Abstract
Oral opioids have been used for centuries for treating pain, with the modern era beginning in the 19th century with the discovery of morphine. Nonintravenous opioids can be categorized into three structural groups: naturally occurring alkaloids, semisynthetic alkaloids, and synthetic opioids. Most nonintravenous opioids are metabolized by the cytochrome P450 enzyme into inactive metabolites; however, morphine undergoes glucuronidation to produce metabolites that are renally cleared and may accumulate with renal insufficiency. Nonintravenous opioids have many routes of administration, including the ultrashort-acting transmucosal opioids, short-acting, extended-release and long-acting oral opioids, and continuous-acting transdermal opioids. Common side effects include constipation, nausea, sedation, pruritus, and respiratory depression. Tolerance develops to most of these effects, with the notable exception of constipation. Concomitant use of opioids and other central nervous system depressants can lead to profound sedation, respiratory depression, and death, particularly with benzodiazepines, propofol, and alcohol. Acute pain and cancer-related pain are long-standing indications for the use of nonintravenous opioids. However their use for chronic pain is controversial without established long-term efficacy and concerns for development of addiction and increases in opioid overdose deaths. Selection of a nonintravenous opioid is based on time to onset, needed duration, available routes of administration, opioid tolerance, and side effect profile. Emerging developments in nonintravenous opioids include buprenorphine for opioid dependence, peripherally restricted µ antagonists for opioid-induced constipation, concerns about suppression of immune and endocrine function, and increasing recognition of sleep-disordered breathing with opioids.
Keywords
Non-intravenous Opioids: Chemical Structure, Non-intravenous Opioids: Routes of Administration, Non-intravenous Opioids: Metabolism, Opioids: Renal Failure, Non-intravenous Opioids: Equivalency and Conversion, Cancer Pain: WHO Analgesic Ladder, Chronic Opioids: Side Effects
Historical Perspective
The use of opium for treating pain dates back to at least ancient Egypt, but the modern opioid era began in 1804 when German pharmacist Friedrich Wilhelm Sertürner discovered the naturally occurring opioid morphine. Morphine and opium were widely sold over the counter in liquid, pill, and powder forms throughout the 19th century, and in 1898 the Bayer Company released the first semisynthetic opioid, heroin, as a cough suppressant. Initially touted as less habit-forming than morphine, within a few years heroin was widely crushed and snorted. This, in addition to the rising tide of iatrogenic morphine addiction, led to the Harrison Narcotics Tax Act of 1914 in the United States, requiring physician and pharmacist registration for distributing opioids and largely criminalizing possession of these drugs for nonmedical uses.
In addition to regulatory action, the “opium problem” of the early 1900s led to increased focus on drug development both in the United States and abroad. The desire to identify a substitute for morphine, a drug that would separate the analgesic and addictive properties, led to the synthesis of oxycodone in 1917 in Germany. In the United States the Committee on Drug Addiction was formed in 1921 and tested a number of newly developed synthetic and semisynthetic opioids over the next 50 years, yet a powerful opioid pain reliever without habit-forming properties remains elusive.
The second heroin epidemic of the mid-1900s led to the Controlled Substances Act of 1970 in the United States, requiring manufacturers, distributors, and providers who dispense or administer controlled substances to register with the Drug Enforcement Administration (DEA). Later, in response to the need for opioid abuse treatment, the Narcotic Addict Treatment Act of 1974 decriminalized the use of opioids, primarily methadone, to permit legally treating opioid dependence with opioid replacement therapy.
The 1990s ushered in growing attention to the problem of undertreated chronic pain. With this came aggressive marketing of opioids by the pharmaceutical industry, new pain management standards implemented by The Joint Commission on the Accreditation of Health Care Organizations, and relaxed laws governing prescribing of opioids by state medical boards. Prominent physicians and medical societies promoted the use of opioids to treat chronic pain with the misinformed assertion that opioids are safe and effective, with no dose ceiling or long-term untoward effects. These and other factors culminated in a rapid rise in the number of opioid prescriptions dispensed in the early 2000s, followed by an even more rapid rise in opioid-related overdose deaths.
While opioids unquestionably have a role in the treatment of some types of pain, it is now clear they carry tremendous risks if not used judiciously. This chapter focuses on the clinical application of oral and transdermal preparations of opioid analgesics (for a discussion of basic opioid pharmacology and intravenous opioids, see Chapter 17 ).
Basic Pharmacology
Structure-Activity
Clinically relevant nonintravenous opioids can be categorized into three structural groups: naturally occurring alkaloids, semisynthetic alkaloids, and synthetic opioids. Naturally occurring opioids can be extracted from the seeds of the poppy plant and include morphine and codeine ( Fig. 18.1 ). Although the majority of codeine available worldwide is manufactured from morphine as a semisynthetic alkaloid, codeine is found naturally along with morphine in the poppy seed. Note that codeine simply adds a methyl group on the 3-hydroxyl of morphine.
Semisynthetic alkaloids include hydromorphone (Dilaudid), hydrocodone (Norco, Vicodin), oxycodone (Percocet, Oxycontin), oxymorphone (Opana), and buprenorphine (Suboxone, Subutex). These drugs are derived from morphine, typically with substitutions of ester, hydroxyl, keto-, or methyl groups at the 3 and 6 carbon or 17 nitrogen positions of morphine ( Fig. 18.2 ).
Synthetic opioids are further characterized as phenylheptylamines, including methadone, and phenylpiperidines, including fentanyl. Tramadol and tapentadol are also included in this group. These drugs have unique chemical structures that do not follow a morphine-like pattern ( Fig. 18.3 ).
Mechanism of Action
All opioids exert their primary pharmacologic effects by interactions with opioid receptors at multiple sites in the central nervous system (CNS). The classic µ, κ, and δ opioid receptors are typical G-protein–coupled receptors (see Chapter 17 ). Binding of the opioid leads to an overall reduction in neuronal excitability via membrane hyperpolarization as the result of decreased cyclic adenosine monophosphate production, decreased calcium ion influx, and increased potassium ion efflux.
Tramadol and tapentadol are unique among nonintravenous opioids in that they bind to opioid receptors, but they also exert an analgesic effect through inhibiting reuptake of serotonin and norepinephrine; tramadol primarily inhibits serotonin reuptake and tapentadol primarily inhibits norepinephrine reuptake. Fentanyl also inhibits serotonin reuptake, although the contribution to its clinical analgesic effect is unclear.
Metabolism
The majority of nonintravenous opioids are metabolized by the cytochrome P450 system, primary via the 3A4 and 2D6 isoforms. Notable exceptions include morphine, hydromorphone, and oxymorphone. Morphine is chiefly metabolized via glucuronidation to the metabolites morphine-3-glucuronide (M3G), which has CNS neuroexcitatory effects, and morphine-6-glucuronide (M6G), an analgesic 50 times more potent than morphine. Hydromorphone and oxymorphone are the cytochrome P4502D6 metabolites of hydrocodone and oxycodone, respectively. They undergo glucuronidation as well as some reduction. Less is known about the activity of their metabolites, although hydromorphone-3-glucuronide may have CNS neuroexcitatory effects.
Most opioids are metabolized to inactive metabolites, although some, such as tramadol and codeine, are prodrugs that require metabolism to an active metabolite for clinical effect. Morphine is again a notable exception in having active metabolites. See Table 18.1 for a summary of opioid metabolism, metabolites. and their activity.
| Medication | Metabolism | Metabolites | Metabolite Activity |
|---|---|---|---|
| Morphine | Glucuronidation | M3G M6G | Neuroexcitatory Active |
| Codeine | Glucuronidation (80%) CYP2D6 CYP3A4 | C3G C6G Morphine Norcodeine | Possibly neuroexcitatory CNS-toxic Active Active Inactive |
| Hydrocodone | CYP2D6 CYP3A4 | Hydromorphone Norhydrocodone | Active Inactive |
| Hydromorphone | Glucuronidation Reduction (minor) | H3G | Possibly neuroexcitatory |
| Oxycodone | CYP2D6 CYP3A4 | Oxymorphone Noroxycodone | Active Inactive |
| Oxymorphone | Glucuronidation Reduction (minor) | 6-OH-OXM OXM3G | Inactive Inactive |
| Buprenorphine | CYP3A4 | Norbuprenorphine | Active |
| Methadone | CYP3A4 CYP2B6 (minor) | EDDP | Inactive |
| Fentanyl | CYP3A4 | Nor-fentanyl | Inactive |
| Tramadol | CYP2D6 | M1 | Active |
| Tapentadol | Glucuronidation | TAP-OG | Inactive |
Clinical Pharmacology
Pharmacokinetics
Opioids are unique in their availability across many routes of administration. In addition to intravenous and neuraxial administration, covered in previous chapters, they can be administered clinically by transmucosal (buccal, sublingual, or intranasal), oral, and transdermal methods. Experimental methods include inhaled opioids.
Transmucosal opioids are considered ultrashort-acting as they achieve peak plasma concentration within 10 to 20 minutes with an analgesic effect of 60 to 120 minutes. Among oral opioids there are both short-acting and extended-release formulations of multiple agents such as hydrocodone, hydromorphone, and oxycodone. There are also long-acting agents such as methadone and buprenorphine. Short-acting oral opioids allow for “as-needed” dosing for episodic or breakthrough pain and generally achieve peak plasma concentrations within 30 to 60 minutes. Extended-release formulations and long-acting agents allow for less frequent dosing and more stable analgesia in patients with constant pain as they can ameliorate large fluctuations in serum opioid levels or the so-called “peak-and-trough” effect seen with short-acting opioids. However, they differ widely in their individual pharmacokinetic properties ( Fig. 18.4 and Table 18.2 ).
| Opioid | Time to Peak Plasma Concentration | Duration of Effect | t 1/2 |
|---|---|---|---|
| Transmucosal | |||
| Buccal fentanyl | 10–20 min | 1–2 hr | 4.5 hr |
| Intranasal fentanyl | 5–10 min | 60–90 min | 4.5 hr |
| Oral Short-Acting | |||
| Oxycodone | 1–1.5 hr | 2–4 hr | 3.5 hr |
| Hydrocodone | 1–1.5 hr | 2–4 hr | 3.5 hr |
| Oral Extended-Release | |||
| Morphine | 4.5 hr | 8–12 hr | 2–3 hr |
| Oxycodone | 4.5–5 hr | 12 hr | 3.5 hr |
| Oral Long-Acting | |||
| Methadone | 1–7 hr | 6–12 hr a | 8–59 hr |
| Buprenorphine | 100 min | 24–36 hr | 24–42 hr |
| Transdermal | |||
| Fentanyl | 24 hr | 48–72 hr | 24 hr |
| Buprenorphine | ~48 hr | 7 days | 26 hr |
a Methadone has a duration of analgesia that is much shorter than the duration of effect used to suppress withdrawal symptoms when used as maintenance therapy for opioid dependence.
Fentanyl and buprenorphine are unique because transdermal delivery systems enable continuous delivery. Modern transdermal patches use an inert polymer matrix impregnated with dissolved drug that has evolved from early transdermal systems that consisted of a simple drug reservoir separated by a rate-limiting membrane. Drug delivery with transdermal patches is a result of the concentration gradient between the patch and skin, is proportional to the area of exposed skin, and allows for a near zero-order delivery of medication at steady state without being subject to first-pass metabolism. This reduces, though does not eliminate, variability in serum opioid concentration. Additionally, this gradient is in part temperature-dependent, with increased absorption occurring at higher temperatures. Serious adverse effects and deaths have occurred with concurrent application of external heat, such as with electric heating blankets, saunas, and hot tubs.
Pharmacodynamics
Like intravenous opioids, nonintravenous opioids exert their activity through agonism of the µ-opioid receptor (see Chapter 17 ). Given their common mechanism of action, most µ-opioid receptor agonists are pharmacodynamically equivalent and produce similar effects when used in equivalent equipotent doses.
The µ-opioid agonist-antagonists are exceptions to this general rule because of their more complicated µ-receptor activity profile. Buprenorphine, the most commonly used partial agonist outside the perioperative setting, is a partial agonist at the µ receptor and an antagonist at the κ receptor. Buprenorphine exhibits a ceiling effect for analgesia and respiratory depression compared with full agonists. Tramadol has a low affinity for the µ receptor, and analgesia is only partially reversed by administration of the specific µ-receptor antagonist naloxone, presumably because of its serotonin reuptake inhibition activity. Because of this low µ-receptor affinity, the analgesia produced by tramadol might be suboptimal for severe pain.
Therapeutic Effects
Activation of µ-opioid receptors produces analgesia, which is the primary therapeutic effect of opioids. Other effects such as sedation, decreased gastrointestinal motility, and antitussive properties have clinical applications but are typically secondary considerations for opioid selection and administration (see Chapter 17 ).
Adverse Effects
Common side effects of opioid analgesics prescribed in the ambulatory setting include constipation, nausea, sedation, confusion, dry mouth, pruritus, and respiratory depression. Less frequent side effects include urinary retention, myoclonus, and mood effects, both euphoria and dysphoria. These side effects can be dose-limiting and even life-threatening, but tolerance to most side effects occurs with continued opioid therapy, the major exception being opioid-induced constipation (OIC).
Respiratory Depression
Respiratory depression is the most dangerous adverse effect associated with µ-agonist drugs in either ambulatory or inpatient settings. Unrecognized respiratory depression when manifest in its severe form can lead to fatal respiratory arrest. More than 165,000 deaths were attributed to overdoses related to prescription opioid medications from 1999 to 2014 in the United States; the overwhelming majority of these deaths are due to respiratory arrest.
Managing and monitoring opioid-induced respiratory depression in the ambulatory setting is challenging. The Centers for Disease Control and Prevention (CDC) Guideline on Prescribing Opioids for Chronic Pain released in 2016 recommends an increase in the frequency of follow-up as well as consideration of prescribing naloxone for emergency rescue if a patient’s dosage from all combined sources of opioids reaches or exceeds 50 mg oral morphine equivalents (OME) per day because of the higher likelihood of respiratory depression.
Sedation
Centrally mediated µ-receptor agonism is responsible for the sedation observed with opioid administration. Sedation is a common dose-limiting side effect outside the perioperative setting, particularly in the setting of patients with cancer pain and pain in the elderly, although it is generally temporary as tolerance occurs over time with stable opioid dosing. Combining oral and transdermal opioids with other CNS-active medications can lead to a greater than anticipated sedating effect.
Constipation
µ Receptors are highly concentrated throughout the mucosa and submucosa of the gastrointestinal tract. The concentration of µ and κ receptor is most dense in the stomach and proximal colon. OIC is multifactorial but is due in part to an increase in nonperistaltic motility, delayed transit time, and increased sphincter tone at the pylorus and ileocecal junction. Given the high frequency of OIC, a prophylactic bowel regimen should be considered when initiating opioid therapy. In addition to traditionally used agents such as stool softeners, osmotic laxatives, and stimulant laxatives, newer therapies are available for treatment of OIC (see “ Emerging Developments ”).
Nausea
Opioid-induced nausea and vomiting are common side effects, particularly for opioid-naive patients. Fortunately, habituation frequently occurs within several days but may necessitate treatment with antiemetic medications. Ultimately, switching to an alternative opioid, altering the route of administration, or reducing the dose may be required to manage the nausea effectively. Patients can have idiosyncratic responses to different opioid analgesics and switching to a different opioid may reduce or resolve nausea, although the scientific foundation for this observation is not well established.
Pruritus
More commonly seen with parenteral or neuraxial administration, pruritus can still occur with oral, transdermal, and transmucosal administration. Patients typically become tolerant to opioid induced pruritus and infrequently require treatment. With rotation to another opioid, pruritus often resolves. If opioid-induced pruritus does require treatment, antiemetics such as ondansetron or promethazine or antihistamines such as diphenhydramine or hydroxyzine, can be used.
Tolerance and Dependence
Tolerance and dependence are considered normal adaptive physiologic responses to ongoing opioid therapy. Tolerance is the need for increased dosing to maintain a defined degree of analgesia in the absence of disease progression or changes in other external factors. Dependence can be physical and/or psychological. Physical dependence occurs from a progressive tolerance to both the therapeutic and adverse effects of opioids and is characterized by the appearance of withdrawal symptoms with rapid dose reduction, abrupt discontinuation, or exposure to opioid antagonists.
Tolerance and dependence should be distinguished from opioid abuse. As defined by numerous professional societies, opioid addiction is “a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.”
Other Adverse Effects
Myoclonus can occur with high-dose opioid therapy, particularly with morphine, secondary to accumulation of the metabolite M3G. Transitioning to a new opioid often results in improvement or resolution of myoclonus. Urinary retention can result from opioid administration, although this effect is variable. µ Agonists increase urinary tract smooth muscle tone, although in some cases this can produce urinary urgency as opposed to true urinary retention. Conversely, opioids reduce gastrointestinal tract sphincter tone. This can result in dysfunction of the sphincter of Oddi, which controls the flow of bile and pancreatic secretions into the duodenum. Acute biliary-type pain attacks and dilation of bile duct have been reported and these effects are reversed with naloxone. Opioids can affect reward pathways in the brain and induce euphoria in select patients, but can cause dysphoria in others. These responses are due in part to opposing effects of µ receptor and κ receptor agonism on dopamine levels in the nucleus accumbens, substantia nigra, and striatum, offering an explanation for seemingly idiosyncratic dysphoric reactions to different opioids.
Drug Interactions
Concomitant use of opioids and other CNS depressants can lead to profound sedation, respiratory depression, and death, particularly with gamma aminobutyric acid (GABA) A agonists such as benzodiazepines, barbiturates, propofol, and alcohol. These interactions are synergistic. Opioid-associated urinary retention and constipation are compounded by the coadministration of drugs with significant anticholinergic activity. Of particular clinical significance is the increased incidence of constipation in the setting of concomitant use of opioids and ondansetron owing to the effect of ondansetron on serotonin-mediated gastrointestinal peristalsis. Constipation is a common adverse effect associated with ondansetron, occurring in nearly 10% of patients treated for nausea and vomiting associated with chemotherapy, and can be worsened by opioid therapy in this patient population. The synthetic opioids, including fentanyl, methadone, tramadol, and meperidine, are all weakly serotonergic and have been implicated in multiple reports of serotonin syndrome when used in combination with other serotonergic medications such as monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants, and lithium.
Multiple opioids undergo phase I metabolism via the cytochrome P450 system, particularly CYP2D6 and CYP3A4. These enzymes are affected not only by allelic variations but also by many other medications that act as substrates, inhibitors, and inducers. Common inducers include anticonvulsant agents and pentobarbital. Calcium channel blockers, selective serotonin reuptake inhibitors, benzodiazepines, many psychotropic agents (see Chapter 12 ), and multiple antibiotics act as both a substrate and an inducer of CYP 450 enzymes, and many opioids have substantial interaction potential with these commonly used agents. See Table 18.3 for a summary of these interactions.
| Medication | Dose | Dose Interval | Notes |
|---|---|---|---|
| Morphine | Reduced | Increased | |
| Codeine | Avoid | Avoid | Metabolized to morphine with unpredictable serum concentrations |
| Hydrocodone | Reduced | Increased | |
| Hydromorphone | Reduced | No change | Preferred agent |
| Oxycodone | Reduced | Increased | |
| Oxymorphone | Reduced | Increased | |
| Buprenorphine | Unknown | Unknown | Appears safe but limited data |
| Methadone | Reduced | Increased | |
| Fentanyl | Reduced | Increased | Preferred agent |
| Tramadol | No change | Increased |
Special Populations
Renal Insufficiency
The liver is the major site for biotransformation and elimination of most opioids; however, the majority of opioid metabolites are renally cleared. Although these metabolites are often inactive or minimally active, an important exception is morphine. Morphine is metabolized to the inactive metabolite M3G and the active analgesic metabolite M6G, which has an analgesic potency near that of morphine. Accumulation of M6G leading to respiratory depression in patients with altered renal clearance mechanisms constitutes the basis for avoiding morphine therapy in patients with renal failure. Because codeine is metabolized to morphine it should also be avoided in patients with renal insufficiency.
Oxycodone and oxymorphone both have active metabolites. In uremic patients the elimination half-life is lengthened and excretion of metabolites is impaired; however, the clinical relevance of this is largely unstudied in the setting of renal insufficiency. Tramadol produces the metabolically active metabolite M1, and an increased dosing interval of 12 hours is recommended in patients with compromised renal function.
Fentanyl, methadone, and buprenorphine are considered safe in patients with renal insufficiency and do not require dose adjustment. Hydromorphone is also a preferred opioid in patients with renal impairment, although it has a potentially active metabolite. In the setting of dialysis, hydromorphone levels are reduced to 40% of predialysis levels, whereas fentanyl and buprenorphine are not dialyzable and levels remain unchanged following dialysis.
Hepatic Impairment
The liver is the major site of metabolism for most opioids; thus patients with liver disease who require opioid treatment present unique challenges. Impaired liver function not only leads to changes in the pharmacokinetic properties of drugs but can also lead to alteration in plasma protein binding and the plasma concentration of unbound “free” drug. This altered drug disposition can lead to increased therapeutic effect and an increase in adverse effects, potentially manifest as sedation, respiratory depression, and potentiation of hepatic encephalopathy. Unfortunately, there is limited data to guide specific dosing recommendations of opioids in the ambulatory setting in patients with liver failure.
Because their metabolites are inactive, fentanyl and hydromorphone are often the preferred agents in patients with liver disease. However, lower starting doses, slower dose titration, and increased dose intervals are recommended when initiating ambulatory therapy with any of the commonly used opioids in patients with significant hepatic insufficiency. Limited data exists for buprenorphine, although it has been used without adverse effect in patients with concurrent liver dysfunction owing to hepatitis C and, with caution and close monitoring, appears to be safe in patients with liver disease. See Table 18.4 for a summary of recommendations.
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