Abstract
This chapter discusses the specifics about major opioids (meperidine, morphine, oxycodone, oxymorphone, hydromorphone, methadone, buprenorphine, fentanyl, sufentanil, alfentanil, remifentanil) in pain management and offers important insights into recent developments regarding their judicious use. Opioids have been among the most frequently prescribed class of medications in the United States since the 1990s and represent one of many therapeutic options to treat patients with chronic nonmalignant pain. However, their use in this patient population remains controversial. Widespread use has resulted in a public health care crisis due to the simultaneous increase in misuse, abuse, addiction, diversion, and overdose. To preserve legitimate access to these potent but potentially dangerous pain relievers, clinicians must employ tools to guard against diversion, misuse, and abuse. Consequently, numerous guidelines have been created by national and state pain societies and federal and regulatory agencies to educate clinicians on rational opioid prescribing.
Keywords
alfentanil, buprenorphine, fentanyl, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, remifentanil, sufentanil
Opioids remain an important option for the treatment of substantial pain despite the recognition of heightened risks and growing analgesic options from other drug groups. Over the past several decades, opioid prescribing for chronic nonmalignant pain (CNMP) has become more widespread, resulting in opioids being the most frequently prescribed class of drugs in the United States. Looking at the top 25 most dispensed prescriptions in the United States, hydrocodone, tramadol, and oxycodone ranked as number 1, 21, and 22, respectively. In 2012, some 259 million opioid prescriptions were written by health care providers, and there was a parallel increase in the rate of overdose deaths associated with opioid analgesics. From 1999 to 2014, there were approximately 165,000 overdose deaths due to opioid pain relievers. In 2014, 61% of drug overdose deaths involved opioids (including heroin). Equally important are the nonfatal opioid overdoses, which have increased sixfold over the past 15 years. The Drug Abuse Warning Network (DAWN) reported that of the greater than 1.2 million Emergency Department visits in 2011 involving nonmedical use of prescription medicines, over-the-counter drugs, or other types of pharmaceuticals, opioids accounted for 29%; and nonmedical use of opioids accounted for an increase of 183% in medical emergencies from 2004 to 2011. Dart et al., in analyzing the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System data from 2002 to 2013 for opioid-related adverse events, found a parallel relationship between the legitimate dispensing of opioids and opioid diversion and abuse. In addition to this is the parallel increase in the rate of opioid addiction, affecting 2.5 million adults in 2014. Emerging data, however, suggest that prescription opioid abuse may be decreasing. Although the legitimate use of opioids in select and monitored patients with CNMP has been supported by consensus statements developed by national organizations, such as the American Pain Society (APS) and American Academy of Pain Medicine (AAPM), prescribing remains increasingly controversial, with polarized arguments on both sides of the debate over the risk and effectiveness of opioids in treating CNMP.
Rationale
Opioids produce reliable analgesia, and their adverse effects (e.g., constipation, nausea and vomiting, sedation, and respiratory suppression) often can be preempted, treated, or reversed. Opioid therapy can be an integral part of a multidisciplinary approach to acute and chronic pain management. An attempt to optimize a patient’s pain management may include concurrently combining opioids with nonopioid adjuvant analgesics (nonsteroidal antiinflammatory drugs [NSAIDs], acetaminophen, antidepressants, anticonvulsants, etc.), physical therapy, psychological therapy, and/or injection therapies. Much of the debate concerning the role of chronic opioid therapy (COT) for the management of CNMP, however, has centered on whether opioids should be used as a first-line treatment or whether they should be used at all on a chronic basis. The Centers for Disease Control (CDC) recently produced guidelines that suggest use of nonpharmacologic as well as nonopioid pharmacologic therapy prior to opioid therapy. Health care professionals should not utilize opioid therapy as a first-line treatment for CNMP for the following reasons: (1) nonpharmacological and nonopioid medications, such as NSAIDs and anticonvulsants or tricyclic antidepressants (TCAs), can be efficacious as first-line treatments for CNMP secondary to arthritic pain and neuropathic pain, respectively; (2) injection therapies may be effective and obviate the need for opioids; and (3) opioid treatment carries substantial side effects as well as liability profiles (see further on), and the risk-benefit ratio often demands that alternative treatments be implemented before instituting COT. An opioid trial may be considered when alternative analgesics, injection therapies, physical therapy, and psychological therapy have been inadequate, contraindicated, or otherwise exhausted. Although nonopioid drugs may appear to be better and/or safer choices for patients with CNMP, long-term use of such agents also may have deleterious or life-threatening effects.
Guidelines
Since opioids are controlled substances with potential for abuse, they are regulated by federal and state agencies. In addition to unintentional overdose, major concerns for opioid prescribers include the potential of diversion through fraud, theft, forged prescriptions, or illegal activities of unprincipled health care professionals. In 1998 the House of Delegates of the Federation of State Medical Boards (FSMB) of the United States established and adopted the Model Guidelines for the Use of Controlled Substances for the Treatment of Pain, which offered prescribing expectations for state medical boards. These guidelines have been updated multiple times, most recently in 2013, and have been converted to a model policy. The policy includes definitions of addiction, pseudoaddiction, tolerance, physical dependence, and substance abuse ( Box 42.1 ). It emphasizes the importance of an evaluation, physical examination, and follow-up to monitor and evaluate for therapeutic efficacy, which includes the patient’s functional status. The model policy also recommends the use of specialty consultations and additional referrals when patients present with complex histories, troubling adverse effects, lack of progress toward analgesia or improved function, or any issues outside the purview of the prescriber’s expertise. Other organizations have published guidelines for the use of chronic opioids in patients with CNMP. The APS and AAPM have published consensus guidelines for rational approaches to prescribing opioids and avoiding potential adverse effects. In these guidelines, information regarding risk assessment tools is included ( Table 42.1 ). Finally, as stated earlier, the CDC also published comprehensive guidelines in 2016 with regards to opioid prescribing in patients with CNMP ( Table 42.2 ).
Section III: Definitions
For the purposes of these guidelines, the following terms are defined here:
Addiction —Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include the following: impaired control over drug use, craving, compulsive use, and continued use despite harm. Physical dependence and tolerance are normal physiological consequences of extended opioid therapy for pain and are not the same as addiction. According to the 2013 Federation of State Medical Board’s Model Policy, there are updated definitions that have been adopted by the American Society of Addiction Medicine that state addiction is “a primary, chronic disease of brain reward, motivation, memory and related circuitry” and that “without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.”
Physical Dependence —Physical dependence is a state of adaptation that is manifested by drug class–specific signs and symptoms that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Physical dependence, by itself, does not equate with addiction.
Pseudoaddiction —The iatrogenic syndrome resulting from the misinterpretation of relief-seeking behaviors as though they are drug-seeking behaviors that are commonly seen with addiction. The relief-seeking behaviors resolve upon institution of effective analgesic therapy.
Substance Abuse —Substance abuse is the use of any substance(s) for nontherapeutic purposes or use of medication for purposes other than those for which it is prescribed.
Tolerance —Tolerance is a physiologic state resulting from regular use of a drug in which an increased dosage is needed to produce a specific effect, or a reduced effect is observed with a constant dose over time. Tolerance may or may not be evident during opioid treatment and does not equate with addiction.
The terms “pain,” “acute pain,” and “chronic pain” are defined in Chapter 3 , Taxonomy.
| Risk assessment tool | Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1.0-14Q Opioid Risk Tool (ORT) DIRE (Diagnosis, Intractability, Risk, Efficacy) Score: Patient Selection for Chronic Opioid Analgesia |
| Monitoring tools | Pain Assessment and Documentation Tool (PADT) Current Opioid Misuse Measure (COMM) |
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Although federal and state law enforcement agencies are the principal regulators of prescription drug abuse, public and congressional outcry over opioid misuse, addiction, and diversion prompted the US Food and Drug Administration (FDA) to get involved. By authority of the FDA Amendments Act (FDAAA) of 2007, the FDA can require drug manufacturers to implement Risk Evaluation and Mitigation Strategies (REMS) to ensure that the benefits of the drug outweigh the risk. Although REMS can include any drug, in 2009 the FDA notified manufacturers of sustained-release opioids (SROs) and long-acting opioids (LAOs) that a “class-wide” opioid-specific REMS would be required to include proposed communication and education materials, a medication guide, elements to ensure safe use, a patient package insert, enrollment forms, and prescriber and patient agreements. Because of the significant abuse potential of transmucosal immediate release fentanyl (TIRF) products, in December 2011 the FDA also required “class-wide” opioid REMS for this class of medications in addition to the SRO and LAO medications. The TIRF REMS Access Program applies to all rapid-onset fentanyl preparations, which currently applies to the Abstral (fentanyl) sublingual tablet, Actiq (fentanyl citrate) oral transmucosal lozenge and its generic equivalents, Fentora (fentanyl citrate) buccal tablet, Lazanda (fentanyl) nasal spray, and Onsolis (fentanyl) buccal. Pharmaceutical companies are required to implement an opioid REMS program, but participation for clinicians is voluntary. Whether this might change in the future remains to be seen.
To date, REMS programs for SROs and LAOs have increased knowledge with regard to opioid prescribing and a significant number of clinicians are reported to be implementing changes as a result of REMS programs. However, the full impact of REMS on opioid prescribing remains to be seen. Listed below are important websites detailing the REMS blueprint as well as access to the current list of opioids that require REMS:
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http://www.fda.gov/forindustry/userfees/prescriptiondruguserfee/ucm361870.htm#Training , accessed June 1, 2017.
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http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&REMS=17 , accessed May 24, 2016
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http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&REMS=60 , accessed May 24, 2016
Initiation of Chronic Opioid Therapy
In the absence of comorbid risk factors (e.g., hepatic or renal impairment, age, etc.), there is no direct evidence to support the use of one opioid over the other. Due to recent evidence comparing LAOs/SROs with SAOs, the CDC guidelines recommend that clinicians should initiate an opioid trial with an SAO instead of an LAO/SRO and that the lowest effective dose should be prescribed for patients. A patient with moderate to severe acute and/or chronic pain who has not improved with nonopioid therapies is a potential candidate for opioid analgesics. Although opioids lack an absolute upper limit to dosing necessary to control a patient’s pain, dose escalation should be carried out in a judicious manner, as opioids do not have any known benefits for CNMP but the risks of opioids are well documented and dose-dependent.
The severity and frequency of the patient’s pain should determine whether “as needed” (PRN, pro re nata ) versus “around-the-clock” dosing is necessary. For example, in those with acute pain secondary to an injury or surgery, PRN dosing with an SAO may be sufficient if the anticipated healing process is rapid and short. In those with either a slow and prolonged recovery process or persistent chronic pain, an SAO used on a PRN basis can produce a “rollercoaster” effect, whereby patients have pain, take analgesics, and experience brief periods of relief followed by repetition of this cycle when the pain returns. Typically COT aims to avoid perpetuation of this phenomenon by producing stable analgesia that is targeted less at total abolition of pain and more toward augmentation of the patient’s function at a tolerable level of pain. Recent guidelines suggest starting with an SAO as an initial trial even if use of an LAO is anticipated. Since the usual goal of opioid administration for the treatment of chronic pain is to achieve sustained analgesia over regular intervals, SAOs may be given at fixed dosing intervals, just as with an LAO or SRO. Such a strategy permits consistent delivery for reaching steady-state levels and may avoid the peak-and-trough effect associated with on-demand dosing.
If a patient responds to an SAO and tolerates its side effects, COT may be best delivered by converting to an equianalgesic LAO or SRO if dosing permits. Ideally, an LAO or SRO should not be combined with an SAO. Benefits of using an LAO or SRO include achievement of safe, effective steady-state levels with regard to fixed dosing intervals and lack of a compounded nonopioid analgesic which may impose a ceiling dose. Although fixed dosing with an SRO or an LAO has been presumed to provide more sustained levels of analgesia, improved compliance, less reward-associated reinforcement of potentially dysfunctional cycles where pain and pain medication become a conditioned part of the patient’s life, and poses less risk of addiction or abuse, these beliefs have becoming increasingly challenged. Published studies have failed to conclusively prove these proposed benefits of SROs and LAOs over SAOs or fixed dosing over PRN dosing. Nonetheless, the use of fixed dosing may prevent the delays in delivery that can occur with PRN dosing. Still, consensus in this area of pharmacotherapy remains elusive at present.
Administration
The convenience of orally administered opioids has made this the preferred route of delivery. Many patients with cancer or acute postoperative pain, however, are unable to tolerate oral ingestion or temporarily are not permitted oral ingestion. Therefore having multiple means of administering opioids is advantageous. An intravenous (IV) or subcutaneous (SQ) infusion is commonly used in terminally ill patients in pain, often with fixed dosing for constant effect. Both routes avoid the first-pass effect and can be supplemented by PRN doses for breakthrough pain. The SQ route has several advantages, including faster onset of analgesia compared with most oral preparations (although slower than IV administration), uncomplicated access in patients with poor venous access, and safer administration compared with the intramuscular (IM) route in patients with bleeding disorders or reduced muscle mass.
A common system for delivering IV opioids is patient-controlled analgesia (PCA), most commonly using morphine, hydromorphone, or fentanyl. Widely used for treating postoperative pain, PCA is rapidly finding broader use in treating cancer pain. PCA immediately delivers a preprogrammed IV or SQ dosage of an opioid when the patient activates a handheld button, thereby permitting rapid analgesia without needing a nurse to deliver an IV PRN dose. By placing a maximum limit on the dose and frequency of opioid administered, the physician helps the patient titrate his or her opioid requirement. Because the PCA machine records the patient’s individual dosing and frequency parameters, useful information can be obtained about the patient’s analgesic requirements, which also simplifies subsequent conversion to a non-PCA opioid regimen.
Alternatives for patients unable to use IV or oral preparations include rectal (suppositories are available containing morphine, hydromorphone, and oxymorphone), sublingual, buccal, intranasal, transdermal, epidural, or intrathecal routes of administration. Epidural and intrathecal opioids—commonly used in the perioperative, postoperative, obstetric, and cancer populations—make opioids directly available to the opiate receptor–rich neuraxis. These two forms of selective analgesia have the advantage of requiring relatively small quantities of opioids, thereby reducing the risk of central and autonomic complications. Patient-controlled epidural analgesia (PCEA), a newer variant of patient-controlled drug delivery systems, administers epidural dosages of opioid, and potentially other drugs, via a similar mechanism such as IV PCA.
Treatment Endpoints and Opioid Selection
Since pain is an untestable hypothesis that can neither be proved nor disproved, using pain relief as the endpoint of opioid therapy is also untestable and subjective. One of the most feared adverse effects from COT is drug addiction, which manifests as the compulsive use of a drug that causes dysfunction and its continued use despite the harm related to that dysfunction. In 2013, the estimated rate of opioid misuse and abuse affected nearly 2 million people. Thus clinicians are advised to focus on functional improvement as an objective endpoint of analgesia, since this also offers evidence of opioid efficacy in contrast to addiction. The challenge, however, is to develop outcome measures for COT beyond a lower pain score that distinguish function from dysfunction and that emphasize therapy expectations, goal setting, goal monitoring, and collaboration with the patient’s entire treatment team. Two critical issues related to treatment endpoints in COT include (1) defining what outcomes should be expected and followed to demonstrate an effective and safe trial of opioids and (2) determining when and how opioid therapy should be discontinued (or tapered) if the treatment is either effective or ineffective. Clinical studies in this area are limited.
Markers of opioid benefit in patients treated for CNMP include subjective pain reduction and evidence of improved functional status and quality of life. Determining functional improvement can be accomplished with standardized instruments (Short Form [36] Health Survey and Oswestry Disability Index, among others) or through a simple process of ascertaining limitations in function and quality of life prior to treatment and following these endpoints through the course of opioid therapy. The ideal functional assessment model should be simple, brief, individualized, and comprehensive—something that most formalized scales fail to accomplish. There are many examples of functional goals, including daily exercise, returning to work, and sleeping in a bed as opposed to a lounge chair. Supporting evidence of these functional goals is important for validation and documentation purposes.
Psychological and social factors as well as coexistent diseases that may influence pain perception and suffering can affect the overall assessment of pain. Initiation of opioid therapy is unlikely to offer concomitant and proportional improvement in all of these areas. If the psychological amplifiers of pain perception have not been adequately addressed, opioid-induced analgesia may not be maximally effective. Likewise, analgesia and functional improvement resulting from opioid therapy may be discordant with improvements due to psychological treatment. Many possible variations in efficacy and functional gain may dictate flexibility in ascertaining treatment endpoints.
Because pain reduction is subjective, it can serve as only a single aspect of adequate COT. Consider, for example, the patient who has constant pain rated “6 out of 10” (“0” being no pain and “10” being severe pain) with significantly associated disability. Although opioid therapy may only decrease the patient’s pain from a 6 to a 5, a successful outcome has been achieved if the patient demonstrates improvements in activities of daily living (ADL), ability to participate in physical rehabilitation, and/or ability to return to work. Conversely, an opioid trial can be considered counterproductive if the patient reports increased pain relief without observable functional gains and possibly even signs of functional loss (daytime sedation, impaired cognition, voluntary unemployment, dysfunctional interpersonal or family relationships, diminished physical activity, or legal difficulties).
Although the effectiveness of opioid therapy is a primary concern, an equally important part of opioid management relates to deciding when to discontinue treatment if it is deemed to be unsatisfactory. Determination of a treatment failure requires consideration of multiple contributing factors, including (1) underdosing; (2) inappropriate dosing schedule; (3) improper drug delivery route; (4) potentially diminished opioid responsiveness relating to the nature of the pain generator (e.g., neuropathic pain); (5) involvement of unresolved contributors to pain, such as physical, psychological, and social disability; and (9) development of side effects that limit dose escalation. Apparent opioid ineffectiveness from a single opioid may not predict the same ineffectiveness from other opioids.
The duration of opioid therapy remains a question with no clear consensus among practitioners and minimal science to guide the debate. Pharmacologic tolerance to opioids can develop during treatment and may require either escalating the dose to maintain the same level of analgesia or switching to a different opioid. Deciding to raise the dose requires reassessment of the risks and benefits and medical decision making that would warrant accepting these increased risks. The need to rotate to another opioid is expected to arise in less than 2% to 3% of cases. Although some clinical studies have suggested stabilizing the opioid dose requirement following an initial dose increase, it is possible that periodic increases may be warranted during COT. For opioid-tolerant patients, changing from one opioid to another requires knowledge of equianalgesic dosages. Since cross-tolerance between opioids may be incomplete, a patient who has become tolerant to one opioid can respond with effective analgesia to another opioid of less than equianalgesic dose. Management of pain in tolerant patients can be a challenge because typical dosages for the opioid-naive patient do not apply. In such cases, opioids are slowly and incrementally increased until analgesia with tolerable side effects is reached. However, it is important to note that the risks of opioid therapy are dose-dependent and that CDC guidelines now suggest specific dose ranges for opioid prescribing. Analgesia occurring only in conjunction with intolerable side effects indicates that the particular opioid is suboptimal and that there may be a need to change to a different opioid or that the pain is not opioid-sensitive. Analgesia occurring only in combination with sedation after an individual trial of most or all opioids suggests opioid-insensitive pain. Additionally, analgesia may also be related to effects associated with sedation rather than direct antinociceptive properties of the drug. As one would expect, side effects without analgesia indicate failure of that particular opioid. In such cases, another opioid may be worth trying, as it may not share the same profile. Clearly, determining the duration of effective opioid therapy must be individualized based on treatment efficacy balanced with side effects and progression or regression of the underlying disease process. Ultimately it may be impossible to know how much pain would be present without opioid therapy unless the medication is tapered.
Selected Opioids
Meperidine
Although meperidine (Demerol) is a common analgesic, particularly by the IM route, its primary use in the pain management setting has steadily declined due to its potential for neurotoxicity. Meperidine was developed in Nazi Germany as a synthetic opioid with relatively weak μ-opioid receptor agonist properties. Compared to morphine, it is one-tenth as potent and has a slightly more rapid onset and shorter duration of action. At equianalgesic doses, meperidine produces less sedation and pruritus and may be more effective in treating neuropathic pain. However, it possesses significant cardiac (orthostatic hypotension and direct myocardial depression), anticholinergic, and local anesthetic properties, which decrease its therapeutic window. Epidural or spinal administration of meperidine, unlike other opioids, can produce sensory, motor, and sympathetic blockade. Meperidine has been used in the operative setting for the treatment of postanesthesia shivering.
Meperidine has a relatively short half-life of 3 hours and prolonged administration (>3 days) is problematic due to the potential for accumulation of normeperidine, its neurotoxic metabolite. Meperidine is demethylated in the liver to normeperidine, which has a half-life of 12 to 16 hours and is well documented to produce central nervous system (CNS) hyperactivity and ultimately seizures. Since normeperidine is excreted by the kidneys, its adverse effects are most commonly although not exclusively seen in patients with renal impairment. Normeperidine toxicity initially manifests as subtle mood alteration and may progress to potentially naloxone-irreversible tremors, myoclonus, and seizures. Because the hyperexcitability due to normeperidine can also occur in patients with normal renal function, chronic administration of meperidine is not recommended. Finally, for patients on monoamine oxidase inhibitors, coadministration of meperidine can have potentially fatal outcomes. Caution may be prudent in coadministering meperidine and any other serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), tramadol, or methadone.
Morphine
Morphine is the prototypical mu-opioid receptor agonist against which all other opioids are compared for equianalgesic potency. It can be given via oral, IV, epidural, or intrathecal routes for perioperative and postoperative pain management. As an SAO, it is available in instant-release (IR) formulations (morphine, MSIR, and Roxanol). As an SRO (MS-Contin, Oramorph-SR, Kadian, and Embeda), its dosing frequency ranges from every 8 to every 24 hours. Unique among currently available SROs, Embeda contains both morphine (an opioid agonist) and naltrexone (an opioid receptor antagonist). It was the first “abuse-deterrent” opioid formulation on the market. When taken as directed, naltrexone remains inert. However, if the medication is crushed for IV injection, naltrexone will antagonize the effects of morphine.
With repeated dosing, morphine’s oral bioavailability ranges from 24% to 40%. Morphine’s low bioavailability and relative hydrophilicity make it less than ideal as an analgesic. Because of the delay in transport across the blood-brain barrier, morphine has a slower onset of action than other opioids. Conversely, morphine has a relatively longer analgesic effect of 4 to 5 hours relative to its plasma half-life (2–3.5 hours), thereby minimizing its accumulation and contributing to its safety. The disproportionate duration of analgesia versus plasma half-life is due in part to its low solubility and slower elimination from the brain compartment relative to the plasma concentration. Although morphine’s pharmacologic activity is primarily due to the parent compound, morphine’s efficacious and toxic effects can also be mitigated or perpetuated by two of its major metabolites: morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G). M3G lacks any μ- and δ-opioid receptor activity and accounts for approximately 50% of morphine’s metabolites. It has been shown in animals to cause generalized hyperalgesia, CNS irritability, seizure, myoclonus, and development of tolerance. Whether this explains why neuroexcitatory side effects occur in humans exposed to chronic dosing of morphine has yet to be conclusively proven. Although M3G is devoid of opioid receptor activity, its true mechanism of action remains unknown. Conversely, M6G is a μ- and δ-opioid receptor agonist and accounts for approximately 5% to 15% of morphine’s metabolites. M6G has intrinsic opioid agonism and sustains analgesia in addition to side effects. The route of morphine administration may account for variations in concentration of both glucuronide metabolites. Because the IV and rectal routes of administration avoid hepatic biotransformation, their glucuronide concentrations are less than with oral administration. Chronic use of oral morphine ultimately results in higher circulating concentrations of the glucuronides (mean ratios of M3G:M6G range from 10:1 to 5:1) than the parent compound. Patients experiencing side effects attributable to M3G and/or M6G may be candidates for rotation to an alternative opioid.
Since morphine’s elimination is dependent on hepatic mechanisms, it should be used with caution in cirrhotic patients. However, enterohepatic cycling and extrahepatic metabolism of morphine have also been reported to occur in the gastric and intestinal epithelia. The glucuronides can also undergo deconjugation back to morphine by colonic flora and subsequently be reabsorbed. Because morphine metabolites are excreted through the kidneys, the dose should be adjusted in those with renal impairment in order to minimize the risk of adverse side effects associated with the accumulation of glucuronide metabolites. Smith reported that although respiratory depression, sedation, and vomiting due to relatively high concentrations of M6G can be reversed by naloxone, the most concerning adverse effect in patients with compromised renal function is encephalopathy and myoclonus. Studies have found that the ratio of M6G and M3G to morphine correlated with increased blood urea nitrogen or creatinine levels. Ultimately, morphine’s analgesic effects and side effects are likely related to complex interactions between the parent compound and its glucuronide metabolites. Exactly how specific diseases, polypharmacy, and patient age influence ratios of the individual glucuronide metabolites to morphine remains unclear.
Oxycodone
Oxycodone is a semisynthetic congener of morphine that has been used as an analgesic for over 80 years. As an SAO, it is available in IR preparations as a single agent (oxycodone, OxyIR, or Roxicodone) or compounded with acetaminophen (Percocet, Endocet, or Roxicet) or aspirin (Percodan or Endodan). IR oxycodone has been shown to deliver equivalent analgesia as the sustained-release (SR) version (OxyContin). In April 2010, the FDA approved a (“tamper-resistant”) formulation of OxyContin that is more difficult to break, crush, chew, or dissolve for snorting or IV injection. In July 2014, the FDA approved an “abuse-deterrent” version of SR oxycodone-naloxone named Targiniq Extended-Release (ER): The naloxone blunts the euphoric effects of oxycodone if the user crushes and snorts or injects the drug. Postmarketing studies are still needed to determine its efficacy in reducing misuse and abuse.
SR oxycodone possesses many of the characteristics of an ideal opioid, including no ceiling dose, minimal side effects, minimal active metabolite, easy titration, rapid onset of action, short half-life, long duration of action, and predictable pharmacokinetics. In comparison to SR morphine, it has a prolonged pharmacokinetic profile, which theoretically allows it to be administered solely on an every-12-hour dosing schedule. This, however, reflects a characteristic of the drug delivery system rather than a property of the drug itself. The oral bioavailability of oxycodone (55%–64%) relative to morphine (24%–40%) can account for variations in dose conversion ratios between the two drugs. Milligram-to-milligram, oral oxycodone is more potent than morphine and has a shorter onset of analgesia with less plasma variation. Accordingly, oxycodone is associated with fewer side effects (hallucinations, dizziness, and pruritus) than morphine.
Although it possesses some intrinsic analgesic properties via activation of the κ-opioid receptors, oxycodone appears to have lower affinity than morphine for the mu-opioid receptor in rat studies. It undergoes hepatic metabolism via the cytochrome P450 2D6 enzyme, where it is converted into oxymorphone, an active metabolite with high affinity for the μ-opioid receptor, and via CYP3A4 to noroxycodone, an inactive metabolite. In the approximately 10% of the population with genetically low levels of the cytochrome P450 2D6 enzyme, lower concentrations of oxymorphone may account for the fact that higher than usual doses of oxycodone may be necessary to obtain pain relief. Analgesic efficacy may also be decreased in those concurrently taking medications that competitively inhibit the P450 2D6 enzyme. Analgesic efficacy may be increased in those patients concurrently taking medications that inhibit the P450 3A4 enzyme. Whether the relationship between impaired hepatic metabolism and decreased analgesia has anything to do with lower levels of oxymorphone remains uncertain. Therefore careful dose titration must be ensured for those concurrently taking medications with potential drug interactions such as SSRIs, TCAs, azoles, mycins, or neuroleptics. Finally, because the kidneys excrete oxycodone and its metabolites, the dose should be adjusted in cases of renal dysfunction.
Oxymorphone
Oxymorphone is a semisynthetic opioid that has been available as an IV preparation (Numorphan) since 1959 and subsequently as a rectal suppository (Numorphan). It was not until 2006 that an oral formulation (Opana IR and ER) was released. Oxymorphone is primarily a μ-opioid receptor agonist that has more affinity for the μ-opioid receptor than morphine and is 10 times as potent as morphine when given intravenously. Oxymorphone’s affinity for the δ-opioid receptor is greater than that of morphine, with agonism decreasing tolerance as well as potentiating μ-opioid receptor–mediated analgesia. In general oxymorphone has little or no affinity for the κ–opioid receptor, has less histamine release from mast cells than morphine, and is more fat-soluble than morphine and oxycodone. However, oxymorphone does not redistribute into fat stores but rather dissociates slowly from receptors in the CNS. The increase in lipophilicity leads to maximum plasma concentrations in 30 minutes, compared with 1.2 hours for immediate-release morphine.
Although well absorbed in the gastrointestinal (GI) tract, oxymorphone’s bioavailability is only 10% due to extensive first-pass hepatic metabolism. Even though the bioavailability of oxymorphone is lower than that of morphine (24%–40%) or oxycodone (55%–64%), oxymorphone’s greater lipid solubility facilitates its ability to cross the blood-brain barrier and may account for its rapid onset of analgesia: The time to maximum plasma concentration is shorter for oxymorphone IR (30 minutes) compared with morphine IR (1.2 hours) and oxycodone IR (1.5 hours). The onset of analgesia for the IR formulation occurs in 30 to 60 minutes and follows linear pharmacokinetics, allowing for predictable dosing. For the ER formulation, steady-state occurs in 3 days with every-12-hour dosing.
Oxymorphone is hepatically metabolized and renally excreted. It requires dosing adjustment for hepatic and renal impairment. For those with moderate to severe hepatic impairment, oxymorphone is contraindicated. Because moderate to severe renal impairment can result in bioavailability as high as 57% to 65%, clinicians should proceed with caution and reduce dose accordingly. The main metabolite of oxymorphone, oxymorphone-3-glucorinide, has unknown activity and is produced in the liver via uridine diphosphate glucuronosyl transferase enzymes after reduction or conjugation with glucuronic acid. A secondary metabolite, 6-OH-oxymorphone, is formed by reduction by an unknown enzyme and possesses analgesic activity. There appears to be minimal interaction with the cytochrome P450 enzyme systems such that oxymorphone is not metabolized by the CYP2D6 enzyme and does not interact with the CYP2C9 or CYP3A4 enzymes. Compared with other strong opioids, oxymorphone has similar efficacy in the treatment of acute, chronic, and cancer pain and a similar side-effect profile. Since taking this medication with food can greatly increase the maximum plasma concentration, it is advisable to avoid eating at least 1 hour prior to or 2 hours after taking this medication. Alcohol should be avoided, as it can produce an almost 300% increase in the plasma concentration.
Hydromorphone
Hydromorphone is a hydrogenated ketone analogue of morphine that can be formed by the N-demethylation of hydrocodone. It can be given via oral, IV, epidural, or intrathecal routes for perioperative and postoperative pain management. As an oral medication, it is available in an IR formulation (hydromorphone or Dilaudid) and an SR formulation (Exalgo), with the latter affording once-daily dosing for chronic pain management.
Like morphine, hydromorphone is hydrophilic, possesses strong μ-opioid receptor agonist activity, and has a similar duration of analgesic effect (3 to 4 hours). However, side effects of pruritus, sedation, and nausea and vomiting occur less frequently with hydromorphone than with morphine. Depending on whether it is administered orally or intravenously, hydromorphone’s milligram-to-milligram potency is estimated to be 5 to 7 times that of morphine, respectively. Hydromorphone bioavailability ranges from 20% to 80% when administered by the oral route. Onset of analgesic effect occurs within 30 minutes when administered orally and 5 minutes when administered intravenously. The peak analgesic effect of IV hydromorphone occurs within 8 to 20 minutes, most likely because its hydrophilicity impairs its ability to cross the blood-brain barrier.
Although it is hydrophilic, it is 10 times as lipid-soluble as morphine. This feature, plus its greater milligram-to-milligram potency compared with morphine, allows equianalgesic doses to be infused subcutaneously but in smaller volumes (10 or 20 mg/mL). Possessing 78% of the bioavailability of IV hydromorphone, subcutaneously administered hydromorphone offers a safe alternative for hospice patients with impaired GI function and requires less maintenance than would be required with an IV site.
Hydromorphone undergoes hepatic biotransformation into hydromorphone-3-glucuronide (H3G), its primary metabolite, with both the parent compound and metabolite being renally excreted. Like morphine’s M3G metabolite, H3G is an active metabolite that lacks analgesic efficacy but possesses potent neuroexcitatory properties that are 10 times stronger than those of the parent compound and that have been shown to produce neuroexcitation (allodynia, myoclonus, and seizures) when administered directly into the lateral ventricle of rat brains. Because H3G is produced in such small quantities, its effects are negligible except in cases of renal insufficiency, where it may accumulate. Nonetheless, because H3G is produced in such small amounts, hydromorphone is preferable to morphine in patients with renal insufficiency. Concentrations of H3G are dose-dependent and clear with time once hydromorphone is discontinued.
Methadone
According to the American Heritage Dictionary, the name methadone is a derivative merging of the words that describe its chemical structure, 6-dimethylamino-4,4-diphenyl-3-heptanone. When one hears the word methadone, many images come to mind. Although clinicians trained in the use of methadone to treat pain may envision the drug as a potential source of analgesia, patients and other health care providers may have difficulty separating the idea of methadone from heroin addiction and drug rehabilitation programs. In 2008, a total of 268,071 patients in the United States were using methadone in opioid treatment programs and nearly 720,000 patients were using methadone to treat chronic pain. The wide use of methadone is likely due to its many attractive features as an analgesic medication: low cost (wholesale price is approximately 5% to 7% that of the more expensive proprietary SROs), high bioavailability with absorption and activity within 30 minutes, multiple receptor affinities, and lack of known metabolites that produce neurotoxicity. Methadone is well absorbed and has an oral bioavailability (approximately 80%; range 40% to 99%) that is approximately threefold that of morphine. Its sublingual bioavailability ranges from 34% to 75%, with higher absorption favored by a higher pH of 8.5 in the sublingual space. Unfortunately methadone’s pharmacokinetics and pharmacodynamics, exemplified by unpredictable bioavailability and high interindividual variability in steady-state serum levels, can make it a challenge to initiate and titrate, thereby increasing the potential for delayed methadone-related side effects. As methadone use as an analgesic has risen, it has gained attention because of a significant increase in unintentional overdoses and has led the FDA in 2006 to issue a manufacturer’s black box warning for QT prolongation and serious arrhythmia. Although methadone accounts for only 2% of the prescribed opioids, it is responsible for 30% of the deaths due to prescription opioid medications. Indeed, initial dosing or escalation of methadone requires more frequent follow-up than other LAOs/SROs.
Methadone, which is structurally unrelated to other opium-derived alkaloids, is available as a hydrochloride powder that can be reconstituted for oral, rectal, or IV administration. It is lipophilic, basic (pK a , 9.2), and usually exists as a racemic mixture of its two isomers, d-methadone (S-met) and 1-methadone (R-Met), both of which have separate modes of action. The d-isomer antagonizes the NMDA receptor, blocks the hERG (human ether-a-gogo related gene) voltage-gated potassium channel, and inhibits serotonin and norepinephrine reuptake, while the l-isomer (R-met) possesses the opioid receptor agonist properties. Among opioid receptor subtypes, methadone demonstrates variable affinity. Animal models demonstrate that it has a lower affinity than morphine for the μ-opioid receptor, which may explain why methadone may have fewer μ-opioid receptor–related side effects. Conversely, methadone has a greater affinity than morphine for the δ-opioid receptor. Although δ-opioid receptor activity is felt to be crucial to the development of morphine-induced tolerance and dependence, methadone’s δ-opioid receptor agonism leads to its desensitization. This feature may partially account for methadone’s ability to counteract opioid-induced tolerance and dependence. Aside from acting as an opioid receptor agonist, methadone also acts as an NMDA receptor antagonist. Numerous studies have demonstrated the involvement of the NMDA receptor mechanisms in the development of opioid tolerance and neuropathic pain. In theory, methadone’s ability to mitigate opioid-induced tolerance and treat neuropathic pain remains an intriguing but unproven concept.
Methadone’s lipophilicity most likely accounts for its extensive tissue distribution (mean volume of distribution, 6.7 mL/kg) and slow elimination (mean half-life, 26.8 hours; range, 15 to 55 hours). Its delayed clearance (mean 3.1 mL/min per kilogram) provides the basis for once-daily dosing for methadone maintenance therapy, thereby preventing the onset of opioid withdrawal syndrome for 24 hours or more. Unfortunately the same does not hold true for analgesia. Furthermore, there is extensive interindividual variation in the relationship between changes in plasma methadone concentration and analgesia. The ability to use methadone for either opioid detoxification or analgesia can be explained by methadone’s biphasic elimination phase. The α-elimination phase (distribution phase), which lasts 8 to 12 hours, equates to the period of analgesia that typically does not exceed 6 to 8 hours. Consequently initial dosing for analgesia may need to be frequent, because steady-state kinetics is required for reaching the biphasic profile. The β-elimination phase (clearance), which ranges from 30 to 60 hours, may be sufficient for preventing opioid withdrawal symptoms but is insufficient for providing analgesia. This provides the rationale for prescribing methadone every 24 hours for opioid maintenance therapy versus every 6 to 12 hours for analgesia.
Unlike other opioids whose breakdown products contribute to potential neurotoxicity, methadone has no known active metabolites. It undergoes hepatic metabolism, primarily N-demethylation, by the cytochrome P450 (CYP) family of enzymes. As a result, methadone has multiple potential drug interactions that can result from induction, inhibition, or substrate competition at several of the CYP enzymes, including CYP3A4, CYP2D6, and CYP2B6. In the absence of other drugs, CYP3A4 is an autoinducible enzyme, which means that methadone can bring about its own metabolism and increase its clearance over time. However, one study found that methadone and its metabolite (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine) did not change significantly over a 9-month period, indicating that autoinduction by methadone may not occur. Patients who have the CYP2B6 ∗6/∗6 genotype, approximately 6% of Caucasians, are poor metabolizers of racemic methadone and are at increased risk of prolonged QTc interval due to high plasma concentrations of (S)-methadone (d-methadone). In addition to the possibility of drug interactions, gastric pH can affect methadone’s degree of absorption. For example, patients who are also taking omeprazole will absorb more methadone.
For most patients, renal excretion of unchanged methadone is insignificant. However, decreases in urinary pH can significantly increase methadone excretion. For example, in patients with acidic urine who are taking high doses of ascorbic acid, about 34% of an administered dose could be excreted in the urine as unchanged methadone. Although changes in urinary pH can also influence the renal excretion of methadone, it does not accumulate in renal failure and does not appreciably filter during hemodialysis. Thus the possibility of methadone toxicity is increased in the setting of polypharmacy and/or changes in either gastric or urinary pH. Finally, variability in protein binding, excretion, and equianalgesic potency can further contribute to methadone’s potential instability by provoking either overdose or withdrawal symptoms. Although signs of toxicity are often clear, signs of decreased analgesia or withdrawal symptoms due to involuntary decreases in free circulating methadone may not be as apparent. Such patients may be erroneously characterized as drug-seeking because they display signs and symptoms of pseudoaddiction, requiring higher doses of methadone.
Methadone has an inherently longer duration of effect than other nonmodified opioids or SROs. Unlike the SROs, methadone tablets can be broken in half or chewed. Methadone is also available in an elixir formulation (1 mg/mL or 10 mg/mL), which is advantageous for those with a gastrostomy feeding tube, thus minimizing the risk of clogging the tube by not having to crush a tablet. In addition, the low-concentration elixir theoretically allows for a relatively more careful and precise titration of methadone, which can potentially minimize the risk of delayed-onset toxicity. Ultimately, methadone’s pharmacodynamic property as an LAO makes it beneficial for those with impaired GI absorption secondary to “short-gut syndrome” or “dumping syndrome.” It can also be used for patients with renal impairment, since it does not accumulate in renal failure and is insignificantly removed during dialysis.
The many attractive features of methadone relate to its pharmacologic complexity. This, however, can increase the risk of side effects, especially in patients with cardiac issues, those with concomitant illness, or those on multiple medications. As awareness of the proarrhythmic potential—prolongation of QTc interval resulting in torsades de pointes—of methadone has increased, experts have developed consensus guidelines to help clinicians safely prescribe methadone and minimize the risk of cardiotoxicity. The guidelines suggest that clinicians inform patients of methadone’s risk of proarrhythmia, look for a history of cardiac disease, obtain a baseline electrocardiogram followed by periodic monitoring of the QTc interval, and be aware of other factors or medications that might contribute to a QTc prolongation ( Table 42.3 ). Furthermore, uncertainty remains regarding methadone’s equianalgesic dosing conversion. A recent review of opioid conversion ratios used with methadone found a relatively strong positive correlation between the previous morphine dose and the final methadone dose and dose ratio, but ratios varied widely. Contrary to logic as it relates to tolerance, methadone appears to have greater potency (milligram-per-milligram) in patients rotating from high dosages of other opioids. Its antagonism of the NMDA receptor may help explain why methadone appears to have increasing potency as a patient’s daily morphine-equivalent dose increases when converting from another opioid to methadone. In the opioid-tolerant patient, the exact equianalgesic dose for methadone as a conversion from morphine-equivalents is uncertain. Older equianalgesic tables are usually based on studies that included normal controls or opioid-naive patients; therefore they do not take into account chronic opioid exposure. This tends to lead to excessive dosages. A panel comprising experts from the American Academy of Pain Medicine and American Pain Society recommended that a safe starting dose in most opioid-naive adults is 2.5 mg orally every 8 hours with subsequent dose increases no more often than weekly. This same panel could not recommend a particular method for converting patients from other opioids to methadone but did suggest that opioid-tolerant patients generally should start at doses no higher than 30 to 40 mg/day, even those previously on high doses of other opioids. Converting from methadone to another opioid is even less clear due to the small number of studies available to offer uniform guidelines. A recent study attempted to quantify the conversion ratio when transitioning from methadone to morphine and determined that it is approximately 1:5. Therefore methadone presents the inexperienced clinician with the challenge of predicting effects, not only in the face of unreliable and confusing equianalgesic dosing ratios but also because of its potential for drug interactions, metabolic instability related to altered hepatic metabolism or renal clearance, and protein-binding changes. In making a conversion to or from methadone, use extreme caution and reference the methadone package insert for the most updated information.
