide adequate pain control for patients in the emergency department while minimizing the availability of opioids for abuse or diversion. Recently, the American College of Emergency Physicians, American Academy of Emergency Medicine, 14 states (AK, AZ, CA, CT, DE, HI, MA, MD, ME, OH, OK, OR, PA, and WA), and New York City have established opioid prescribing guidelines specifically for emergency medicine providers.121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, and 133 In addition, numerous other states have adapted opioid prescribing and pain treatment guidelines for all health care providers.121 Emergency department–specific guidelines generally recommend prescribing small quantities (eg, a 3-day supply) of short-acting opioids for acute pain. They also discourage replacing lost, stolen, or destroyed prescriptions.24, 124, 132, and 133 These guidelines also advocate for the use of PDMP to review prescription history and to identify potential at-risk patterns for “doctor shopping.”24, 123, and 134 Some health care providers have expressed concerns that these guidelines may result in undertreatment of pain, especially for those patients who use emergency department as their source of primary care. Others argue that prescribing guidelines can interfere with their professional independence and judgment.135

    PDMPs have been advocated as a promising tool to decrease inappropriate opioid prescribing and to identify patients with at-risk pattern for misuse. To date, 49 states (except Missouri) have operational PDMPs.136 and 137 However, the state-based PDMPs are not standardized and vary in their complexity and completeness.24 The use of PDMPs has been shown to decrease “doctor shopping”; however, there is inconsistent evidence as to how PDMPs affect health care provider’s opioid prescribing behavior.138, 139, 140, 141, and 142 The possibility that PDMPs have little effect on prescribers’ behavior has been attributed to the difficulty of obtaining PDMP access, lack of use, and incomplete data within PDMPs.24, 138, and 140 To improve provider use, 22 of the 49 states with PDMPs mandated all prescribers of controlled substances to query the PDMP for at-risk pattern for misuse and/or diversion.138 The mandated query of PDMPs, based on the experience from Kentucky, New York, and Tennessee, did decrease the overall number of opioid prescriptions by 7% to 9%.143 However, these mandates face opposition from health care providers to owing to limitations of PDMPs and their intrusion into clinical practice.138

    The impact of the emergency department opioid guidelines on opioid prescribing practice is unknown. One recent study showed that the introduction of an emergency department opioid guideline in 2 academic affiliated EDs decreased the number of discharged patients with opioid prescriptions from 52.7% to 33.8%.144 Its impact on outpatient pain management was not assessed and further investigation is needed. The use of opioid prescribing guidelines is voluntary and not a mandated practice. Each emergency department provider must use his or her clinical intuition and judgment to adequately address and treat the pain experienced by each patients in the emergency department. Although emergency department providers are not the leading prescribers of opioids, appropriate prescribing practice is essential to help decrease the availability of opioids for abuse or diversion.

    Opioid pain medication abuse is one of the leading public health problems in the United States. Health care providers have contributed to the current opioid abuse epidemic through our prescribing practices. In 2012, 4.2 billion prescriptions were written in the United States; 289 million (6.8%) were for opioids, an increase of 11.7% from 2007.145 There has been a concerted effort among government, state, and professional organizations, and members of medical specialties to address the increasing incidence of opioid abuse and overdose-related deaths. Nationally, numerous medical specialties have made conscientious effort to decrease inappropriate opioid prescribing. Between 2007 and 2012, large decreases in opioid prescriptions were noted in emergency medicine (–8.9%), followed by dentistry (–5.7%) and surgery (–3.9%).145 Numerous states have developed emergency department opioid prescribing guidelines, and implemented PDMPs and health care provider education programs. Patient-directed interventions also need to be developed with a focus on remediating the deficiencies in patients’ understanding of the risk of opioid use and the expected outcome of “adequate” pain management.146 and 147

    Summary

    There is an epidemic of opioid abuse in the United States. The risk of heroin abuse has been appreciated for more than a century with it now being considered to have no justifiable medical use. Opioids that are prescribed commonly to treat painful conditions have had a dramatic increase in the rate of abuse, addiction, overdose, and death. The increase in complications corresponds with a dramatic increase in the rate of opioid prescriptions that resulted from pressures placed on practitioners to avoid undertreatment of pain.

    Naloxone is an opioid receptor antagonist that is used to treat opioid overdoses. Its use as a rescue medication by laypersons is becoming increasingly accepted. Other efforts to combat the opioid epidemic include the use of PDMPs and implementation of safe opioid prescribing guidelines. The laws that govern these efforts vary from state to state resulting in a wide range of effectiveness. The efforts to reign in the abuse of opioids will require further research and a reexamination of the balance between the need to treat pain and the recognition that opioid medications are not without risk.

    References

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    • 143 Prescription Drug Monitoring Program Center of Excellence at Brandeis. COE Briefing. Mandating PDMP participation by medical providers: current status and experience in selected states. 2014. Available at: http://www.pdmpexcellence.org/sites/all/pdfs/COE%20briefing%20on%20mandates%20revised_a.pdf. Accessed August 30, 2015.
    • 144 D.A. Del Portal, M.E. Healy, W.A. Satz, et al. Impact of an opioid prescribing guideline in the acute care setting. J Emerg Med. 2015; [Epub ahead of print]
    • 145 B. Levy, L. Paulozzi, K.A. Mack, et al. Trends in opioid analgesic–prescribing rates by specialty, US, 2007–2012. Am J Prev Med. 2015;49(3):409-413
    • 146 M. Conrardy, P. Lank, K.A. Cameron, et al. Emergency department patient perspectives on the risk of addiction to prescription opioids. Pain Med. 2015; [Epub ahead of print]
    • 147 R.J. Smith, K. Rhodes, B. Paciotti, et al. Patient perspectives of acute pain management in the era of the opioid epidemic. Ann Emerg Med. 2015;66(3):246-252.e1

    Footnotes

    Department of Emergency Medicine, University of Maryland School of Medicine, 110 South Paca Street, 6th Floor, Suite 200, Baltimore, MD 21201, USA

    Corresponding author.

    Disclosures: None.


Resources and Guidelines

  • Prescriber Letter #3 FDA-Required REMS Program for Serious Drug Risks

    The ER/LA Opioid Analgesic REMS Companies, 2014

  • Patient Counseling Document

    ER/LA Opioid Analgesics REMS Program Companies, 2014


Guest Editor
Perry G. Fine, MD

Professor of Anesthesiology at the University of Utah School of Medicine, Dr. Fine welcomes you to the REMs Resource.

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