INTRODUCTION — Opioids are widely used for treatment of cancer-related pain because of their safety, multiple routes of administration, ease of titration, reliability, and effectiveness for all types of pain (ie, somatic, visceral, neuropathic). Although neuropathic pain may be more difficult to treat, a favorable response to opioid-based analgesia is often possible. (See "Assessment of cancer pain", section on 'Inferred pathophysiology and treatment implications'.)
Opioids are also drugs that can be misused. The public health consequences of opioid misuse drive the imperative that all clinicians assume responsibility for risk management when these drugs are prescribed for legitimate medical purposes. These issues are discussed elsewhere. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Risk assessment and management for patients receiving opioids'.)
This topic review will cover the use of opioids for cancer-related pain, with an emphasis on optimizing analgesia and minimizing side effects. Assessment of cancer pain, a review of specific cancer pain syndromes, general principles of cancer pain management, an overview of risk management in patients treated with opioids, prevention and management of opioid side effects, the clinical use of non-opioid analgesics (including nonsteroidal anti-inflammatory drugs [NSAIDs] and adjuvant analgesics), nonpharmacologic methods of cancer pain management, management of acute pain (eg, from a new injury or surgical procedure) in the patient chronically using opioids, and issues surrounding pain management in the last weeks of life are covered elsewhere:
●(See "Assessment of cancer pain".)
●(See "Overview of cancer pain syndromes".)
●(See "Cancer pain management: General principles and risk management for patients receiving opioids".)
●(See "Prevention and management of side effects in patients receiving opioids for chronic pain".)
●(See "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs".)
●(See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)".)
●(See "Rehabilitative and integrative therapies for pain in patients with cancer".)
●(See "Cancer pain management: Interventional therapies".)
●(See "Management of acute pain in the patient chronically using opioids for non-cancer pain".)
●(See "Palliative care: The last hours and days of life", section on 'Pain'.)
OPIOID DRUGS USED IN CANCER PAIN MANAGEMENT
Mechanism of action — Opioids act by binding to specific receptors, the best characterized of which are the mu, kappa, and delta receptors. These receptors are present in tissues throughout the body, including both the peripheral and central nervous systems.
Based upon their effects on the mu receptor, opioids are conventionally divided into pure mu receptor agonists, agonist-antagonists (of which there are two subtypes: partial agonists and mixed agonist-antagonists), and pure mu receptor antagonists (table 1). Mu receptor antagonists have no intrinsic analgesic properties; they are used to prevent or reverse opioid effects. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid bowel dysfunction'.)
With few exceptions, the management of chronic cancer pain usually involves the long-term administration of pure mu receptor agonists (table 2 and table 3). However, several of the agonist-antagonist drugs are commercially available in the United States and other countries, and at least one, buprenorphine, is used for treatment of cancer-related pain in some settings. Several other centrally acting analgesics, including tramadol and tapentadol, have some mu agonist effects mixed with other prominent mechanisms and also are used for cancer pain in some circumstances.
Pure mu agonists commonly used for cancer pain
Morphine — Morphine is the prototype opioid drug for moderate to severe cancer pain on the third step of the WHO analgesic ladder (figure 1) . (See "Assessment of cancer pain", section on 'Pain characteristics'.)
The WHO analgesic ladder is usually considered to be a standard for comparison. In the original WHO guidelines, this preference for morphine was not based upon any existing comparative data. Since then, randomized trials and systematic reviews have failed to demonstrate the superiority of morphine over any other mu agonist (such as hydromorphone, oxycodone, oxymorphone, fentanyl, or methadone) in terms of efficacy or tolerability [2-9]. Furthermore, there is very large intraindividual variation in the response to the different mu agonist drugs and no way to predict whether a patient will have a more favorable balance between analgesia and side effects when given morphine or one of the other drugs, unless a previous response to a specific drug helps to guide the choice of agent .
Accordingly, morphine should not be considered the "drug of choice," but rather, just one of many drugs that could be selected for chronic cancer pain. The decision to select one or another is often based upon the experience of the clinician, prior experience of the patient, cost, dosing implications of the formulation, and other factors, including renal and hepatic function. (See 'Practical considerations in opioid use' below.)
Morphine has a short half-life, but it is available in multiple formulations, including immediate-release tablets and modified-release tablets and capsules with prolonged effects after a dose, oral liquid, suppository, and solution for intravenous (IV) and subcutaneous (SC) use (table 2 and table 3), and also may be useful for breakthrough pain when coadministered with a long-acting formulation. (See "Assessment of cancer pain", section on 'Acute versus chronic pain'.)
Regardless of the formulation, morphine is primarily metabolized in the liver and its metabolites are renally excreted. Two active metabolites have been extensively studied, morphine-3-glucuronide (M3G) and morphine-6-gluconoride (M6G) . Preclinical data and limited human studies suggest that M6G contributes to analgesic activity and M3G may be the cause of some of the side effects that occur during morphine therapy, although this is not yet proven [11-14].
Metabolite concentration may be idiosyncratically high as a result of unknown but presumed genetic factors, or more commonly, metabolite concentration may increase relative to the parent compound (morphine) as a result of renal disease that reduces excretion of both glucuronides. These metabolites are not routinely measured in clinical practice. If this occurs, use of the drug may be associated with unanticipated potency or side effects. Clinically, this means that morphine should be administered cautiously in the setting of renal insufficiency, and if fluctuation in kidney function can be anticipated, morphine may not be the preferred opioid given the risk of changes in effects and side effects as metabolite accumulation occurs. (See 'Patients with kidney impairment' below.)
Oxycodone, hydrocodone, hydromorphone, and oxymorphone — As with morphine, hydromorphone, oxycodone, hydrocodone, and oxymorphone all have short half-lives and all are available in multiple formulations. In the United States, all four of these drugs are also available in liquid form as well as long-acting, modified-release formulations.
●Oxycodone – Oxycodone binds to both mu and kappa receptors. Clinical studies have not substantiated systematic differences in efficacy or tolerability compared with morphine or other mu agonists .
●Hydromorphone – Multiple dose forms are available for hydromorphone, including oral liquid, immediate release tablet, extended release tablet, suppository, and solution for IV or SC use. The extended release form of hydromorphone is available in 8, 12, and 16 mg strengths, and is dosed once daily. Caution must be used to avoid medication errors when prescribing this product, as 8 mg tablets are also available as immediate-release hydromorphone tablets.
Hydromorphone is highly soluble in water  and a commercially available concentrated solution (10 mg/mL) facilitates SC or IV administration of relatively high doses. Some clinicians prefer to use hydromorphone in patients with renal insufficiency because its active, renally cleared metabolites appear in relatively low concentration (compared with morphine) and may be unlikely to cause unanticipated effects. (See 'Patients with kidney impairment' below.)
However, the quality of the evidence of the benefits and harms of hydromorphone compared with other opioids for cancer pain is very low .
●Oxymorphone – The analgesic efficacy of oxymorphone appears to be comparable with other opioids . It has a relatively low propensity to release histamine, a characteristic also shared with fentanyl. At least in theory, this may reduce the risk of pruritus or urticaria, although there is no evidence that this difference is clinically relevant. Oxymorphone is available in immediate-release tablets and a generic modified-release tablet. The proprietary long-acting formulation, Opana ER, was voluntarily withdrawn from the United States market in July 2017 at the request of the US Food and Drug Administration because of concerns that the benefits of the drug were outweighed by the risks related to continued injection abuse of the drug, despite a reformulation in 2012 intended to make the drug resistant to physical and chemical manipulation [19,20].
●Hydrocodone – Short-acting hydrocodone is only available in the United States in combination with acetaminophen. The amount of the nonopioid constituent limits use of these short-acting combinations to relatively opioid-naïve patients with moderate or severe pain.
Long-acting formulations of hydrocodone (Zohydro ER and Hysingla ER) are available in the United States for the management of pain severe enough to require daily, around-the-clock, long-term analgesic treatment and for which alternative treatment options are inadequate. These formulations contain only hydrocodone and, like other single entity pure mu agonists, are classified as Schedule II controlled substances. Although the analgesic efficacy of long-acting hydrocodone has been shown in a placebo-controlled trial conducted in patients with chronic low back pain, the only data addressing efficacy in cancer populations are from observational studies . Also like other oral, modified-release, long-acting opioid formulations, these drugs are formulated to deter abuse by crushing, chewing, or dissolving . (See "Abuse deterrent opioids".)
Fentanyl — Fentanyl is a highly lipophilic opioid that may be used parenterally or in formulations developed for transdermal or oral transmucosal delivery. The transdermal formulation is used for chronic pain. Both the non-oral route and the relatively infrequent dosing (every two to three days for transdermal fentanyl) are considered advantages by some patients. Although data from clinical trials about the potential for a relatively reduced risk of constipation from transdermal fentanyl are conflicting [23-26], three meta-analyses have found a significant advantage for transdermal fentanyl over sustained release oral morphine in terms of this side effect [27-29]. Transdermal fentanyl may be preferred over an orally administered opioid in the setting of poor gastrointestinal tract absorption or dysphagia, and for patients in whom constipation has been or is expected to be difficult to manage. Fentanyl may also be preferred over morphine in patients with kidney impairment due to lack of active metabolites. (See 'Patients with kidney impairment' below.)
Exposing the patch to heat (eg, an increase in body temperature, use of a heating pad or warming blanket during surgery) may cause an unintentional increase in systemic fentanyl absorption, which may increase the risk of respiratory depression. In addition, fentanyl patches contain metal, which can pose a risk for local skin burn during magnetic resonance imaging (MRI) . Clinicians should advise patients to remove the patch before an MRI procedure and replace it after completion of the scan. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging", section on 'Drug infusion pumps and patches'.)
Decreased absorption may also be a concern in cachectic patients .
Rapid-onset transmucosal preparations of fentanyl are discussed below. (See 'Management of breakthrough pain' below.)
Levorphanol — Levorphanol is distinguished by its relatively long half-life (approximately 12 to 16 hours). Experience in the use of this drug is relatively limited in the US, but it should be viewed as another option for the treatment of cancer pain, particularly when other mu agonists have not been well tolerated or are unavailable.
Methadone — Methadone is a mu agonist opioid, but it has a unique pharmacology that presumably underlies both the observation that some patients experience a surprising degree of analgesia after being switched to even a relatively low dose, and the fact that others experience unanticipated toxicity [32-34]. Methadone is equally effective to morphine for cancer pain , and among the potential benefits of methadone use are its low cost, high oral bioavailability, and long duration of action; it is also the only long acting opioid available in a liquid formulation [36,37]. Because only approximately 20 percent of a dose is eliminated unchanged by the kidneys and there are no active metabolites, methadone, when dosed appropriately, may also be a particularly useful drug in patients with kidney disease. (See 'Patients with kidney impairment' below.)
The fact that methadone is effective in treating the opioid craving that occurs in those with opioid addiction has been used as a rationale for the use of this drug in those patients who develop aberrant drug-related behavior when given another mu agonist for cancer pain and for those who are a high risk of these behaviors before starting therapy. Although methadone can be used to treat pain in those with a history of opioid use disorder, but in doing so, clinicians must carefully document that the treatment is for pain and not for addiction. The targeted use of methadone to manage addiction is highly regulated in the United States and permitted only when the clinician is licensed to provide this treatment. (See "Medication for opioid use disorder", section on 'Methadone: Opioid agonist'.)
Although it is a valuable analgesic agent in patients with chronic cancer pain, methadone's unique pharmacology is also associated with a risk of unintentional overdose and the drug should be prescribed only by those who are familiar with its pharmacology. Guidelines for safe administration must be followed to reduce the risk of overdose. Clinicians who have questions about these guidelines or who lack experience may wish to seek assistance from a palliative care consultant before prescribing this drug.
The pertinent safety issues are summarized as follows:
●Appropriate candidates – Not all patients are appropriate candidates for methadone; providers should perform a risk assessment before initiating methadone therapy. The following patients are potentially inappropriate candidates :
•Patient lives alone, or has poor cognitive function and no responsible caregiver
•Obstructive or central sleep apnea
•Prognosis less than the projected time to achieve steady state (minimum 5 to 7 days)
•History of, or high risk for, QTc prolongation (including at risk for hypokalemia, hypomagnesemia, or structural heart disease)
•Multiple transitions in care likely
●Half-life and dosing titration – Methadone has a variable half-life, which averages approximately 24 hours but ranges from 12 hours to almost one week . Since five to six half-lives are required before steady state plasma concentrations are approached, the time required before a methadone regimen can be considered stable varies from several days to several weeks. Due to this highly variable and prolonged terminal half-life, methadone has the highest risk among opioids of accumulation and overdose during initial titration to effect, and during dose adjustment in chronic use. This has two clinical implications:
•For most patients, it is better to adjust the dose at intervals that are likely to allow the effects of the prior dose change to be realized (eg, every five to seven days rather than a shorter time frame) . To start therapy in opioid-naïve patients, some palliative care clinicians prescribe a low fixed-dose regimen (eg, 2.5 mg orally two or three times per day) along with a short-acting oral opioid (eg, morphine 5 to 10 mg or hydromorphone 1 to 2 mg) that is dosed on an every-four-hour "as needed" basis . The methadone dose is then titrated every five to seven days (in increments of no more than 5 mg per day) and the need for the "as needed" opioid is expected to decline over time.
Another approach to achieve safe titration of first-line methadone, which we favor for patients with moderate to severe cancer pain, uses a low initial daily dose of methadone (2.5 to 5 mg per day) combined with a maximum of three daily rescue doses of 2.5 mg allowed every two to four hours as needed . The "as needed" doses can be converted to fixed dosing two to three times daily once pain stabilizes. A palliative care consultation may be warranted for patients with severe pain who do not respond to this regimen within 48 hours.
•Monitoring of the effects produced by a dose change must recognize the prolonged period during which the drug concentration is rising; one approach is a required "check-in" by the patient every two to three days for at least five to seven days or until the effects produced by the change in dose are observed to be stable.
●Difficulty in estimating equianalgesic doses for patients already receiving opioids – Perhaps even more challenging, methadone is marketed in most of the world as a racemate containing a 1:1 mixture of the d- and the l-isomer. The d-isomer is a relatively potent N-methyl-D-aspartate (NMDA) inhibitor and not an opioid. NMDA antagonists are associated with nonopioid analgesia and with reversal of opioid tolerance. These effects may explain the observation that methadone can be far more potent than would be expected from published equianalgesic dosing tables, particularly when administered to patients with substantial prior opioid exposure. Concern about this unexpected potency must be addressed by selecting a cautious initial dose when switching from another drug to methadone.
Guidelines from an expert panel for safe and appropriate use of methadone in hospice and palliative care recommend the following approach to dosing of methadone in opioid-tolerant patients :
•For patients receiving <60 mg oral morphine per day or equivalent (OME), the initial methadone dose should be no more than 7.5 mg oral methadone daily (eg, 2.5 mg three times daily).
•For patients receiving 60 to 199 mg OMEs and <65 years of age, use a 10:1 conversion (ie, 10 mg OME:1 mg oral methadone).
•For patients receiving ≥200 mg OME and/or patients >65 years of age, use a 20:1 conversion (ie, 20 mg OME:1 mg oral methadone).
•These and other guidelines also recommend converting to a methadone dose no greater than 30 to 40 mg per day, regardless of the previous opioid dose .
•The methadone dose should not be increased before five to seven days and should not be increased by more than 5 mg/day up to 30 to 40 mg/day, and then can be increased by 10 mg/day (after five to seven days).
●QTc prolongation and need for ECG monitoring – Methadone can prolong the QTc interval [41-43], a phenomenon that predisposes to a life-threatening cardiac arrhythmia, torsades du pointe. The clinical importance of this effect continues to be controversial, but it is prudent to consider the effect when starting therapy or increasing the dose. With the exception of patients with advanced illness and limited prognosis, for whom the need to address pain and avoid potentially burdensome monitoring  may exceed concerns about this risk, all patients should undergo a check of a baseline ECG prior to the start of methadone therapy . A documented ECG from within the past year may suffice if the clinical status of the patient has been stable in the interim.
Methadone should be used very cautiously in those with a QTc interval >450 milliseconds; and generally should not be used if the QTc interval exceeds 500 milliseconds. For patients who have QTc prolongation, potentially reversible causes, such as hypokalemia or hypocalcemia, should be sought, and reversed, if present.
Decisions about repeat ECGs should consider the baseline level of risk and the extent to which the monitoring is burdensome . In those judged to need close monitoring, a repeat ECG may be done in several weeks, or after the dose is increased to approximately 40 mg/day and then again when the dose reaches approximately 100 mg/day . For patients on a stable dose of methadone, a repeat ECG would be indicated only in the event of a new onset condition that may impact cardiac conduction or the administration of another drug that prolongs the QTc interval (table 4). Although clear guidelines are lacking, it is reasonable to consider periodic additional ECGs if the dose continues to be increased. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
●Drug-drug interactions – Methadone is metabolized by CYP3A4 and CYP2B6 isoenzymes, and to a lesser extent, by other CYPs (2C19, 2C9, 2D6); drugs that function as inhibitors of CYP3A4 may increase methadone levels, and patients receiving concomitant treatment with one of these inhibitors should have methadone doses reduced. On the other hand, patients undergoing concomitant therapy with a CYP3A4 or 2B6 inducer may experience decreased methadone levels and reduced efficacy or withdrawal. A table listing several known inducers and inhibitors of CYP3A4 is provided (table 5).
Note that some drugs identified as strong CYP3A4 inhibitors can decrease methadone exposure (ie, opposite of expected effect) by an uncertain mechanism (eg, ritonavir boosted antiretroviral regimens including lopinavir-ritonavir, saquinavir ritonavir, darunavir-ritonavir, tipranavir-ritonavir). Thus, interactions should be carefully analyzed whenever drug therapy with methadone is adjusted. The Lexicomp drug interactions (Lexi-Interact) tool is available within UpToDate for this purpose.
Pure mu agonists rarely used for cancer pain — Within the large group of pure mu agonist drugs, there are some that are of historical importance but are now rarely, if ever, used for cancer pain.
Codeine — The World Health Organization (WHO) original analgesic ladder for treatment of cancer pain (figure 1) , first published in the 1980s, referred to codeine as the prototype "weak" or "mild" opioid and recommended it for the first "rung" of the ladder as a preferred drug for moderate cancer pain. In the intervening years, however, these views have changed. The "weak" designation is now understood to be pharmacologically inappropriate, and although codeine could be used to treat moderate pain in the patient with limited to no opioid exposure, there is very limited evidence of a positive therapeutic index in any type of cancer pain [44,45]. It is now appreciated that any pure mu agonist, including those previously recommended for severe pain as the third "rung" of the analgesic ladder, could be effectively used for moderate to severe pain in opioid-naïve patients if started at a relatively low dose. This approach, which effectively eliminates the second "rung" of the analgesic ladder has been endorsed in guidelines for cancer pain management from the National Comprehensive Cancer Network (NCCN) and other organizations, including the European Association for Palliative Care [46,47] and the most recent guidelines for management of cancer pain from the WHO . One study found that low-dose morphine (up to 30 mg daily) reduces pain significantly as compared with codeine (or tramadol) with or without acetaminophen in patients with moderate cancer pain, with similar tolerability and an earlier effect .
Codeine is available in combination with acetaminophen. These combination drugs restrict the amount of codeine that can be delivered because of concern about acetaminophen toxicity. The maximal daily dose of acetaminophen is recommended to be 3 g/day, and lower in those with known liver disease or risk factors for liver disease. (See "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs", section on 'Hepatic toxicity'.)
The use of codeine has also been questioned as more information appeared concerning genetic variation in its metabolism. The analgesic efficacy of codeine requires conversion to morphine via the CYP2D6 isoenzyme of the P450 hepatic enzyme system. CYP2D6 is highly polymorphic, with over 90 known allelic variants. Five to 10 percent of patients inherit a slow metabolizer phenotype, and they derive only limited or no therapeutic benefit from codeine because it will not be converted to its active moiety. Conversely, patients who are ultra-rapid metabolizers based on CYP2D6 genotype may have higher than expected morphine levels. This can lead to unintended toxicity. Similar effects have been described in patients receiving hydrocodone and oxycodone but without the presumed clinical relevance perceived with codeine [50,51]. This variation in population genetics and the resulting uncertainty in effects when dosing begins , combined with the limited doses available in combination products, suggest that codeine should not be among the preferred drugs for cancer pain management.
Meperidine — Meperidine also is not preferred for use in the cancer pain population. It is metabolized into a compound (normeperidine) that is relatively toxic, and associated with tremulousness, delirium, and seizures. The metabolite has a longer half-life than the parent compound, and its concentration in blood rises for several days with repeated administration. Some patients will therefore develop normeperidine toxicity with repeated dosing over days. The metabolite is renally excreted, and its concentration increases (with greater risk of toxicity) in the setting of renal insufficiency. It is safer to select an alternative mu agonist for the management of chronic pain.
Mixed-mechanism drugs: Tramadol and tapentadol — Tramadol and tapentadol are centrally acting analgesics whose mode of action is based both on the mu receptor binding and monoamine (serotonin and norepinephrine) reuptake blockade. Tramadol is widely used in some countries for moderate to severe cancer pain as an alternative to other opioids [53,54], but it is not used as commonly in the United States. Evidence is limited comparing either drug with other opioids in terms of either efficacy or tolerability in patients with cancer-related pain:
●A Cochrane review of four randomized trials of tapentadol compared with either placebo or an active control in 1029 adults with moderate to severe cancer pain concluded that there were insufficient data for pooling and statistical analysis of the four trials . Overall, there was low quality evidence that tapentadol was no more or no less effective for pain relief than morphine or oxycodone, and there was no advantage of tapentadol in terms of serious adverse events.
●Similarly, a Cochrane review of 10 studies comparing tramadol with either placebo or an active control in 958 adults with moderate to severe cancer pain concluded that there was limited, very low-quality evidence from randomized trials that tramadol produces pain relief in some adults with pain due to cancer, and very low-quality evidence that it is not as effective as morphine .
Based on this limited evidence and clinical experience, it is reasonable to conclude that either tramadol or tapentadol could be used to treat cancer pain, but there is no known advantage in selecting one or the other over the pure mu agonist opioids that are conventionally used for this indication.
Mixed agonist-antagonist drugs — Because it has the capacity to induce withdrawal in opioid-tolerant patients, we reserve the use of buprenorphine for individuals with new-onset, moderate or severe cancer pain, and limited or no prior opioid treatment. It may be particularly useful in those with kidney impairment or when the potential for respiratory depression is a concern. Beside buprenorphine, we generally suggest not using drugs of the mixed agonist-antagonist group (butorphanol, dezocine, pentazocine, and nalbuphine) for cancer pain management.
Buprenorphine — Buprenorphine is available as a treatment for opioid addiction and as a treatment for pain. (See "Medication for opioid use disorder", section on 'Buprenorphine: Opioid agonist'.)
Buprenorphine has a complex pharmacology. It is a partial agonist at the mu opioid receptor, where it has very high affinity but relatively low intrinsic activity; it also produces some antagonism at the kappa receptor and other opioid receptors. As a partial mu agonist, it may have a ceiling effect for analgesia, but clinical experience with higher doses for the treatment of pain is limited, and the extent to which there is a clinically meaningful ceiling effect is uncertain. As a high-affinity drug, it can displace other mu agonists from the receptor and therefore has the ability to induce withdrawal if it is administered to patients who are already physically dependent on a pure mu agonist drug. This potential for abstinence when switching from another opioid to buprenorphine can be managed but is a problem that must be considered if buprenorphine treatment is being planned for a patient who may already be physically dependent on another opioid . The problem of induced withdrawal does not exist or is minimal if buprenorphine is used in patients with very limited or no prior opioid treatment.
Buprenorphine is available in multiple formulations. The transdermal formulation was developed for the treatment of chronic pain. In the United States, transdermal buprenorphine became available in 2010 (Butrans 5, 10, or 20 mcg/hour, all intended for seven-day use). The transdermal patch carries a warning against exceeding 20 mcg/hour due to the risk of QT prolongation. An alternative is a long-acting (daily or twice-daily administration) buprenorphine buccal film, which is initiated in the opioid-naïve patient at a dose of 75 micrograms once or twice daily if needed and well tolerated.
One of the advantages of buprenorphine is its relatively lower potential for respiratory depression compared with other agents [58,59]. However, experience with buprenorphine in the management of cancer pain is limited. Anecdotal reports, a few small prospective uncontrolled studies, and at least two small placebo-controlled randomized trials (conducted over a period of approximately two weeks) support at least short-term effectiveness and safety in patients with severe cancer-related pain [60-64]. Few comparative studies have been performed against other long-acting opioids, and the quality of the evidence from two such trials is uncertain [65,66]. Nonetheless, a 2009 consensus statement from an international panel with expertise in palliative care and pain treatment endorsed the use of transdermal buprenorphine where available .
Clinicians should be aware that there are a number of reports of dental problems associated with the use of buprenorphine formulations that are dissolved in the mouth, including the buccal formulation. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Buprenorphine for chronic pain'.)
Given the limited evidence, the doses of transdermal buprenorphine that are available in the United States, and the need to manage the risk of withdrawal when switching to buprenorphine from another pure mu agonist opioid, it is reasonable to consider buprenorphine only in those who are relatively opioid naïve, typically patients with new-onset, moderate, or severe cancer pain. More recent reviews, including one used to inform the work of an expert panel, note that buprenorphine pharmacology may make it a favorable drug for chronic pain treatment [57,68] and encourage further consideration of its use. This applies to cancer pain as well. For example, one setting in which buprenorphine may be particularly useful is in the cancer patient with kidney impairment who is opioid-naïve and has moderate or severe cancer pain, especially when there is a concern for respiratory depression [69,70]. (See 'Patients with kidney impairment' below.)
Other drugs — Besides buprenorphine, we generally suggest not using drugs of the mixed agonist-antagonist group (butorphanol, dezocine, pentazocine and nalbuphine) for cancer pain management. This is because of a ceiling effect for analgesia, and the capacity to induce withdrawal when administered to patients already receiving other opioids of the mu agonist class.
PRACTICAL CONSIDERATIONS IN OPIOID USE
Prescribing restrictions and risk management — Opioids have the potential for misuse, abuse and addiction, and are regulated by government. In the United States, these drugs are designated "controlled substances" under a federal law known as the Controlled Substances Act (table 6). Clinicians are responsible for prescribing in a manner consistent with federal and state laws and regulations, and also have responsibility for implementing best practices that minimize the risk of abuse-related outcomes. Issues in risk management when these drugs are prescribed are addressed elsewhere. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Risk assessment and management for patients receiving opioids'.)
Selecting the opioid — The literature on opioid comparative efficacy and effectiveness  precludes an evidence-based approach to opioid selection. Accordingly, recommendations continue to be based on clinical experience. The following represents of general approach:
●Patients who are opioid naïve and have pain severe enough to warrant opioid therapy can be offered one of the opioid-nonopioid combination products or one of the pure mu agonists at a low initial dose.
If acetaminophen-oxycodone is used, the dose of the opioid usually is 5 mg per tablet; a lower dose (2.5 mg per tablet) should be considered in older or very frail adults (table 7).
If acetaminophen-hydrocodone is used, the usual dose of the opioid is 5 to 7.5 mg per tablet; 2.5 and 10 mg hydrocodone-acetaminophen combinations are also available. The initial prescription usually is one to two tablets every three hours, as needed.
●For most patients with cancer pain who are relatively opioid naïve, we prefer a single-entity pure mu agonist at a low dose. Options include oral morphine (5 to 10 mg orally every three to four hours), oral oxycodone (2.5 to 5 mg orally every four hours), hydromorphone (1 to 2 mg orally every three to four hours), or transdermal fentanyl (12 mcg/hour every 72 hours). (See 'Pure mu agonists commonly used for cancer pain' above.)
Methadone is another option. To start therapy in opioid-naïve patients, some palliative care clinicians prescribe a low fixed-dose regimen (eg, 2.5 mg orally two or three times per day) along with a short-acting oral opioid (eg, morphine 5 to 10 mg or hydromorphone 1 to 2 mg) that is dosed on an every-four-hour "as needed" basis . The methadone dose is then titrated every five to seven days (in increments of no more than 5 mg per day) and the need for the "as needed" opioid is expected to decline over time. (See 'Methadone' above.)
Transdermal or buccal buprenorphine also should be considered. (See 'Buprenorphine' above.)
●If a patient is given a short-acting drug and needs several doses per day (or if a bedtime dose does not permit uninterrupted sleep through the night), a switch to a long-acting formulation is commonly undertaken to improve convenience and adherence. There is no evidence that any one of the commonly used, long-acting formulations that are available in the US, including morphine, hydromorphone, oxycodone, oxymorphone, fentanyl, and buprenorphine is more likely to be effective than any other . Selection usually is determined by the patient's prior experience with opioids, the clinician's experience, cost and availability, and formulation.
As noted, there is some evidence that transdermal fentanyl is less constipating than oral morphine and the former drug may be preferred if constipation has been a challenging problem. If an oral formulation is given, some patients prefer once-daily dosing (eg, with hydromorphone or morphine) rather than twice-daily dosing (eg, with oxycodone).
Although methadone is far less costly and can be used effectively as a long-acting drug for cancer pain (usually requiring oral dosing three times per day and sometimes twice a day), the challenges inherent in the safe prescribing of this drug suggest that it should be considered a first-line treatment option only by clinicians experienced in its use. Clinicians with limited experience may consider obtaining a consultation from a specialist in palliative care or pain management to assist with the initiation of methadone therapy. Even experienced clinicians usually consider methadone only in the event that trials of one or more of the other pure mu agonist drugs fail to provide an adequate balance between analgesia and side effects. (See 'Methadone' above and 'Switching to methadone' below.)
Patients with kidney impairment — The following considerations are important when managing chronic pain in cancer patients with significant kidney impairment [73-75]. It should be noted that these recommendations are largely based upon pharmacokinetics and clinical experience; there is very little high-quality clinical evidence to support opioid choice in patients with kidney impairment .
Drugs to avoid
●Meperidine (Demerol) should not be used, since its active metabolite, normeperidine, accumulates with renal dysfunction and can cause serious central nervous system (CNS) toxicity. Given the prevalence of renal dysfunction in the cancer population, and the potential for normeperidine toxicity even in those with normal renal function, particularly if the dose is increased to manage poorly controlled pain, meperidine is generally not preferred for cancer pain management.
●Morphine is metabolized in part to a potent opioid metabolite, morphine-6-glucuronide, and a metabolite, morphine-3-glucuronide, which is associated with neurotoxicity. These metabolites are renally excreted and there is concern that their accumulation in patients with renal insufficiency may lead to unanticipated changes in morphine potency or side effects . Although the current evidence for these neurotoxic effects consists only of very-low-quality studies with conflicting findings , morphine should be administered carefully in the setting of kidney impairment. Close monitoring for neurotoxic effects (eg, sedation, cognitive impairment, myoclonus) is particularly important if kidney function is changing; in this situation, the decision to use morphine should be reconsidered. (See "Prevention and management of side effects in patients receiving opioids for chronic pain".)
●Oxycodone may be used among patients with kidney impairment but, like morphine, raises concerns about the impact of renally-excreted metabolites that may accumulate in this setting. These metabolites, noroxycodone and oxymorphone, are produced in the liver and may have relatively high concentration in patients with advanced kidney impairment . (See "Management of chronic pain in advanced chronic kidney disease", section on 'Drugs that should be avoided'.)
●Both codeine and tramadol can accumulate in patients with kidney impairment, enhancing both their effects and side effects.
Preferred drugs — Preferred opioids in the setting of kidney impairment may be those whose metabolism does not pose an increased risk:
●Hydromorphone, for example, has active metabolites but these are produced in relatively low concentration (compared with morphine) and may be less likely to cause unanticipated effects in the setting of kidney impairment. Although this drug is often selected for this reason, it is important to recognize that accumulating metabolites can cause problems, particularly with higher doses [79-81].
●Fentanyl, buprenorphine, and methadone lack active metabolites and also are considered in the setting of kidney impairment on this basis. Although methadone is another option for patients with chronic kidney impairment, concerns about the risks associated with methadone, however, speak against the use of this drug in patients who may be metabolically unstable (ie, acute kidney impairment, severe chronic kidney impairment), and clinicians may prefer to use fentanyl, buprenorphine, or hydromorphone in patients with kidney impairment. (See 'Methadone' above and 'Buprenorphine' above.)
Patients with chronic liver disease — Most opioids are at least partially metabolized by the liver, complicating their use in patients with chronic liver disease . However, safe prescribing of analgesics for patients with chronic liver disease is possible as long as a few general guidelines are followed (table 8). In general:
●Lower initial starting doses for most opioids are warranted in patients with chronic liver disease, and clinicians should be cautious prescribing opioids at "regular" dosing intervals until patients have demonstrated that drug level does not become too high during the chosen dosing interval. As the liver disease progresses, prolonged dosing intervals may be needed.
●Codeine and meperidine should be avoided entirely in patients with chronic liver disease. Codeine is a prodrug that is converted to morphine via the CYP2D6 isoenzyme of the P450 hepatic enzyme system; pain control may be compromised by diminished metabolism. In hepatic disease, meperidine clearance is reduced, and the half-life is prolonged.
Management of breakthrough pain — Breakthrough pain is a transitory severe acute pain that occurs on a background of chronic pain that is otherwise adequately controlled by a sustained release, long-acting, transdermal or parenteral opioid regimen [83,84]. Given its high prevalence in patients with cancer pain, and its negative clinical consequences, a treatment approach known as "rescue" dosing has become a widely accepted approach. Management of other types of acute pain (eg, from a new injury or surgical procedure) in patients chronically using opioids for non-cancer pain is addressed in detail elsewhere. (See "Management of acute pain in the patient chronically using opioids for non-cancer pain".)
Clinically significant breakthrough pain usually is managed by prescribing a rescue drug, which is usually a short-acting opioid offered on an as-needed basis. The rescue dose is separate from the fixed scheduled opioid regimen and may be used by the patient to treat episodic acute pain or, at times, to prevent its occurrence. In most situations, the rescue drug is chosen to be one of the single entity oral opioid formulations, such as immediate-release morphine, oxycodone, hydromorphone, or oxymorphone. Based on clinical experience, a typical dose chosen for the rescue is in the range of 5 to 15 percent of the basal daily requirement of opioid . (See 'Practical considerations in opioid use' above.)
If the dose selected for rescue dosing does not yield satisfactory effects, the dose should be increased as necessary. If the dose of the fixed scheduled opioid regimen is changed, the usual approach is to proactively increase or decrease the oral rescue dose so that it remains roughly proportional to the baseline dose (ie, in the range of 5 to 15 percent of the basal daily requirement of opioid).
Breakthrough pain also may be targeted with one of the newer rapid-onset, transmucosal fentanyl formulations, which are specifically indicated for cancer-related breakthrough pain in patients who are opioid tolerant. Six formulations of transmucosal fentanyl are now available in the United States: an oral transmucosal fentanyl lozenge (Actiq), an immediate-release transmucosal tablet formulation (Abstral), an effervescent fentanyl buccal tablet (Fentora), a nasal spray (Lazanda), and a sublingual spray (Subsys) (table 9). In the United States, all of these products, including generics, have a mandatory shared risk evaluation and mitigation strategy (REMS), the purpose of which is to reduce the risk of misuse and unintentional overdose. To prescribe any of these drugs, clinicians must complete online education, and each patient treated requires registration of the patient, clinician, and pharmacist. Because of data suggesting that transmucosal fentanyl preparations were still being prescribed to opioid-naïve patients, in December 2020, additional regulations beyond education and registration were put into place by the US Food and Drug Administration, requiring that opioid tolerance be verified and documented by both the prescriber and the outpatient pharmacy, prior to each individual prescription . (See "Cancer pain management: General principles and risk management for patients receiving opioids".)
Studies of these transmucosal immediate-release fentanyl (TIRF) formulations have established efficacy, with an onset of effect that is faster than that expected from oral formulations [87-93]. Comparative effectiveness against one of the typical short-acting oral formulations has been determined for the nasal and oral fentanyl formulations [88,90,94], at least in terms of the onset of pain relief. Sublingual fentanyl may also be preferred by patients over subcutaneous morphine . Studies that have compared the different TIRF drugs are limited .
Based on the existing comparative data and clinical observations, it is likely that the more rapid onset of the TIRF formulations are highly favorable for some patients. Due to cost and limited experience, however, these drugs are generally considered only after a patient has demonstrated a poor response to an oral rescue dose. Patients with very-rapid-onset pain might also be considered for an early trial. Given the lack of comparative data, there are no recommendations about which of the many formulations might be preferable.
Regardless of the formulation selected, the recommended starting dose is the lowest or next-to-lowest available. This recommendation, which is contrary to the use of proportionate dosing that characterizes oral rescue doses, is made because controlled trials have not confirmed that a dose proportionate to the baseline dose is needed to observe effects. Although some experts do endorse the use of proportionate dosing with the TIRFs, safety considerations suggest that initiation of therapy with a low dose followed by dose titration is appropriate.
Selecting the route of administration
Oral — The oral route is usually preferred for chronic treatment of cancer pain because of convenience and flexibility. Many cancer patients require alternative routes of analgesic administration at some time during the course of their illness.
In most patients, orally administered, non-transmucosal, immediate-release formulations have a peak analgesic effect at 1 to 1.5 hours, while the analgesic peak with most modified-release oral formulations is approximately three to five hours.
Some of the immediate release opioids, such as morphine and oxycodone, are also available in liquid formulations, which may be useful for patients with odynophagia or dysphagia or who can only receive medications through feeding tubes.
Oral modified-release medications should never be crushed because of the potential for toxicity related to the sudden release of the full dose in the tablet or capsule (a phenomenon known as "dose dumping"). Several of the modified-release opioids can "dose dump" if coadministered with alcohol, which can dissolve the matrix in which the drug is embedded. It is best to inform patients that alcohol consumption should be avoided during the hours around administration of each dose.
Use of the oral route may not be feasible in patients with oral mucositis, dysphagia, bowel obstruction, or severe nausea. Some of the modified-release morphine formulations (eg, Kadian) are capsules that can be opened and sprinkled on food without changing the delivery characteristics; this can permit the administration of a modified-release drug through a feeding tube, if necessary, but the pellets can clog all but the largest feeding tubes. Liquid methadone or transmucosal fentanyl or buprenorphine, for those with adequate fat reserves, may be better choices for those patients. (See 'Transdermal' below.)
Transdermal — Transdermal fentanyl is widely used for chronic pain. Each transdermal patch provides 48 to 72 hours of relatively stable drug delivery for most patients. (See 'Fentanyl' above.)
Transdermal fentanyl may be preferred over an orally administered opioid in the setting of poor gastrointestinal tract absorption or dysphagia, or if constipation is an issue. Transdermal fentanyl may also be preferred by patients who are distressed by the number of tablets required to manage medical disorders and for those whose adherence to treatment would be improved by use of the transdermal route.
Transdermal fentanyl may not be effective in patients lacking adequate adipose tissue over which the patch can be placed. In such patients, without an adequate subcutaneous drug reservoir, fentanyl serum levels may never become therapeutic, presumably because the drug is not delivered to the blood as a continuous infusion and the liver metabolizes the drug as it is presented to it. Patients with low albumin levels who have frequent infections are at risk for toxicity from transdermal fentanyl because of sudden increases in the free fraction of fentanyl along with increased absorption from the reservoir when the patient's temperature exceeds 102 degrees F.
Transdermal buprenorphine is available in some countries, including the United States. As discussed, efficacy in cancer pain has been addressed in six randomized trials, in which transdermal buprenorphine was compared with placebo, morphine, or transdermal fentanyl [23,62,64,66,97,98]. Although efficacy is likely, the studies were not designed to address long-term effectiveness, making the results difficult to interpret . The available data suggest that transdermal buprenorphine may be useful, as in patients who are relatively opioid naïve and do not have severe pain requiring rapid dose titration; it is not generally considered first line due to the limited experience. (See 'Buprenorphine' above.)
Rectal — Occasional patients are treated with rectal administration of an opioid . In the United States, short-acting rectal formulations are available for morphine (5, 10, 20, 30 mg rectal suppositories), hydromorphone (3 mg) and oxymorphone (5 mg). In addition, there is limited anecdotal experience in the rectal use of a long-acting modified-release formulation [101,102].
The potency of rectally administered opioids is believed to approximate oral dosing, but absorption is variable and relative potency may be higher or lower than expected [102,103]. For this reason, a switch from oral to rectal dosing is usually accompanied by a reduction in the equivalent dose. (See 'Equianalgesic opioid dose conversion' below.)
Subcutaneous and intravenous administration — Among patients with a progressive illness like cancer, it is commonplace for a pain regimen that was initially administered via an oral or transdermal route to be switched, at least temporarily, to continuous intravenous (IV) or subcutaneous (SC) infusion. As an example, this switch may happen if a patient who has been on a chronic stable doses of a long-acting opioid is hospitalized with an acute pain crisis. The intramuscular route is not generally used because it is painful and provides no pharmacological advantage.
Continuous SC infusion can be easily accomplished using a "butterfly" catheter inserted under the skin of the chest wall or abdomen; the needle can remain in place for a week or more, and any drug with an injectable formulation can be administered in this way . Methadone is not preferred via the SC route as it can act as an irritant to the skin.
In order to maintain the comfort of an infusion site, the SC infusion rate should not exceed 5 mL/hour. Higher volumes can be delivered, however, if hyaluronidase is added to the infusion. In order to limit the total volume of injectate, hydromorphone may be chosen over fentanyl and morphine because of its greater water solubility ; it is commercially available in a relatively concentrated 10 mg/ml solution for injection.
Patients receiving continuous IV or SC infusion may benefit from access to intermittent administration of a short-acting drug for breakthrough pain. The IV route has the most rapid onset of action. When administered as an IV bolus, some drugs, such as fentanyl, have a peak onset almost immediately, whereas other drugs, such as morphine, may require 15 to 30 minutes because of the time required to penetrate the blood-brain barrier.
Patient-controlled analgesia — A pump with a patient-controlled analgesia (PCA) option can be used to administer continuous infusion by either the IV or SC route, and thereby facilitate the option of "rescue doses." PCA devices are programmed for the size of the dose, the minimum time between doses (lockout interval), and the cumulative dose allowed in one or four hours (several times higher than the anticipated need). Some pumps allow separate programming of doses delivered by the patient or the clinicians, respectively.
While it is widely recommended [46,47], most of the evidence supporting the benefit of PCA over other methods of titration has come mainly from reports of single arm trials, small cohorts, and literature review articles [106-110]. However, at least one small randomized trial (n = 214 patients) supports better outcomes for PCA versus non-PCA hydromorphone titration for severe pain in opioid tolerant patients, with a significantly shorter time to successful titration of hydromorphone dose with PCA . Notably, for opioid-naïve patients (43 percent of those enrolled), the time to achieve successful titration of hydromorphone dose was not significantly different with PCA as compared with a non-PCA approach.
Although safe and efficacious PCA settings for morphine, hydromorphone, and fentanyl are widely accepted when this modality is used for acute postoperative pain, the settings are usually quite different when PCA is selected for cancer pain. Patients typically have a prior opioid regimen that is switched to an appropriate dose of a continuous infusion. The supplemental rescue dose administered via the PCA pump is selected to be roughly in the range of 5 to 15 percent of the prior total daily dose. In contrast to acute pain, the treatment of which often involves access to PCA delivered doses every six to seven minutes, the so-called lockout period when PCA is used to deliver rescue doses to opioid tolerant patients during chronic infusion may be longer, such as 10 to 30 minutes, if higher rescue doses are needed to provide pain relief.
Intrathecal and intraspinal administration — Properly selected patients can benefit from interventional pain management approaches, such as intraspinal opioid administration (epidural or intrathecal, collectively called "neuraxial" analgesia) . A systematic review of intraspinal techniques for cancer pain , which included one randomized trial comparing neuraxial analgesia via an implanted programmable pump against conventional analgesic therapy , concluded that intraspinal therapy can be equally or more effective than systemic analgesic therapy and yield analgesia with relatively fewer side effects.
Patients whose pain has not responded to optimally administered systemic opioid therapy should be considered for referral to a specialist in pain management for evaluation of this and other neuraxial techniques, among other interventional strategies for pain management. (See "Cancer pain management: Interventional therapies".)
Dose titration — Following selection of a starting dose, adjustment is almost always required to optimize an opioid regimen and sustain its benefits over time. Dose individualization is the key to optimizing the outcomes of opioid therapy [115-119].
Continuous or frequently recurrent pain is most effectively managed with a fixed schedule, "around-the-clock" opioid regimen, which is usually combined with "as needed" rescue doses for breakthrough pain. Dose titration to achieve adequate pain relief from a fixed scheduled regimen is attainable in most cases.
Conventionally, dose titration is accomplished in one of two ways. The fixed scheduled dose can be increased by 30 to 100 percent of the total dose taken in the prior 24 hour period (with the percent increase informed by the severity of the pain, the degree of medical frailty or comorbidities that may increase opioid risk, and the existing formulations). Alternatively, the fixed scheduled dose can be increased by a daily amount that is determined by averaging the total amount of supplemental rescue medication taken during the prior few days (adjusted for the estimated equianalgesic potency, if needed (table 3 and table 10)). These step-wise methods of dose escalation ensure safety as the dose is increased. Caution is needed, however, if the increase in the baseline dose is not expected to be accompanied by a reduction in the use of rescue medication (such as may be the case if rescue is needed for predictable painful events, like dressing changes). If the increase in the baseline dose is relatively high, such as >50 percent, this increment combined with the unchanging use of rescue could lead to side effects associated with an increase in total dose higher than intended.
As a general rule, the dose of an opioid can be increased until a favorable balance between analgesia and side effects is obtained, or the patient develops intolerable and unmanageable side effects. (See "Prevention and management of side effects in patients receiving opioids for chronic pain".)
Although it is generally understood that dose escalation can continue without regard to a maximum dose, the need for a relatively high dose (eg, a dose equivalent to >200 mg morphine) in an individual patient should prompt a careful reassessment. Some patients will have pain that does not appear to be diminishing even as doses increase and others may demonstrate troubling behaviors or incipient side effects like mild signs of cognitive impairment. Some have an excessive pill burden. These observations may suggest consideration of an alternative strategy.
Ideally, the interval between dose escalations should be long enough to allow a new steady state (which requires five to six half-lives, irrespective of the route or drug) to be approached following each dose adjustment:
●Two to three days for the modified-release oral formulations.
●Three to six days for the transdermal patch.
●Although five days is usually sufficient to judge the full effect of a change in methadone dose, the variability of this drug's half-life means that occasional patients will require much longer periods (up to several weeks) to ensure that effects have become stable. (See 'Methadone' above.)
For patients with severe pain, more rapid dose escalation is needed. However, when doses are escalated at intervals shorter than those necessary to approach steady state (five to six half-lives), there is a possibility of "overshooting." In this phenomenon, the patient undergoing rapid dose titration reports benefit, but continuation of the successful dose later results in toxicity as drug levels continue to rise toward steady state.
When rapid dose titration is needed to address poorly controlled pain, the risk of overshooting should be assessed. The risks are greater when the drug has a relatively long half-life (the greatest concern is with methadone) or the patient is medically frail. In some cases, hospitalization should be considered for the express purpose of monitoring aggressive escalation of the dose. Hospitalization during a period of particularly intense pain, or "pain crisis," is a medically appropriate option for selected patents.
As the dose of the fixed schedule opioid regimen is increased, the dose of the "rescue" drug also must be increased. In most cases, the dose of this short-acting medication should remain in the range of 5 to 15 percent of the total daily dose . The exception to this is found when using the rapid-onset transmucosal fentanyl formulations, which may have effects at doses that are not proportional to the fixed schedule dose . In the case of these drugs, the starting dose should be low and dose titration proceeds with the commercially available dose units, stopping at a level associated with benefit. (See 'Management of breakthrough pain' above.)
The following case illustrates the stepwise methods for dose titration, applying these approaches to a patient receiving relatively high doses of an opioid.
A patient with slowly progressive breast cancer, who has undergone several periods of opioid dose adjustment because of worsening pain, is taking long-acting oxycodone 240 mg twice daily plus "rescue" doses consisting of five tablets of short-acting oxycodone 5 mg (25 mg per dose); on each day, approximately four rescue doses are needed. She has no side effects except for constipation, which has been controlled with laxatives. When her pain worsens again, she is assessed, and in the absence of unmanageable side effects, the decision is made to further escalate the dose. Her total daily dose of oxycodone has been 480 mg (long-acting) plus 100 mg (rescue) or 580 mg. There are two approaches to dose increase:
●One approach to increasing the dose is to add 30 to 50 percent to the total daily dose (30 percent of 580 = 174). The largest oxycodone tablet is 80 mg, and an increase of 30 percent can be easily accomplished by adding one 80 mg tablet to each of the fixed doses: a fixed regimen of 320 mg twice daily. The rescue dose can be changed to 35 mg per dose at the same time.
●The alternative approach, adding the total daily rescue dose, or 100 mg/day in this case, to the fixed scheduled dose yields a more conservative outcome but still one in the range to be useful.
Both strategies are appropriate and safe; any smaller increment is unlikely to be beneficial.
This case also illustrates a typical pattern observed during long-term treatment of cancer pain. The opioid dose is usually maintained for a prolonged time, unless there is progression in the pain-producing pathology. Recurrent pain or the new occurrence of side effects necessitates a new assessment, and often, another period of dose titration. Although the use of relatively high doses requires careful reevaluation, some patients continue to benefit if stepwise dose titration is continued.
It is worth noting that updated 2022 guidelines for prescribing opioids for chronic pain from the United States Centers for Disease Control (CDC) recommend careful consideration of the risks and benefits of therapy for daily doses at or above 50 mg (morphine equivalents) ; however, these guidelines specifically exclude patients with active cancer, and other guidelines such as from the National Comprehensive Cancer Network (NCCN) and ASCO do not provide a daily ceiling dose for patients with active cancer or cancer survivors [119,123]. (See "Cancer pain management: General principles and risk management for patients receiving opioids".)
Pain that respond poorly to opioids alone — When a patient's pain is poorly responsive to an opioid, ie, when a favorable balance between analgesia and side effects cannot be obtained and treatment-limiting side effects occur without adequate pain control, it might be related to the type of pain (neuropathic pain may less likely to respond adequately to opioids alone than pain related to ongoing tissue injury) or other issues, such as a high propensity to develop side effects (eg, presence of preexisting cognitive impairment, frail older adults). (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain'.)
Clinicians must be attuned to the occurrence of opioid poorly responsive pain [124,125], recognize it promptly, assess potential contributors (table 11), and be prepared to offer an alternative strategy for pain management.
The first step is to reassess the patient for factors that may be driving the pain or predisposing to side effects. This assessment should include questions about psychosocial and spiritual concerns. If aberrant substance use is suspected, a detailed history relevant to aberrant substance use outcomes (nonadherence, addiction, and diversion) should be done. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Risk assessment and management for patients receiving opioids'.)
A physical examination should be completed, and diagnostic studies ordered, as indicated.
If a potentially treatable etiology of the poorly responsive pain cannot be identified, and it is clear that additional analgesic benefit is not being derived from dose escalation of a single opioid, a new plan of care must be developed. This may involve any one of a large number of options (table 12) , each of which must be evaluated in terms of benefit and burden, within the context of the larger goals of care. Strategies for prevention and management of common opioid side effects are covered elsewhere. (See "Prevention and management of side effects in patients receiving opioids for chronic pain".)
How to perform opioid rotation — A common approach to the management of poorly responsive pain is known as "opioid rotation," which is defined as a switch from one opioid to another in an effort to provide better outcomes. The rationale for this strategy is based on pharmacologic and clinical observations that suggest that a change in drug is more likely than not to improve the balance between pain relief and side effects .
Equianalgesic opioid dose conversion — Each opioid drug has a different potency, defined as the dose necessary to produce a given effect. When switching from one opioid to another, the starting dose of the new drug must be informed by the difference in their relative potencies. The starting dose of the replacing drug must be close enough to its predicted equianalgesic dose to prevent the development of withdrawal (if the dose of the new drug is too low) or unintentional overdose (if it is too high). Equianalgesic dose tables (table 2 and table 3 and table 10) have been developed as a means for comparing potencies among opioids.
Although it is essential to know the approximate equianalgesic dose between drugs when switching from one to the other, this is only the first step. Although the relative potency estimates represent the best science after more than 40 years of studies , application of the ratios in the equianalgesic dose table to the clinical setting must be done cautiously because of the following issues:
●Individual patients may not have the characteristics of those who were included in the relative potency studies.
●There is very large individual variation in drug metabolism and pharmacodynamics, indicating that even patients with similar characteristics may have very different responses to different drugs.
●Tolerance to adverse effects during long-term treatment does not occur to different drugs in the same way. This "incomplete cross-tolerance" means that a new drug can have unexpectedly strong effects.
●Because of variations in drug absorption, a dose reduction may be needed when switching from one route of administration to another (eg, from oral to rectal dosing), even for the same drug. (See 'Rectal' above.)
To ensure that opioid rotation is done safely, clinical guidelines have been developed that incorporate reductions in the calculated equianalgesic dose . These reductions have been conceptualized as ranges, one automatic and one based on specific patient characteristics, and clinical judgment must be used to apply them (table 13) .
Switching to methadone — Methadone is an effective drug for cancer pain , and among its potential benefits are low cost, high oral bioavailability, and long duration of action; it is also the only long acting opioid available in a liquid formulation. (See 'Methadone' above.)
However, given the complexity of this drug's pharmacokinetic profile, a change from any of the pure mu agonist drugs to methadone is the most challenging aspect of opioid rotation, and the optimal way to switch is debated. It is clear that the ratios that appear on standard equianalgesic dose tables, which were derived from studies of patients receiving relatively low doses, may be far from the actual methadone dose required to achieve a good outcome. In one study, for example, there was no correlation between high morphine milligram equivalent (MME) doses (ie, >1200 mg/day) and the final methadone dose after stabilization in patients being rotated to methadone . The authors suggested a fixed maximum methadone dose of no more than 30 mg/day for patients receiving >1200 mg/day of morphine or MMEs.
We agree with guidelines from an expert panel, which outlined the following approach to dosing of methadone in opioid-tolerant patients :
•For patients receiving <60 mg oral morphine per day or equivalent (OME), the initial methadone dose should be no more than 7.5 mg oral methadone daily (eg, 2.5 mg three times daily).
•For patients receiving 60 to 199 mg OMEs and <65 years of age, use a 10:1 conversion (ie, 10 mg OME:1 mg oral methadone).
•For patients receiving ≥200 mg OME and/or patients >65 years of age, use a 20:1 conversion (ie, 20 mg OME:1 mg oral methadone).
•These and other guidelines also recommend converting to a methadone dose no greater than 30 to 40 mg per day, regardless of the previous opioid dose .
•The methadone dose should not be increased before five to seven days, and should not be increased by more than 5 mg/day up to 30 to 40 mg/day, and then can be increased by 10 mg/day (after five to seven days).
There are two dominant strategies for introducing methadone: the "stop and go" approach, where the current opioid is immediately replaced by methadone, and the three-day switch, where the dose of the current opioid is reduced step-wise by one-third each day, and substituted with one-third of the equianalgesic dose of methadone, over three days [132-137]. There is insufficient evidence to select one strategy preferentially over another . The “stop and go” approach may increase the risk of poorly controlled pain, particularly when pain is severe. If there is concern about this, a PRN (q4h) rescue dose of a short-acting opioid (such as morphine or hydromorphone at a dose equianalgesic to one-sixth of the prior total daily dose) may be added to the starting methadone dose. Switching over a three-day period is probably a preferable strategy as it may avoid methadone accumulation and toxicity, particularly in patients on high doses of opioids and will avoid major pain exacerbation caused by stopping all the current opioid before the methadone levels are adequate to provide sufficient analgesia [10,12,139].
Switching from methadone — There have been no studies of approaches to increase the safety and efficacy of rotation from methadone to another pure mu agonist opioid The switch must begin with the calculated equianalgesic dose of the new opioid.
Many clinicians use a 1:3 conversion rate from methadone to oral morphine, as suggested by McPherson . As an example, an individual receiving 7.5 mg of methadone twice daily would receive an initial dose of 45 mg (15 X 3) oral morphine per day.
The methadone is stopped concurrent with initiation of the new drug, but monitoring during the next few days is essential, given the relatively long half-life of methadone. As methadone levels decline, the initial dose of the new drug may require substantial up-titration.
In the absence of studies demonstrating the safety and efficacy of rotation from methadone to other opioids, we would urge caution when using this approach if the dose of methadone is relatively high (eg, above 60 to 80 mg per day) and suggest obtaining a consultation from a palliative care clinician or anesthesia pain specialist before attempting a transition. If none is available, we recommend calculating the anticipated total dose of the new opioid that will be needed and providing one-half of that dose as a fixed scheduled dose and the other one half on an "as needed" basis in the first 24 to 48 hours.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care" and "Society guideline links: Neuropathic pain" and "Society guideline links: Cancer pain".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Managing pain when you have cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Role of opioids – Opioids are widely used for treatment of cancer pain because of their safety, multiple routes of administration, ease of titration, reliability, and effectiveness for all types of pain (ie, somatic, visceral, and neuropathic).
●Choice of initial opioid
•The management of chronic cancer pain usually involves the long-term administration of pure mu receptor agonists (table 2 and table 3). (See 'Opioid drugs used in cancer pain management' above.)
•The oral and transdermal routes are preferred for treatment of chronic cancer pain. (See 'Selecting the route of administration' above.)
•For most patients with moderate to severe pain, we would choose initial treatment with morphine, oxycodone, hydromorphone, oxymorphone, or transdermal fentanyl. (See 'Pure mu agonists commonly used for cancer pain' above.)
Other acceptable options are transdermal buprenorphine or a mixed-mechanism drug such as tramadol or tapentadol. (See 'Buprenorphine' above and 'Mixed-mechanism drugs: Tramadol and tapentadol' above.)
Because of genetic variation in metabolism of codeine and an inability to predict drug effects, we suggest not using codeine in this setting (Grade 2B). We also suggest not using meperidine because of toxicity concerns (Grade 2B). (See 'Pure mu agonists rarely used for cancer pain' above.)
•If a short-acting mu agonist is selected, morphine has the longest history of use for the treatment of cancer pain and is usually considered the standard for comparison across opioid drug classes. However, any of the single entity drugs can be selected (table 3), and there is no evidence to suggest superior efficacy or tolerability for any one agent over another in most circumstances. However:
In the setting of poor gastrointestinal tract absorption or dysphagia, and for patients in whom constipation has been or is expected to be difficult to manage, we suggest transdermal fentanyl over an orally administered opioid (Grade 2B). (See 'Selecting the opioid' above and 'Selecting the route of administration' above.)
For patients with kidney impairment, we suggest hydromorphone or fentanyl rather than morphine or oxycodone (Grade 2C). (See 'Patients with kidney impairment' above.)
•Lower initial starting doses for most opioids are warranted in patients with chronic liver disease, and clinicians should be cautious prescribing opioids at "regular" dosing intervals until patients have demonstrated the lack of toxicity at the chosen dosing interval. As the liver disease progresses, prolonged dosing intervals may be needed. (See 'Patients with chronic liver disease' above.)
•Given the challenges inherent in the safe prescribing of methadone, the drug should not be administered, without assistance, by clinicians who are unfamiliar with its unique pharmacology. It is usually considered for a trial after treatment with one or more alternative pure mu agonist opioids has been ineffective. If the clinician is not clear about the procedures that should be followed to ensure the safe use of methadone (starting dose, monitoring, timing of dose escalation, etc), it is best to seek the help of a palliative care consultant before starting this therapy. (See 'Methadone' above.)
●Titration and switch to a long-acting formulation
•Following selection of a starting opioid dose, adjustment is almost always required. Continuous or frequently recurrent pain is most effectively managed with a fixed schedule, "around-the-clock" opioid regimen. Although the absolute dose of the opioid is inconsequential as long as the balance between analgesia and side effects remains acceptable for the patient, the need to titrate to relatively high doses should be accompanied by careful reassessment of the pain and drug effects. (See 'Dose titration' above.)
•If a patient is needing several doses of a short-acting opioid per day (or if a bedtime dose does not permit uninterrupted sleep through the night), a switch to a long-acting modified-release formulation can improve convenience and adherence (table 2).
●Managing breakthrough pain
•Patients with breakthrough pain should be offered a short-acting supplemental opioid on an as needed basis in conjunction with a fixed scheduled long-acting drug. The rescue drug is typically a single entity oral formulation, such as immediate release morphine, oxycodone, hydromorphone, or oxymorphone. A typical dose chosen for rescue is 5 to 15 percent of the basal daily requirement of opioid. (See 'Management of breakthrough pain' above.)
•Breakthrough pain may also be targeted with one of the newer rapid-onset, transmucosal fentanyl. Due to cost and limited experience, the transmucosal drugs are generally considered only after a patient has demonstrated a poor response to an oral rescue dose. If this approach is chosen, the initial rescue dose should be one of the lowest commercially available doses and not based upon the basal daily opioid requirement.
•For patients with severe pain, rapid titration of the opioid dose may be achieved using intravenous dosing at short intervals. A technique for accomplishing this involves the use of a patient-controlled analgesia (PCA) pump to administer a continuous infusion of opioid by either the intravenous or subcutaneous route, plus intermittent bolus "rescue doses." The intravenous route has the fastest onset of action. (See 'Subcutaneous and intravenous administration' above.)
●Managing refractory pain – Several options are available for patients who develop treatment-limiting side effects during opioid dose titration (table 12).
•One approach, opioid rotation, may improve the balance between pain relief and side effects. (See 'How to perform opioid rotation' above.)
When switching between opioids, equianalgesic dose tables (table 2 and table 3 and table 10) have been developed as a means for comparing potencies between opioids. However, application of the ratios in the equianalgesic dose table to the clinical setting is limited by incomplete cross-tolerance and other factors. Clinical guidelines have been developed that incorporate reductions in the calculated equianalgesic dose based upon specific patient characteristics; clinical judgment must be used to apply them (table 13). (See 'Equianalgesic opioid dose conversion' above.)
Conversion to and from methadone requires special care given the uncertainty as to the appropriate ratio to use in conversion from another pure mu agonist to methadone. Initially, when transitioning to methadone from an alternative opioid, we suggest that the calculated equianalgesic dose (table 3) be reduced by 75 to 90 percent (table 13) . Regardless of the oral morphine equivalent dose, we would not initiate methadone at a dose higher than 30 mg/day. (See 'Switching to methadone' above and 'Switching from methadone' above.)
•Another approach that could be considered in patients who have specific types of pain for which opioid therapy alone is frequently ineffective (eg, neuropathic pain) is the use of adjuvant analgesics in conjunction with opioid therapy. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain'.)
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