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Opioids: An Overview 

Opioids: An Overview
Chapter:
Opioids: An Overview
Author(s):

Daniel J. Leizman

, Alparslan Turan

, and Shahbaz Qavi

DOI:
10.1093/med/9780199349302.003.0005
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date: 18 October 2019

Key Points

  • The U.S. Food and Drug Administration (FDA) defines opioid tolerance as use of 60 mg morphine equivalence for 7 days or longer. A significant number of hospital admissions would meet this definition of opioid tolerance.

  • Management of opioid-dependent patients’ pain in the hospital setting can be challenging for the physician as well as for nursing staff and other healthcare providers.

  • It is advisable that the same maintenance dosage of opioids be continued for chronic pain patients in the hospital unless contraindicated; one can consider increasing the dose for acute pain or surgery.

  • Conversion and rotation of opioids should be carried out effectively and safely in hospitalized patients.

  • Patients who state a better effect of one opioid than that of another should not be categorized as “drug seekers” because genetic and other individual variations may influence individual sensitivity to opioid pharmacotherapy.

  • Inpatient pain management care of hospitalized patients serves as the foundation of their treatment plan and as a conduit for what is done subsequently for them as outpatients.

Introduction

Opioids are often used as a component of treatment for moderate to severe chronic, nonmalignant pain. The past 15 years have seen an increase in prescriptions of opioids for treating chronic pain, as well as increases in opiate diversion and abuse, in overdose-related deaths, and in the number of individuals being treated for opiate addiction.1,2 The guiding therapeutic goal of opioid therapy for chronic pain management should be achieving satisfactory patient analgesia and maximizing functional ability. Use of the lowest possible dose is recommended, to decrease the likelihood of side effects and physical and behavioral complications. Behavioral and psychosocial complications of opioid therapy include concomitant substance abuse (including concomitant illicit opioid use), addiction, multisourcing opioids from various providers, diversion, use of prescription opiates to achieve an opiate high, and self-medicating mood disturbances. The success of opioid therapy for chronic pain management should be assessed subjectively in terms of self-reported patient pain levels but also, more importantly, objectively in terms of functional outcome measurement. Inpatient pain management care of hospitalized patients serves as the foundation of their treatment plan and as a conduit for what is done subsequently for them as outpatients.

In terms of the history of opioid use, it is not known where and when the first opium poppy was first cultivated. The first written records of historical use of opioids for therapeutic benefit dates back to the third century b.c.e. Their introduction into Western medicine for the relief of pain has earned these drugs a unique place in medical and public perception.3 While the term opiate is commonly used as a synonym for opioid, the appropriate use of this term is restricted to the natural alkaloids found in the opium poppy (Papaver somniferum). Conversely, the term opioid refers to both synthetic substances and opiates, as well as to opioid peptides.

Opioids exert their main analgesic activity on opioid receptors. Opioids are known to be the most potent analgesics available. Thus with the imperative to treat patients’ moderate to severe pain, opioids have been established as the most important tool in the treatment of pain usually associated with cancer and pain associated with terminal illness.4 Patients with moderate to severe chronic nonmalignant pain are also commonly prescribed opiate medications.5,6

Epidemiological studies indicate that use of opioids for chronic non-cancer pain has increased substantially over the last two decades. In one large U.S. survey, the proportion of office visits for chronic musculoskeletal pain in which any opioids were prescribed doubled from 8% in 1980 to 16% in 2001.2 Use of more potent opioids (such as morphine, hydromorphone, oxycodone, and fentanyl) has also increased.7 Over the same two decades, the proportion of office visits in which prescriptions for potent opioids were given increased from 2% to 9%.2

The etiologies of these non-cancer chronic pain conditions are often musculoskeletal and neurological in origin.8,9 Examples include cervical spinal stenosis, cervical spondylosis, cervical radicular pain, lumbar spinal stenosis, lumbar degenerative disc disease, lumbar radicular pain, degenerative joint disease, traumatic orthopedic injuries, postherpetic neuralgia, and various types of neuropathic pain of peripheral and central origin.8,9,10,11

Although the term chronic non-cancer pain encompasses pain associated with a wide diversity of conditions, common treatment goals, regardless of the underlying cause, are pain relief and/or improvement in physical and psychological functioning. Physicians should limit long-term opioid prescribing to patients with well-defined pain conditions who have not responded to non-opioid treatments and for whom opioids have been shown to be effective. The prescribing physician is often challenged with the need to treat chronic pain by relieving pain and improving function yet minimizing unwanted side effects and the risk of complications.

With this framework in mind, this chapter discusses the concepts and use of opioid therapy for managing chronic non-cancer pain. It includes descriptions of various chemical groups of opioids and delivery routes of opioid therapy. Common side effects and concerns of using opioid therapy area also presented, as is evidence of the efficacy of opioid therapy for chronic pain management. Opioid conversion and opioid rotation are defined, and examples of application in patient care are given. Finally, recommended principles for guiding chronic pain management are summarized.

Opioid Compounds and Treatment Options

Opioid compounds have been classified as short- or long-acting on the basis of their duration of action. The short-acting compounds have a more rapid increase and decrease in serum levels compared to long-acting compounds. Long-acting opioids have less fluctuation in plasma concentration, which is associated with higher patient satisfaction because of fewer inadequate pain control periods. Studies comparing short-acting to long-acting opioids in regard to analgesia have shown inconsistent results, with no superiority of one over the other. When dosed on a fixed schedule, they have very similar total systemic opioid concentrations and pain control. Decisions regarding which type to use to treat chronic pain should be individualized to patient needs and response to treatment regimens.

Opioids are also classified as full agonists, partial agonists, or mixed agonist-antagonists, depending on their effect on opioid receptors. Most commonly used drugs, such as morphine, hydromorphone, codeine, oxycodone, oxymorphone, hydrocodone, methadone, levorphanol, and fentanyl, are classified as full agonists. Partial agonists (e.g., buprenorphine) have a ceiling effect and are less effective at opioid receptors. Mixed agonist-antagonists (e.g., pentazocine, butorphanol, and nalbuphine) either block or don’t affect one opioid receptor while activating a different opioid receptor (Table 5.1).

Table 5.1 Opioid Classifications Based on Source and Related Structural Group

Opioid Analgesic

Source of Chemical

Morphine-Related Structure with 6-Hydroxyl Group

Related Structural Group

Alfentanil

Synthetic

Meperidine

Alphaprofine

Synthetic

Meperidine

Buprenorphine

Semi-synthetic

No

Morphine

Butophanol

Synthetic

No

Morphine

Codeine

Natural

Yes

Morphine

Dezocine

Synthetic

Morphine

Dihydrocodeine

Semi-synthetic

Yes

Morphine

Fentanyl

Synthetic

Meperidine

Hydrocodone

Semi-synthetic

No

Morphine

Hydromorphone

Semi-synthetic

No

Morphine

Levorphanol

Semi-synthetic

No

Morphine

Meperidine

Synthetic

Meperidine

Methadone

Synthetic

Unique

Morphine

Natural

Yes

Morphine

Nalbuphine

Semi-synthetic

Yes

Morphine

Oxycodone

Semi-synthetic

No

Morphine

Oxymorphine

Semi-synthetic

No

Morphine

Pentazocine

Synthetic

Morphine

Propoxyphene

Synthetic

Methadone

Sufentanil

Synthetic

Meperidine

Tramadol

Synthetic

Unique

Immediate-Release Medications

Immediate-release medications are designed for occasional and temporary pain relief because they work fast, but this pain relief is usually short-lived. Thus these short-acting medications are used “as needed for pain,” but they can also be used as scheduled drugs. Commonly used medications include morphine, hydromorphone, oxymorphone, codeine, fentanyl, hydrocodone, and oxycodone. Codeine, hydrocodone, and oxycodone are also available in combination with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID).

Intravenous Medications

Intravenous pain medications are most commonly employed during the immediate postoperative period. Intravenous opioids are usually given alone, and most commonly include morphine sulfate, fentanyl, hydromorphone, and, rarely, meperidine and tramadol (Table 5.2). The intravenous route has several advantages, including absorption and bioavailability, ability to bypass the oral route when oral administration is not available or not indicated, and ease of administration on a scheduled or as-needed basis. There are also a number of disadvantages of intravenous application: the need to maintain an indwelling intravenous catheter, potency of drugs, increased risk of incorrect dosage or drug misidentification, possibility of infection, and requirement of having a healthcare professional to administer medications.

Table 5.2 Commonly Used Intravenous Drugs

Opiod

PRN Dosing

PCA On-demand Dosing

Morphine

1–4 mg

0.5–1.0 mg

Hydromorphone

0.5–2 mg

0.1–0.3 mg

Fentanyl

25–100μ‎g

5–25 μ‎g

Patient-Controlled Analgesia

Patient-controlled analgesia (PCA) is an effective and unique method for administering opioids to patients for pain relief, and it gives patients a sense of control over their pain. The drugs are given via the help of a pump and require an indwelling intravenous, transdermal, intrathecal, or incisional articular catheter. PCA provides significant benefit to nurse-administered medications because response time is minimal and patient satisfaction is higher with PCA. The pumps are usually easy to operate, and limited dosing is accepted as safe. Even pediatric patients have been able to use PCA successfully. A very important safety feature of PCA is that patients who are oversedated will not be able to press the button to obtain dangerous doses of the drug. This safety feature is only overridden if someone else pushes the button for them. Patients must be cognitively and physically capable of understanding the use of PCA, which limits use in many pediatric patients and in confused, elderly patients. Another critical factor in decreasing errors with use of PCA is patient and family education.

Common indications for PCA are postoperative pain, severe acute pain, cancer pain, or the patient being unable to tolerate oral medications. Most common medications used are opioids—morphine, fentanyl, and hydromorphone; local anesthetics—bupivacaine and ropivacaine; or clonidine or baclofen. Sometimes a combination of these drugs is used—specifically, local anesthetics are combined in epidural or intrathecal use to achieve synergistic effect at lower doses without increasing the side effects that would result if used alone at higher doses. The PCA is employed until transition to oral medications is possible, the pain is well controlled, and the patient can tolerate oral medications.

The PCA device can be used with or without a background infusion. If a background is used, then a continuous rate needs to be included in the settings. Settings include a bolus dose (patient demand dose); a period when the patient cannot obtain the medication, called a lockout period; and number of doses per hour, defining the maximum amount of medication that can be delivered. The number of unsuccessful demands a patient makes is often used as a guide to adjusting the settings of PCA. However, there may be other reasons for increased demand rate other than pain, including anxiety, patient confusion, or inappropriate patient use.

Most cancer and chronic pain patients will need PCA demand and continuous dosing. Studies have shown conflicting results as to whether opioid use with PCA is more effective than using conventional methods of opioid analgesia. There also seems to be no consensus on difference in incidence of side effects; however, respiratory depression due to oversedation seems to be less common with PCA.

Non-opioid analgesic drugs, such as ketamine, and/or antiemetics like ondansetron have been added to the opioids in PCA to improve analgesia and possibly decrease side effects. Currently, there is no clear evidence to suggest any benefit from the combination over independent administration of the same drug.

Oral Medications

Morphine

Morphine is one of the most commonly used and oldest known prototype of pure μ‎-agonist. Only about 40% of the administered dose reaches the central compartment because of presystemic elimination (i.e., metabolism in the liver). Morphine has two active metabolites, morphine-6-glucuronide and morphine-3-glucuronide. Morphine-6-glucuronide binds to the opioid receptor and is responsible for long duration of action in patients with renal failure. Morphine-3-glucuronide contributes to some adverse effects, such as myoclonus and confusion. These side effects are much more apparent in patients with renal failure. Morphine is available in immediate-release and extended-release formulations. Immediate-release and extended-release formulations seem to vary little in their degree of pain relief, side effects, or adverse events.

Immediate-release oral morphine drugs achieve steady state in 24 hours when given in a fixed dosing regimen. Although there is no relationship between blood levels and analgesic effect, efficient analgesia will not occur below certain minimum blood levels. The elimination of morphine occurs primarily as renal excretion of active metabolites. A small portion of the glucuronide conjugate is excreted in the bile. The elimination half-life of morphine is between 2 and 4 hours.

Morphine immediate-release tablets are available; dosing is 5–30 mg PO every 4 hours in opioid-naïve patients. Oral solution dosing is 10–20 mg PO every 4 hours in opioid-naïve patients. In addition, 5 mg oral immediate-release morphine is usually given for rescue.

Hydromorphone (Dilaudid)

Hydromorphone is a semi-synthetic opioid (hydrogenated ketone of morphine) agonist that was introduced into clinical practice in the 1920s. Hydromorphone has a short half-life (2 to 3 hours), which facilitates dose titration but complicates efforts to use it for chronic pain. Compared to morphine, hydromorphone is more potent. The equianalgesic ratio in the literature ranges from 2 to 12; however, the most commonly accepted ratio is about 7:1 (morphine to hydromorphone). Side effects with hydromorphone are similar to those of opioids in general and most often include constipation, nausea, and sedation. Hydromorphone is metabolized in the liver, with approximately 62% of the oral dose being eliminated by the liver on the first pass. For orally administered immediate-release preparations, the onset of action is approximately 30–40 minutes and duration is 3–4 hours. Hydromorphone is preferred over morphine for patients with decreased renal clearance, to decrease the risk the toxicity from accumulation of morphine metabolites. Patients with hepatic and renal impairment should be started on a lower starting dose. Hydromorphone is metabolized to 3-glucoronide metabolite, which has been associated with dose-dependent excited behaviors, including allodynia, myoclonus, and seizures in animal models.

Hydromorphone is available not only in tablets but also in an oral liquid form, which makes it more suitable for patients who have swallowing and gastrointestinal problems. The usual starting dose for hydromorphone tablets is 2 mg to 4 mg, orally, every 4 to 6 hours, and for oral liquid is 2.5 mL to 10 mL (2.5–10 mg), every 3 to 6 hours. Furthermore, a breakthrough dose should be given. It is important that dosage is individualized because adverse events can occur at doses that may not provide complete relief from pain.

Oxycodone

Oxycodone is a phenanthrene class opioid provided in pure form, or in combination with acetaminophen or aspirin. Bioavailability of oxycodone is high and the half-life is 3 hours. It is metabolized in the liver by glucuronidation to noroxycodone, and by 2D6 to oxymorphone, which is excreted in urine. Since oxycodone is dependent on the cytochrome P450 (CYP) 2D6 pathway for clearance, it is possible that drug–drug interactions can occur with CYP 2D6 inhibitors. Furthermore, there is considerable variation in the efficiency and amount of CYP 2D6 enzyme produced between individuals. Unpredictable individual responses to treatment are sometimes related to these properties of the drug.

Oxycodone tablets contain different amounts of acetaminophen—325, 500, and 650—and 2.5 mg, 5 mg, 7.5 mg, and 10 mg active drug. When these drugs are used, care must be taken to not exceed the recommended maximal dose of the coanalgesic (for example, 4 g or less of acetaminophen per day). The modified-release formulation of oxycodone is now widely used for management of chronic pain.

Methadone

Methadone is a synthetic medication used to treat opioid addiction and is prescribed as an opioid of choice for patients with chronic pain and comorbid substance use disorders. Methadone occurs in R- and S-enantomeric forms. The R-form binds to opioid receptor and S-form blocks the N-methyl-D-aspartate (NMDA) receptor. Methadone is rapidly absorbed from the stomach, with 60%–70% bioavailability, and analgesic effect starts in 30 to 60 minutes. Analgesia from methadone lasts for 4-6 hours, thus a dosing of up to 3–4 times per day is suggested for analgesia. Methadone is metabolized to inactive forms by liver and intestinal CYP 3A4 and CYP 2D6. Metabolites of methadone are then excreted in feces and urine. Mild and moderate liver and renal disease do not seem to affect pharmacokinetics. Age doesn’t seem to affect clearance. Patients with end-stage renal disease require a 50% decrease in dosing.

The most frequent side effects seen with methadone are respiratory depression and sedation. Methadone has been associated with prolongation of the QT interval, which can cause life-threatening cardiac arrhythmia. Methadone dosing requires close monitoring, use of low starting doses, an adequate interval between dose changes, and caution when treating patients who have heart disease or use medications that have effects on the QT interval. Weight gain, sexual dysfunction, decrease in testosterone levels, constipation, and cognitive slowing are some of the common side effects related to chronic methadone use.

Equianalgesic doses for methadone and other opioids are not well defined. Usually, chronic pain treatment with methadone should begin with a low dose (5 mg 2–3 times a day) and then gradually increase, depending on the response. Low cost and long half-life make it affordable for patients who cannot otherwise obtain sustained-release opioids. The opioid equianalgesic table is located on the cover of this book.

Levorphanol

Levorphanol is a synthetic morphine analogue and the optical isomer of dextromethorphan. It has μ‎, κ‎, and δ‎ agonist, as well as NMDA antagonist effects. The NMDA antagonist effect makes it more suitable for treating neuropathic pain. Levorphanol is well absorbed after oral administration and reaches peak plasma concentrations in approximately 1 hour. It is metabolized in the liver and is eliminated as the glucuronide metabolite through the kidneys. It has a similar degree of respiratory depression properties to those of other opioids.

Like methadone, there is a variable dosing equivalent: for morphine doses less than 100 mg, the conversion factor is 12:1, while doses over 600 mg may need a conversion factor of 25:1. There is cross-tolerance among opioids when converting a patient from morphine to levorphanol. The total daily dose of oral levorphanol should begin at approximately 1/15 to 1/12 the total daily dose of oral morphine that the patient previously required. It should then be adjusted in accord with the patient’s clinical response.

Buccal Medications

Fentanyl

Fentanyl is a highly lipophilic opioid that can be absorbed through membranes, including transmucosal membranes. Transmucosal fentanyl absorption, through oral mucosa, is more rapid than oral absorption. It is better tolerated in patients with dysphagia, nausea, or vomiting and minimizes first-pass metabolism.

The very first fentanyl intended for oral transmucosal use was introduced in 1999. Oral transmucosal fentanyl citrate (OTFC) is a buccal formulation of a fentanyl lozenge on a lollipop. Fentanyl is available in six strengths: 200 μ‎g, 400 μ‎g, 600 μ‎g, 800 μ‎g, 1200 μ‎g, and 1600 μ‎g. The patient places and then rubs the fentanyl against the mucosa, which dissolves over 15 minutes. One-quarter of the OTFC`s total dose is absorbed by the buccal mucosa, and 75% of the dose is swallowed and then absorbed from the gastrointestinal tract, where two-thirds is eliminated via first-pass metabolism. The bioavailability of OTFC is therefore ~50% of the total dose. The main use of these drugs is for breakthrough pain (BTP) in chronic pain or acute postoperative pain. When compared with an intravenous route, pain relief is lower, but ease of use brings advantages. Second generations of delivery systems, like buccal tablets and buccal soluble film, provide a refinement enabling better drug absorption.

Fentanyl buccal soluble film is approved for treatment of BTP. Fentanyl is included in a film that adheres to the buccal mucosa inside of the cheek, dissolving within 15–30 minutes, releasing fentanyl, which passively diffuses into the bloodstream. It requires a minimal quantity of saliva. The proportion of the fentanyl that undergoes transmucosal absorption is approximately 50%, and the absolute bioavailability is approximately 71%. The usual starting dose is 200 μ‎g per episode and can be increased by 200 μ‎g increments. For persisting pain, an 800 or 1200 μ‎g dose can be given as well. Each dose must be separated by 2 hours.

Fentanyl buccal tablets have been designed to treat episodes of BTP. Fentanyl buccal tablets involve an effervescent drug-delivery system to penetrate across the buccal mucosa. Dosing is 100, 200, 400, 600, and 800 μ‎g and can be repeated after 30 minutes if pain control is insufficient. The median time to peak plasma concentration is about 50 minutes, possibly due to a large dose absorbed transmucosally. In studies, patients stated that the 30-minute post-dose medication performance was “good” to “excellent” in 41% of BTP episodes, compared with 26% of episodes treated with oxycodone (p < 0.0001), and more patients preferred fentanyl buccal tablets over oxycodone.

All of the transmucosal versions of the fentanyl start to be effective after 30 minutes, with similar analgesic efficacy; treatment selection should be based on side-effect profiles, ease of use, and suitability for the individual patient.

Extended-Release Medications

Extended-release medication by definition means that these drugs slowly release in the body over an extended period of time. Extended-release and long-acting opioids are available in several forms—tablets, liquids, and skin patches.

Efficacy of Long-Term Opioid Therapy for Treatment of Chronic Nonmalignant Pain

Opioid medication therapy is typically very efficacious in relieving acute pain; however, there is limited information in the literature regarding long-term use. Available data have demonstrated modest benefit in relation to pain intensity.12 Recent reviews evaluating long-term use of opioids found only modest evidence of efficacy,13 and there are few trials comparing opioids with other drugs.14 Currently, there is no high-quality evidence to suggest superior efficacy of any specific opioid preparation or formulation in long-term use.15

Efficacy of Opioid Therapy for Chronic Pain Management with Functional Outcome Measurement

Data demonstrating improvements in quality of life and/or functional improvement with opioid therapy are lacking in the literature. Additionally, general physical activity monitoring in chronic pain rehabilitation is usually limited to functional indices like range of motion, endurance exercises, or self-reporting.16,17

Side Effects of Opioid Therapy and Related Concerns

Treating chronic pain with long-term opioid usage comes with particular concerns. These include opioid tolerance, opioid-induced hyperalgesia, drug/dose escalation, overdose-associated death, abuse, and diversion.18,19,20 Prescription opioid abuse is currently an epidemic in the United States, causing addiction, greater healthcare utilization, and 70% drugs going to abusers.21,22 The common side effects and complications of opioid therapy are as follows:

  • Constipation

  • Decreased testosterone

  • Opioid-induced hyperalgesia

  • Overdose

  • Opioid dependence

  • Opioid-dependent neonates

  • Opioid tolerance, efficacy issues, drug/dose escalation issues

  • Misuse and/or addiction (19%–26% of hospitalized patients have substance use disorders)

  • Respiratory depression (though not common in chronic usage if being used regularly according to instructions)

Use of the newer opioid antagonists with only peripheral action may help avoid some of the side effects without losing the central opioid analgesic effects. This is possible because of either limited systemic bioavailability of these medications or a peripherally restricted site of action, as they don’t cross the blood-brain barrier. One of the available medications, alvimopan, may help with ileus associated with opioid use. It is important to note, however, that alvimopan is contraindicated in patients taking therapeutic doses of opioids for more than 7 days. Another peripherally acting μ‎-receptor antagonist, methylnaltrexone, can be used as well. It is a quaternary naltrexone derivative, which is restricted from crossing the blood-brain barrier. It blocks peripheral opioids’ side effects on the gastrointestinal tract, mainly constipation. It is administered subcutaneously. Because of limited systemic availability of the extended-release naloxone formulation, a combination of extended-release naloxone with extended-release oxycodone can be used during the rehabilitation phase to lessen the degree of opioid-induced motor stasis of the bowels without decreasing its analgesic effects. Naloxegol is an oral agent which has been recently approved for opioid-induced constipation.

Another common side effect of opioids is itching. The precise control of opioid-induced itching through peripherally acting opioid receptor antagonists has not yet been successful, however, possibly because of a central component in the mechanism of opioid-induced itching.

Opioid-dependent patients typically experience less nausea and itching than their opioid-naïve counterparts. Respiratory compromise, however, and unwarranted sedation are quite common. One of the reasons for these effects is concomitant use of benzodiazepine anxiolytics and other sedative agents, which invariably are requested by many opioid-dependent patients. Consumption of high doses of opioids can bring about circumstances in which an intensive care team needs be involved to save the patient’s life. Patients with impaired kidney function or other significant comorbidities, morbidly obese patients, children, and older adults are particularly at high risk. Telemetry and other tools for monitoring these patients are important to set up when significant doses of opioids are used in managing acute or chronic pain in opioid-dependent patients. However, even with thorough monitoring, untoward events are common. The opioid-sparing approaches discussed elsewhere in this book are thus recommended for management of acute or chronic pain in opioid-dependent patients.

Efficacy Related to Formulation and Route of Delivery

Recently developed long-acting opioids provide convenient dosing and uniform blood levels, resulting in uninterrupted analgesia.23 Properties of long-acting opioids are reported to contribute to better pain control, improvement in functional outcomes, and a decrease in the tendency of escalation in dosing, resulting in a better safety profile.24,25 Furthermore, lower peak serum levels of long-acting opioids, compared to those with short-acting opioids, are expected to induce less psychoactive effects (abuse potential).24 Still, available studies do not adequately address the possible beneficial effects of long-acting opioids or compare them with most commonly prescribed short-acting opioids. Therefore, more extensive studies with long-term follow-up are warranted.

Tamper-resistant drugs have formulations modifying the tablet, capsule, or patch in order to neutralize the active component and make it undesirable for abuse or unintended use.26,27 These formulations aim to address concerns regarding abuse of opioids, however, they cannot address situations where individuals take more drugs in order to experience euphoria.26 Benefits of these products need to be evaluated in expansive long-term clinical trials looking at different aspects of abuse.

Opioid Conversion and Rotation

It is advisable that the same maintenance dose of opioids be continued for chronic pain patients in the hospital, unless contraindicated, and that one consider increasing the dose for acute pain or surgery. Therefore, conversion and rotation of opioids in hospitalized patients are predictable. The distinction between conversions and rotation is as follows.

Opioid conversion involves using the same opioid compound but through different route of delivery. Examples of conversion include intravenous fentanyl to transdermal fentanyl, intravenous morphine to oral morphine, and intravenous methadone to oral methadone (see Appendix A).

Opinions vary regarding the conversion of oral opioids to intravenous and back, and regarding opioid rotation. Most parenteral doses of opioids can be decreased from oral doses because intravenous or intramuscular administration bypasses bowel absorption and first-pass hepatic metabolism. This is unambiguously the case with intravenous hydromorphone and morphine, which have about three times greater bioavailability and systemic potency than equianalgesic oral preparations. The exception is oxycodone and its extended-release formulations, which have substantial oral bioavailability but low intravenous bioavailability. Individual patient differences should be taken into consideration when conversion options are considered. Related factors include individual pain perception, age, gender, medical conditions, and genetic variations that may alter the metabolism and excretion of medications.

Opioid rotation is changing one opioid to another. The drug is typically administered via the same route, but a different chemical compound is used. The switch from one opioid to another is made usually because the parenteral form of medication is unavailable (for example, the patient has been taking oxycodone at home but is now in the hospital and NPO). Another reason for using opioid rotation is to improve treatment response or to reduce side effects. The definitive mechanisms by which opioid rotation improves overall response to treatment are not yet known. Positive therapeutic effect may be related to incomplete cross-tolerance to dissimilar opioids that act differently on diverse types and subtypes of opioid receptors. As a result, opioid rotation may decrease tolerance, help lower the opioid dose, and thus decrease unfavorable effects. For example, methadone is an opioid receptor agonist and also an NMDA receptor antagonist. Rotation to methadone has been shown to be effective for decreasing the equivalent opioid requirement and reducing acute or chronic pain in the hospital setting.

The disadvantage of using rotation and conversion of opioids during hospitalization is that they raise the risk of medical errors. Active involvement of pharmacy services in management of acute or chronic pain in the hospital setting may increase the safety of opioid use dramatically (discussed in detail elsewhere in this book). In addition, new research may make opioid rotation more effective and safer, by exploring additional factors in its use, such as the role of genetic variations in opioid rotation and conversion.

Summary

The U.S. Food and Drug Administration (FDA) defines opioid tolerance as use of 60 mg morphine equivalence for 7 days or longer.28 A significant number of hospital admissions meet the definition of opioid tolerance.29 Management of opioid-tolerant and opioid-dependent patients in the hospital setting can be challenging for the physician, as well as for nursing staff and other care providers. Most important to the success of inpatient chronic pain management is attentive management of a patient’s pain, with judicious use of opioids. This must be followed with quality care in the outpatient setting. Patients who are engaged in their own care and are motivated to improve and maximize their well-being physically and mentally, despite having a chronically painful condition, will likely fare best. In order to achieve successful chronic pain management, a partnership between patient and physician is required, with a strong commitment to maximizing the total well-being of the patient. If this has not been achieved for the patient as an outpatient, the physician and patient can each be faced with an array of issues during a hospitalization, which may already be a stressful situation. Providing high-quality outpatient chronic pain management will allow for the most ease and least stress of managing chronic pain when the patient is hospitalized, electively or emergently.

The objectives listed in Box 5.1 should be kept in mind with regard to opioid therapy in the management of chronic pain for inpatients.

The practice tools listed in Box 5.2 may help to avoid use of opioids for treatment of acute or chronic pain in patients during hospitalization.

Further medical research is needed to elucidate the role of opioids in the treatment of acute or chronic non-cancer pain in the hospital setting. This research needs to focus on the safety of high-dose opioid therapy required for treating acute pain and objective measurable functional outcomes for chronic pain following discharge from the hospital. The physician must do what is best medically for the patient’s well-being, not necessarily what best pleases the patient or is least taxing or least confrontational for the physician. This can be a difficult task when dealing with patients with chronic pain. Providing this type of care takes extra time and effort, and it requires physician knowledge, empathy, and good judgment, and strong ethical conviction.

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