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Introduction

Morphine, the prototypical opioid drug, was first isolated from the opium poppy in 1803.¹ Since then, a number of additional opioid drugs have been isolated or synthesized. Opioids are commonly used to treat pain, but different opioid analgesics have different properties and indications.^1,2 There are also a number of different opioid formulations available, including formulations that combine opioid and nonopioid analgesics. It is essential for pharmacists to understand the differences between these drugs and formulations, so that they can recommend appropriate therapy for patients.

Mechanisms of Action for Opioid Analgesics

Opioid analgesics are so named because they act at opioid receptors, which are found primarily on neurons in the central nervous system and gastrointestinal tract.³ These receptors can also be found on neurons throughout the periphery and on other cell types, including macrophages and astrocytes.² Opioid receptors are G-protein coupled receptors that, when activated, produce several changes in neuronal cells.^2,4 The activation of opioid receptors leads to a decreased opening of voltage-gated calcium channels, which in turn reduces the release of neurotransmitters from presynaptic terminals. Opioid receptor activation also stimulates potassium currents, which hyperpolarizes the postsynaptic neuron and thereby suppresses neuronal activity.

The pain-relieving effects of opioid analgesics are primarily attributed to their binding at opioid receptors in the brain and spinal cord.² In the brain, an area known as the mesencephalic periaqueductal gray (PAG) contains opioid-sensitive pathways. Activation of opioid receptors in this area blocks the release of gamma-aminobutyric acid (GABA) from tonically active systems that regulate activity in projections to the nucleus raphe magnus (NRM) in the medulla.^2,4 Increased activity in these projections causes an increase in the release of serotonin and norepinephrine from descending inhibitory neurons in the dorsal horn of the spine, resulting in reduced dorsal horn excitability. Opioids additionally act on the nucleus reticularis paragigantocellularis (NRPG) in the medulla, which similarly stimulates increased inhibitory outflow from the NRM to the spinal dorsal horn.⁴ Opioids can also act directly at the spinal level to inhibit the firing of pain transmission neurons in the dorsal horn and inhibit excitatory neurotransmitter release from primary afferent neurons.¹

There are 3 major classes of opioid receptors: mu opioid receptors (MOR), delta opioid receptors (DOR), and kappa opioid receptors (KOR).² Mu opioid receptors are the primary receptors responsible for the analgesic and euphoric effects of opioids.⁵ These receptors are also thought to be responsible for some of the most well-known side effects of opioid analgesics (constipation and respiratory depression). Activation of DOR provides limited analgesia in acute pain, but may play a larger role in the relief of chronic pain. DOR agonism can also have antidepressant and proconvulsant effects. Agonists at KOR can cause either analgesic or proalgesic effects, depending on the agonist. Activation of KOR can also lead to dysphoria, depression, and anticonvulsant effects. Most opioid analgesics used in clinical practice exert their therapeutic effects through MOR agonism, but they typically have some degree of activity at the other opioid receptors as well.^2,5 Different opioid analgesic agents have different degrees of activity at various receptors (Table 1).^1,2

Some opioids are termed “partial agonists” because they bind specifically to opioid receptors but have limited intrinsic activity at those receptors.² These drugs include buprenorphine, nalbuphine, pentazocine, and butorphanol. Buprenorphine is a partial agonist at MOR and an antagonist at DOR and KOR.^1,2 Because of its mixed activity, it may precipitate withdrawal in patients who are physically dependent on full agonist opioid analgesics. Nalbuphine is an antagonist at MOR, but exerts an analgesic effect through strong agonist activity at KOR. Pentazocine also exhibits agonist activity at KOR, with partial agonist or weak antagonist activity at MOR. Butorphanol is primarily a KOR agonist, but it may also act as an MOR partial agonist or antagonist.¹

Some opioid agents that primarily act through MOR agonism have additional modes of action as well. Methadone can block N-methyl-D-aspartate (NMDA) receptors and monoaminergic reuptake transporters in addition to acting as a MOR agonist.¹ This may allow it to be more effective for pain that is difficult to treat, such as cancer-related pain or neuropathic pain, and pain that does not respond adequately to morphine. Levorphanol also has some NMDA antagonist properties and inhibits reuptake of serotonin and norepinephrine.

Tramadol and tapentadol have activity at opioid receptors, but it is thought that they produce their primary analgesic effects via other mechanisms.¹ Tramadol is a centrally acting analgesic with a complex mechanism of action. It acts as a weak MOR agonist, but a significant portion of its analgesic effect is derived from its ability to inhibit serotonin and norepinephrine reuptake. Tapentadol has stronger activity at MOR than tramadol, but it also significantly inhibits norepinephrine reuptake.

Some opioid agents are more potent than others, meaning that they bind to opioid receptors more strongly.^2,6 In general, fentanyl, sufentanil, and buprenorphine are considered high potency opioids, while methadone, oxycodone, morphine, and hydromorphone are considered medium potency and codeine, hydrocodone, tramadol, and tapentadol are considered low potency.⁶ Opioids that are more potent require lower doses to produce a similar analgesic effect (Table 2).⁷ It is worth noting that “equianalgesic” doses from a potency perspective are approximate and may not be directly equivalent for therapeutic purposes: however, a full discussion of opioid conversion in practice is beyond the scope of this module.

Short-Acting Opioid Analgesics: Immediate-Release Formulations and Combination Products

A number of opioid analgesics are available in immediate-release formulations.⁸ These may be single product formulations, or combination formulations that include one or more nonopioid analgesics in addition to the opioid agent. Table 3 provides an overview of the available short-acting products, including indications and dosing recommendations. Short-acting formulations are typically used for acute pain and pain that is not consistently present (for example, pain due to injury or surgery, or breakthrough pain in patients who are taking long-acting opioids for chronic cancer pain).^9,10 Short-acting formulations are also recommended when first initiating opioid therapy for chronic pain; once an effective dose of the short-acting opioid is found, the patient can be converted to a long-acting formulation.^9-11

Many short-acting agents come in multiple formulations.¹² A route or formulation may be selected based on patient characteristics and the desired onset of action. For example, if a patient is experiencing acute, severe pain (ie, cancer breakthrough pain, postoperative pain, sickle cell pain crisis), immediate pain relief is required. The onset of action for oral pain medications is usually around 45 minutes, and the peak analgesic effects are not achieved until 1 to 2 hours after administration. Therefore, an alternate route of administration (such as the intravenous route or transmucosal route) would be more appropriate for patients who require immediate pain relief. Some patients may not be able to swallow tablets, and some patients may not be able to take medication orally at all. These patients will also require alternative formulations (eg, oral solutions, rectal suppositories, parenteral formulations).

Single Agent Immediate-Release Opioid Analgesics

Morphine can be given via oral, parenteral, and rectal routes.^8,13 Onset of action varies by route. When administered orally, morphine has a bioavailability of approximately 20% to 40%.⁸ Onset of analgesia occurs after about 30 minutes, and peak analgesic effect is reached in about an hour.^8,13 Intravenous injection results in a faster onset (5 to 10 minutes), with peak analgesia within 20 minutes. Intramuscular administration achieves peak analgesia in 30 to 60 minutes, while subcutaneous administration achieves peak analgesia in 50 to 90 minutes. Rectal morphine reaches its peak effect within 20 to 60 minutes. Morphine’s effects last for about 3 to 6 hours when given via most routes. However, the effects of rectal morphine may last for up to 7 hours, and epidural or intrathecal morphine can produce analgesia for up to 24 hours.¹³

Morphine has 2 major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).¹² These metabolites are active; M6G contributes to analgesia, while M3G can cause undesirable central nervous system effects, such as seizures.^2,8,12 Both metabolites are renally cleared, so they may accumulate in patients with renal impairment.¹² It is generally recommended to avoid morphine in renally impaired patients.

Codeine itself has low affinity for opioid receptors and therefore lacks a strong analgesic effect.^2,8 However, approximately 10% of the administered codeine dose is metabolized to morphine by CYP2D6 in the liver. It is thought that this conversion is responsible for the bulk of codeine’s analgesic effects. Polymorphisms in CYP2D6 can cause variations in response to codeine.² Some patients may not respond to codeine at all, while others (termed “ultrarapid metabolizers”) may have increased codeine sensitivity. The onset of action for codeine is 30 to 60 minutes.^8,13 Peak effects are achieved at 60 to 90 minutes post-dose, and effects last for 4 to 6 hours.

Hydromorphone is a semisynthetic derivative of morphine.² It has a bioavailability of 60% when given orally, and onset of analgesia occurs within 15 to 30 minutes.^8,13 Peak effect is achieved at 30 to 60 minutes. Intravenous administration allows for a 5-minute onset of action, with peak effect achieved within 10 to 20 minutes.¹³ The duration of action is approximately 3 to 4 hours for all immediate-release formulations, but the suppository may provide a longer duration of effect. Oxymorphone is a potent semisynthetic opioid with an oral bioavailability of 10%.⁸ Bioavailability may be significantly increased in moderate to severe hepatic impairment.

Oxycodone is a semisynthetic opioid commonly used for moderate-to-severe pain.^8,12 Although it is metabolized to oxymorphone in the liver, its analgesic action is primarily attributed to the parent compound.⁸ Oxycodone’s first-pass metabolism is less extensive than that of many other opioids, so oral bioavailability is 60% to 87%. Onset of action occurs about 15 minutes after administration, and maximum effect occurs about 1 to 2 hours post-dose.^8,13 Effects last for 3 to 6 hours.¹³

Fentanyl has several unique applications in pain management. It is highly lipid-soluble, which allows it to pass through the blood-brain barrier quickly.² It has a quick onset of action and a rapid offset of action when given in small boluses (with high doses or prolonged infusions, fentanyl may begin to accumulate, resulting in a longer duration of action). Fentanyl can be administered transmucosally or intranasally for the treatment of breakthrough cancer pain.^8,13 Recommendations for dosing and titration vary by product, and products cannot be directly interchanged. When administered transmucosally, it typically takes effect within 5 to 15 minutes and reaches peak effect in about 20 to 90 minutes, depending on the specific formulation used.¹³ The intranasal spray takes effect within 5 to 10 minutes and reaches peak effect in 15 to 21 minutes. Fentanyl is also available as a solution for injection, which is typically used as an adjunct to anesthesia or for pain associated with surgery or critical illness. Peak concentrations are achieved in minutes with intravenous administration, and effects last for 30 to 60 minutes.⁸

Intravenous sufentanil is primarily used in the context of anesthesia, but a sublingual formulation was approved for acute severe pain in 2018.¹³ This formulation is 53% bioavailable, and it takes effect within 30 minutes, reaching peak effect in 1 hour.^8,13 Effects usually last about 3 hours.¹³ Sufentanil is several times more potent than fentanyl and should only be used under direct medical supervision.⁸

Meperidine can be used for acute pain, but it is not recommended for chronic use, because its active metabolite normeperidine can accumulate and increase the risk of seizures, particularly in renally impaired or elderly patients.^12,13 Although oral meperidine is available, it is typically not recommended for use, because extensive first-pass metabolism can lead to high levels of normeperidine.¹³ Parenteral meperidine takes effect in 5 to 15 minutes, with peak effects in 5 to 7 minutes (intravenous) or 1 hour (intramuscular and subcutaneous). Effects last 2 to 4 hours.

Tramadol undergoes first-pass metabolism and has a bioavailability of 68%; however, bioavailability approaches 100% after multiple doses due to saturable first-pass metabolism.⁸ One of tramadol’s metabolites is active and contributes significantly to its analgesic effect. Onset of analgesic action occurs within 1 hour, with peak effects achieved in 2 to 3 hours. Analgesia lasts for 6 hours.

Butorphanol is available as an intranasal spray as well as an injectable formulation.⁸ The nasal spray can produce analgesia within 15 minutes, and it has a longer duration of action than intravenous or intramuscular administration (4-5 hours vs 2-4 hours). Peak effects are achieved in 1 to 2 hours with intranasal administration.¹³ Tapentadol has an oral bioavailability of about 32%, and absorption may increase with food.⁸ Peak plasma concentrations occur at 1.25 hours, and its half-life is approximately 4 hours.¹³

Nalbuphine must be administered parenterally, because it is metabolized in the gastrointestinal mucosa and it undergoes extensive first-pass metabolism.⁸ When administered intravenously, it has a rapid onset of action (2-3 minutes), with peak effects in 30 minutes. The onset of action with subcutaneous or intramuscular administration is around 15 minutes, and the duration of action for all parenteral routes is 3 to 6 hours.^8,13

Combination Immediate-Release Opioid Analgesic Formulations

Combination therapy with medications from different therapeutic classes is commonly employed as a pain management strategy.^12,14 Combining opioid analgesics with other pain-relieving drugs can help maintain or increase analgesic effectiveness while reducing the risk of opioid-induced adverse effects and allowing for lower doses of the opioid. Opioid analgesics are often coformulated with nonopioid analgesics or other drugs that may complement their pain-relieving actions.⁸

Coformulations with acetaminophen, ibuprofen, aspirin, carisoprodol, butalbital, and caffeine are available (Table 3).⁸ Acetaminophen, ibuprofen, and aspirin are nonopioid analgesics. Carisoprodol is a centrally acting muscle relaxant. Butalbital is a barbiturate: it enhances GABA activity in the thalamus, producing sedative and relaxant effects. Caffeine enhances the effects of analgesics and acts as a central nervous system stimulant.^8,13 Of note, in 2011, the US Food and Drug Administration (FDA) limited the amount of acetaminophen that could be included in a single dosage form (ie, in 1 tablet or capsule) to 325 mg due to the risk of liver injury with acetaminophen overdose.¹⁵ When using a coformulated product that contains acetaminophen, it is important to ensure that the patient does not receive more than 4 g acetaminophen per day. Some combination products are only indicated for the short-term treatment of pain.⁸

Hydrocodone is a short-acting opioid, but it is not available as a single agent immediate-release product.⁸ It is only available in combination with acetaminophen or ibuprofen. Benzhydrocodone is a prodrug of hydrocodone that is only available as a coformulated tablet with acetaminophen. Benzhydrocodone is metabolized to hydrocodone by enzymes in the gastrointestinal tract, so systemic exposure to benzhydrocodone is minimal.

In some cases, short-acting opioid drugs may be coformulated with opioid antagonists to prevent abuse.¹⁴ Pentazocine is available in combination with naloxone, an opioid receptor antagonist.⁸ When administered orally, naloxone is poorly absorbed and has no significant activity; thus, if pentazocine/naloxone is taken orally, naloxone will not interfere with the action of pentazocine. However, if the tablet is crushed and injected intravenously, naloxone will counteract the effects of pentazocine and prevent the user from experiencing a “high.”^8,14 This combination formulation is generally used as a second-line option for moderate-to-severe pain.^8,12 When given orally, pentazocine typically takes effect within 15 to 30 minutes, and analgesic effects last for 3 hours or more.⁸

Long-Acting Opioid Analgesics and Extended-Release Formulations

The category of “long-acting opioids” encompasses two types of opioid analgesics: short-acting opioids that have been formulated into extended-release dosage forms, and opioids that are intrinsically long-acting. Long-acting opioids can be useful in the long-term treatment of chronic pain, because they allow for less frequent dosing and more consistent analgesia.⁹ Patients are recommended to initiate opioid treatment with a short-acting agent; they may then convert to a long-acting agent once an effective dose has been established, if desired.^9-11 Some long-acting opioids are only indicated for use in opioid-tolerant patients.^8,13

Morphine, fentanyl, hydrocodone, hydromorphone, tapentadol, tramadol, oxymorphone, and oxycodone are all short-acting opioids that are available in extended-release formulations.⁸ Intrinsically long-acting opioids include methadone, buprenorphine, and levorphanol. Tables 4 and 5 summarize indications and dosing for the long-acting opioids. The pharmacokinetic characteristics of long-acting drugs and formulations are summarized in Table 6.

Methadone is commonly used in the treatment of opioid dependence, but it can also be used to treat pain.² Its oral bioavailability is variable, ranging from 36% to 100%.⁸ Its half-life is also highly variable, ranging from 8 to 59 hours or longer.^8,13 It accumulates in tissues with repeated administration, so peak analgesic effects of a given dosing regimen may not be seen for 3 to 5 days.^2,8,13 Its peak respiratory depressant effect occurs after its peak pharmacologic effect, so titration should be performed slowly and cautiously to avoid unintentional overdose.²

Buprenorphine has a long duration of action because it is slow to dissociate from MOR.¹ Some formulations of buprenorphine are only indicated for treatment of opioid dependence.⁸ For pain treatment, buprenorphine is available as a transdermal patch, a buccal film, and a solution for injection. Bioavailability of the buccal film is 46% to 65%, and transdermal bioavailability is 15%.

Levorphanol acts similarly to morphine, but it is more potent than morphine and has a prolonged half-life.² This causes it to accumulate with repeated dosing. Oral bioavailability is not known, but it is generally well-absorbed.⁸

Abuse-Deterrent Opioid Formulations

Most opioid analgesics have a high potential for misuse and abuse due to their euphoric effects and ability to cause physical dependence.¹⁷ Opioid misuse and abuse can lead to overdose, which can be fatal. In 2018, more than 67,300 people died of drug overdose in the United States: almost 70% of these overdose deaths involved an opioid drug.¹⁸ The number of overdose deaths involving opioids was 4 times higher in 2018 than in 1999. In light of this ongoing “opioid epidemic,” the FDA has encouraged the development of opioid formulations with reduced potential for abuse.¹⁹

Opioid abuse occurs in a variety of ways.²⁰ These drugs may be swallowed whole, or they may be crushed and swallowed, snorted, smoked, or dissolved for injection. Abuse-deterrent opioid formulations are formulations with properties that have been shown to meaningfully deter abuse.^19,20 These properties may make the drug more difficult to abuse, or make the drug less rewarding to abusers. Of note, abuse-deterrent formulations are not completely abuse-proof, and abuse-deterrent properties may not prevent addiction, overdose, or death. However, it is thought that the risk of abuse with abuse-deterrent formulations is lower than with nonabuse-deterrent formulations.

Abuse-deterrent properties may be conferred through the use of physical or chemical barriers, agonist/antagonist combinations, aversion, unique delivery systems, and/or new molecular entities and prodrugs.²¹ Physical barriers can help prevent the formulation from being chewed, crushed, cut, or ground, while chemical barriers can prevent the extraction of the opioid drug using common solvents. Both types of barriers can limit the amount of drug released when the formulation is manipulated, or change the physical form of the drug so that it is more difficult to abuse.²⁰ Agonist/antagonist combinations include an antagonist to prevent abusers from achieving a “high.” The antagonist may be sequestered so that it is not released unless the product is inappropriately manipulated. Both of these strategies for abuse deterrence are limited by their inability to prevent the abuse of intact tablets.²¹

Aversion is another potential mechanism for abuse deterrence.²⁰ This involves adding a substance to the drug’s formulation that produces an undesirable effect when the dosage form is manipulated or the medication is used at an inappropriately high dose. For example, the formulation may contain an ingredient that irritates the nasal mucosa, thus discouraging potential abusers from attempting to crush and snort the product. Aversion can help limit the abuse of intact tablets, and prevent abuse by chewing or crushing; however, it can also cause adverse effects in patients who are taking the tablets as intended and prevent legitimate dose increases.²¹ Additionally, if an abuser is highly motivated to abuse the drug, aversion techniques may not be sufficient to discourage them.

Certain delivery systems, such as depot injectable formulations or implants, can offer abuse resistance.^20,21 It may be possible to extract the opioid from the delivery system, but it is much more difficult to manipulate these types of formulations. Another way to produce a formulation with abuse-deterrent properties would be to create a new molecular entity or prodrug with intrinsic properties that make it difficult to abuse.²⁰ For example, the drug may require enzymatic activation, or it may penetrate the central nervous system more slowly, reducing the “high” that someone might feel if they abuse the drug.

In order to obtain abuse-deterrent labeling from the FDA, a drug manufacturer must perform studies that examine the potential for abuse.²⁰ Premarket studies can fall into 1 of 3 categories: laboratory-based in vitro manipulation and extraction studies (Category 1), pharmacokinetic studies (Category 2), and clinical abuse potential studies (Category 3). The FDA generally recommends that manufacturers obtain data from all 3 types of studies to demonstrate that a formulation is likely to deter abuse in a meaningful way. However, in some cases, a particular category may not be relevant. Results of Category 1 studies can influence the design of Category 2 and 3 studies, and results of Category 2 studies can help determine the need for Category 3 studies.

The purpose of Category 1 studies is to see how easily the abuse-deterrent properties of the drug can be circumvented.²⁰ These studies should consider ways in which abusers may try to manipulate the drug, as well as ways in which patients may manipulate the drug and inadvertently alter the rate or amount of drug released. Ease of mechanical manipulation (for example, by crushing, cutting, or grinding) should be examined, as well as the potential for dissolution and extraction of the opioid component. Other evaluations may depend on the anticipated route(s) of abuse: for example, if a product can be abused by smoking, the amount of drug produced by vaporization at various temperatures should be explored. For each type of study, the test product should be compared to other available products.

Category 2 studies are designed to compare the pharmacokinetics of the intact drug with the pharmacokinetics of the manipulated drug.²⁰ The methods of manipulation used should reflect the methods that were examined in Category 1 studies and found to produce the greatest amount of drug release. These studies should also compare the pharmacokinetics of the intact and manipulated test product to the pharmacokinetics of intact and manipulated comparator formulations. Relevant pharmacokinetic parameters include maximum concentration (C_max), time to maximum concentration (T_max), area under the curve (AUC), and terminal elimination half-life (T_1/2).

Category 3 studies assess the clinical abuse potential of a drug.²⁰ These studies are also used to determine the FDA’s recommendation for drug scheduling. Typically, these studies are conducted in opioid-experienced recreational drug users who are familiar with the effects of the drug’s conventional formulation. The studies are usually designed as randomized, double-blind crossover studies, with a placebo control and a positive control. The test product is compared to the positive control, and the positive control is compared to placebo as a validation method. Different routes of abuse may be tested, depending on how the drug is likely to be abused in the real world. Likelihood of abuse is determined by how the subjects rate the drug’s effects. Visual analogue scales are used to measure “drug liking,” as well as good and bad effects of the drug and likelihood of taking the drug again.

Postmarketing studies (also referred to as Category 4 studies) are required for opioids with abuse-deterrent labeling.²⁰ These studies assess the real-world impact of the formulation’s abuse-deterrent properties, evaluating its ability to produce meaningful reductions in abuse, misuse, and related adverse outcomes (such as addiction, overdose, and death). Formal Category 4 studies are observational in nature and may use a variety of data sources to assess overall and route-specific misuse and abuse. Rates of misuse and abuse with the abuse-deterrent formulation should be compared to rates of misuse and abuse seen with historically available and currently available nonabuse-deterrent formulations of the same drug. The FDA may require changes to the drug’s abuse-deterrent labeling, if postmarketing studies do not confirm that the formulation meaningfully deters abuse, or if studies show that the abuse-deterrent properties have caused abusers to shift to a riskier route of abuse.

The FDA has approved several products with specific “abuse-deterrent” labeling.^8,19 Currently available products with abuse-deterrent labeling include OxyContin (extended-release oxycodone tablet), Xtampza ER (extended-release oxycodone capsule), Hysingla ER (extended-release hydrocodone tablet), and MorphaBond ER (extended-release morphine tablet).

OxyContin was the first opioid drug to receive FDA abuse-deterrent labeling.²¹ It is labeled as abuse-deterrent for intravenous and nasal routes of abuse.²² A previous formulation of OxyContin was implicated in a large number of opioid-related deaths and emergency department visits during the 2000s.²³ This prompted a reformulation of the drug, and a new formulation with abuse-deterrent properties was approved in 2010. The reformulated version of OxyContin has physical properties that make it difficult to crush and snort or inject.²¹ It also resists attempts at dissolution and drug extraction: when it is put in water, it gradually forms a viscous gel, which is difficult to draw into a needle. A randomized, double-blind, placebo- and positive-controlled study in 27 recreational opioid users with a history of intranasal drug abuse found that overall drug liking and likelihood of taking the drug again were significantly reduced with crushed intranasal reformulated OxyContin vs crushed intranasal original OxyContin.²⁴ Crushed reformulated OxyContin also had lower nasal tolerability. Pharmacokinetic studies performed in these patients found that, when crushed and taken intranasally, reformulated OxyContin had a decreased C_max and an increased T_max compared to the original formulation, with peak effects occurring at 1 to 2 hours after administration vs 30 minutes to 1 hour after administration.

Several observational postmarketing studies have been performed for reformulated OxyContin, but none of these postmarketing data have been included in the product labeling.^21,25 Some postmarketing studies found reductions in OxyContin-specific abuse, diversion, overdose fatalities, and doctor shopping after the reformulation.^21,26-28 One study noted that, while abuse rates of OxyContin decreased after reformulation, abuse rates of heroin and other opioids increased; this could indicate that some people who were previously abusing OxyContin simply switched to other more accessible opioid formulations.^21,28 However, a recent study did not find an association between the reformulation of OxyContin and increased rates of new heroin use among patients who had abused OxyContin prior to the reformulation.²⁹ A survey found that some people continued to abuse OxyContin via the oral route after the reformulation, and some people who had previously abused OxyContin via nonoral routes began abusing it via the oral route.³⁰

Xtampza ER is a microsphere-in-capsule formulation of oxycodone labeled as abuse-deterrent for the intravenous, nasal, and oral routes.^21,22 Relative to immediate-release oxycodone, it is more resistant to grinding, crushing, and extraction.²¹ It is also difficult to draw the melted capsule contents or the microspheres suspended in water into a needle. When crushed or chewed, the formulation maintains its extended-release pharmacokinetic profile.^31-33 In a randomized, double-blind, placebo- and active-controlled study of 38 recreational opioid users, both chewed and intact Xtampza ER had lower drug liking scores and produced less of a subjective “high” compared to crushed immediate-release oxycodone taken orally.³² Similar results were found in a second study of 52 subjects.³⁴ Another randomized, double-blind trial of 39 recreational opioid users found that Xtampza ER, given orally as an intact tablet or intranasally, produced lower drug liking scores and lower drug high scores than intranasal immediate-release oxycodone.³⁵

Hysingla ER is a hydrocodone tablet with physical and chemical properties that make it difficult to crush, break, or dissolve.²¹ It retains some extended-release properties even if physically manipulated, and when put in water, it forms a viscous gel that is difficult to draw into a needle.³⁶ It is labeled as abuse-deterrent for the intravenous, oral, and nasal routes.²² A randomized, double-blind trial of 40 recreational opioid users found that drug liking was lower for orally administered Hysingla ER compared to oral hydrocodone solution, whether Hysingla ER was taken intact, chewed, or ground into fine particles.³⁷ A separate trial of 31 recreational opioid users compared hydrocodone powder to ground Hysingla ER and found that intranasal Hysingla ER produced less drug liking effects than intranasal hydrocodone powder.³⁸ Hysingla ER also caused more nasal irritation.

MorphaBond ER (an extended-release morphine tablet) contains inactive ingredients that make it difficult to cut, crush, or break.²¹ The manipulated tablet also forms a gel when subjected to an aqueous environment. It is labeled as abuse-deterrent for the intravenous and nasal routes.²² MorphaBond ER retains some of its extended-release properties after manipulation.²¹ When crushed and taken intranasally, it has a lower C_max than a nonabuse-deterrent extended-release morphine formulation (MS Contin). A randomized, double-blind, placebo- and active-controlled trial of 25 recreational opioid users found that MorphaBond ER had lower drug liking scores than crushed intranasal MS Contin when given orally (intact) or intranasally (crushed).³⁹

Other abuse-deterrent opioid formulations have been approved; however, some of these have been discontinued, and others were never brought to market.^8,22,25 Some opioid formulations underwent abuse deterrence testing but did not qualify for abuse-deterrent labeling.²¹ These include Oxaydo, an immediate-release formulation of oxycodone, and Zohydro ER, an extended-release hydrocodone formulation. In general, the approved abuse-deterrent opioids have used either physical/chemical barriers or agonist/antagonist combinations to deter abuse.

The impact of abuse-deterrent formulations is still largely unknown, and the evidence that does exist does not consistently demonstrate that these formulations reduce abuse.²² Patients may benefit more from an abuse-deterrent formulation if they are at high risk for abuse, or if they are at high risk of being targeted for diversion.⁴⁰ A significant limitation of these formulations is that most are only available as branded products, which may mean higher costs and lack of insurance coverage.^20-22,25

Conclusion

A variety of opioid drugs are available to treat pain. Opioid analgesics differ from one another in terms of potency, receptor activity, duration of action, indication, and dosage form. It is crucial for pharmacists to be aware of these differences, so that they can recommend an optimal drug and dosage form for a specific patient. Some opioid products have abuse-deterrent properties, but the clinical benefits of such formulations are currently unclear.

References

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