Cancer Pain (PDQ®) 3/4 —Health Professional Version - National Cancer Institute

Cancer Pain (PDQ®)—Health Professional Version - National Cancer Institute

Cancer Pain (PDQ®)–Health Professional Version

Pharmacologic Therapies for Pain Control

In This Section

• Acetaminophen and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
• Opioids
  • General principles
  • Rapid-onset fentanyl formulations
  • Methadone
  • Adverse effects
  • Opioid rotation
  • Barriers related to opioid use
  • Liver disease
  • Renal insufficiency
  • Opioids and risk of addiction
• Gabapentin and Pregabalin
• Venlafaxine and Duloxetine
• Tricyclic Antidepressants (TCAs)
• Corticosteroids
• Bisphosphonates and Denosumab
• Ketamine

Acetaminophen and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Often initiated when an individual has mild pain, acetaminophen and NSAIDs are useful in managing moderate and severe pain as adjunct agents to opioids. No single NSAID is preferred over others, and all are better than placebo for analgesia.[1] As opioid adjuncts, acetaminophen and NSAIDs have shown benefit both in improved analgesia and in decreased opioid use. These agents are used with care or perhaps avoided in patients who are elderly or have renal, hepatic, or cardiac disease.[1] (Refer to the Geriatric cancer patients section in the Treatment of Pain in Specific Patient Populations section of this summary for more information.)

While acetaminophen and NSAIDs provide analgesia on their own, a number of randomized controlled trials have reported that the addition of either agent to opioids may improve pain control and decrease opioid need in cancer patients.[2-4] However, these benefits were not consistently observed across trials.[5,6]

High-potency NSAIDs such as ketorolac and diclofenac are more studied and have shown benefit in the management of cancer pain, but there are no comparative data with older agents to show superiority of one product over others. Prominent side effects are gastrointestinal irritation, ulcer formation, and dyspepsia, with other side effects of concern being cardiotoxicity, nephrotoxicity, hepatotoxicity, and hematologic effects.[7,8] Cyclooxygenase-2 (COX-2)–specific agents such as celecoxib may have a more favorable gastrointestinal side effect profile at a higher monetary cost.[7] Long-term safety and efficacy data remain unclear.

Table 1. Acetaminophen and Selected Nonsteroidal Anti-inflammatory Analgesics

Drug	Dosage	Comments	Reference(s)
COX-2 = cyclooxygenase-2; GI = gastrointestinal; IM = intramuscular; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth.
Acetaminophen	<4,000 mg/d	Dosed every 4 to 8 hours, depending on dose and product used.	[2]
Celecoxib	200–400 mg/d	COX-2 specific. Minimal antiplatelet effects compared with nonselective NSAIDs.	[7]
Diclofenac	100–200 mg/d	Available as immediate- and delayed/extended–release products.	[9]
Ibuprofen	600–2,400 mg/d		[9]
Ketoprofen	100–300 mg/d	Available as parenteral in some parts of the world, which may be preferred.	[7,10]
Ketorolac	40–60 mg/d, generally dosed every 6 hours	Parenteral (IV, IM) ketorolac is used ≤5 days because of concerns about GI adverse events. May also be given PO.	[7]

Opioids

General principles

The use of opioids for the relief of moderate to severe cancer pain is considered necessary for most patients.[1] For moderate pain, weak opioids (e.g., codeine or tramadol) or lower doses of strong opioids (e.g., morphine, oxycodone, or hydromorphone) are often administered and frequently combined with nonopioid analgesics. For severe pain, strong opioids are routinely used; although no agent has shown itself to be more effective than another, morphine is often considered the opioid of choice because of provider familiarity, broad availability, and lower cost.[1] In one well-designed review, most individuals with moderate to severe cancer pain obtained significant pain relief from oral morphine.[11] One study has also noted that low-dose morphine (up to 30 mg orally per day) provided better analgesia than did weak opioids (codeine, tramadol).[12]

Management of acute pain begins with an immediate-release opioid formulation. Once pain is stabilized, the opioid consumption over the past 24 hours is then converted to a modified-release or longer-acting opioid on the basis of the patient’s 24-hour opioid consumption (measured in terms of morphine equivalent daily dose [MEDD]). Randomized controlled trials have shown that long-acting opioids given every 12 hours provide efficacy similar to that of scheduled short-acting opioids given every 4 hours.[13,14] Use of the immediate-release product is continued for management of breakthrough pain.[1] During ongoing pain management, the immediate-release opioids inform the titration of long-acting medication. Rapid-acting oral, buccal, sublingual, transmucosal, rectal, and intranasal products are all acceptable for treatment of breakthrough pain. In people unable to take oral medications, a subcutaneous method of delivery is as effective as the intravenous route for morphine and hydromorphone.

Table 2. Selected Opioid Analgesics

Opioid Drug	Equianalgesic Dosing	Comments	Reference(s)
Buprenorphine	No consensus	Transdermal product and sublingual available. May cause less constipation and nausea than do other opioids.	[15-17]
Codeine	100 mg	Maximum of 360 mg/d. Used with or without acetaminophen.	[1,18]
Diamorphine	Unavailable	Used primarily in the United Kingdom.	[19]
Fentanyl	7.5 µg/h × 24 h ~ 15 mg oral morphine/day	Delivered transdermally, transmucosally, or intravenously. Cachectic patients have decreased absorption from transdermal patch.	[18,20,21]
Hydrocodone	10 mg	Generally used with acetaminophen, for moderate pain only.	[22]
Hydromorphone	3 mg		[10]
Methadone	3 mg (equianalgesic ratio varies widely by dose)	Used primarily for severe pain in non–opioid-naïve patients. Unusual pharmacokinetics require experienced practitioner.	[1]
Morphine	15 mg	Randomized trials supporting use. First-choice opioid because of familiarity, availability, and cost.	[1,18]
Oxycodone	10 mg	Randomized trials supporting use.	[18]
Oxymorphone	5 mg		[10]
Tapentadol	75 mg	Similar to morphine 40–100 mg.	[23]; [24][Level of evidence: I]
Tramadol	150 mg	Use at <400 mg/d with or without acetaminophen. Used for moderate pain.	[1]

Table 3. Routes of Analgesic Medication Administration

Route	Agent	Comments	Reference(s)
NSAIDs = nonsteroidal anti-inflammatory drugs.
Buccal	Fentanyl	Used primarily for breakthrough pain.	[25]
Epidural	Opioids, local anesthetics	Consider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics.	[1]
Intramuscular injection	Opioids, acetaminophen, ketorolac	Typically avoided because of pain from injection.	[10]
Intranasal	Fentanyl	Onset faster than that of transmucosal fentanyl or oral morphine. Used for breakthrough pain.	[25]
Intrathecal	Opioids	Consider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics.	[1]
Intravenous	Most strong opioids (except oxycodone) and some NSAIDs	Availability varies by world region.	[10]
Oral	Most opioids except fentanyl and buprenorphine	Most common and preferred method of administration.	[10]
Rectal	Morphine, methadone	Onset similar to that of oral; possibly better absorption. May be useful for pediatric and end-of-life patients.	[1]
Subcutaneous	Morphine, diamorphine, fentanyl, hydromorphone, ketoprofen, methadone	Benefit similar to that of intravenous; considered an alternative if no oral capacity.	[1,2,26]
Sublingual	Fentanyl, buprenorphine	Used primarily for breakthrough pain.	[16,25]
Topical	Lidocaine	Primarily application of topical anesthetics.	[10]
Transdermal	Fentanyl, buprenorphine	Efficacy similar to that of oral agents for moderate to severe pain in opioid-naïve patients.	[1]
Transmucosal	Fentanyl	Used primarily for breakthrough pain.	[25]

Rapid-onset fentanyl formulations

Rapid-onset opioids are developed to provide fast analgesia without using a parenteral route. Fentanyl, a synthetic opioid 50 to 100 times more potent than morphine, is available in a variety of delivery methods to offer additional options for management of breakthrough pain.[27] Along with rapid onset of action, these products avoid first-pass hepatic metabolism and intestinal digestion.

All rapid-acting fentanyl products are intended for use only in patients already tolerant to opioids and are not initiated in the opioid naïve. However, none are bioequivalent to others, making dose interchange complicated and requiring dose titration of each product individually, without regard to previous doses of another fentanyl product. The dose titration schedule is unique to each product, and it is critical that product information is reviewed individually when each product is used. The risk of addiction with these rapid-onset agents has not been elucidated. In the United States, prescription of these agents requires enrollment in the U.S. Food and Drug Administration’s (FDA’s) Risk Evaluation and Mitigation Strategies (REMS) program.

Table 4. Routes of Fentanyl Administration

Drug	Starting Dose (µg)	Tmax(median, minutes)	Comments	Evidence
DB = double blinded; PC = placebo controlled; RCT = randomized controlled trial; Tmax = time to maximum blood concentration.
Transmucosal fentanyl lozenges (Actiq, generic)	200	20–40	Lozenge on stick, rubbed against cheek. Sugar content may increase dental caries.	Multiple RCTs showing benefit over placebo and oral morphine.
Fentanyl buccal tablet (Fentora)	100, 200, or 400	35–45	Absorption may be affected by mucositis. Before use, wet mouth if dry.	RCT showing benefit over placebo, and open-label study showing benefit for pain rescue; more rapid than oxycodone.
Fentanyl buccal film (Onsolis)	200	60	Before use, wet mouth if dry.	DB, PC, RCT showing benefit.
Fentanyl nasal spray (Lazanda)	100	15–21	Vial contains residual fentanyl when empty, requiring special disposal. Do not use with decongestant sprays.	DB, PC, RCT showed benefit. Open-label RCT showed benefit over transmucosal fentanyl and oral morphine.
Fentanyl sublingual spray (Subsys)	100	40–75	Contains residual fentanyl when empty, requiring special disposal.	Open-label and PC RCT showing benefit.
Fentanyl sublingual tablet (Abstral)	100	30–60	Absorption may be affected by mucositis. Before use, wet mouth if dry.	Multiple PC RCTs showing benefit.

Methadone

Methadone is both a mu-receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist; can be given via multiple routes (oral, intravenous, subcutaneous, and rectal); has a long half-life (13 to 58 hours) and rapid onset of action; and is inexpensive, making it an attractive option for cancer pain control. Because of its NMDA properties, methadone may be particularly useful for the management of opioid-induced neurotoxicity, hyperalgesia, and neuropathic pain, although further studies are needed to confirm these theoretical benefits. Methadone is safer for patients with renal failure, and is preferred for those with known opioid allergies because it is a synthetic opioid. However, methadone also has several distinct disadvantages, including drug interactions, the risk of QT prolongation, and a variable equianalgesic ratio, making rotation more challenging.

Given the complexities related to methadone administration, it is important that this opioid be prescribed by clinicians with experience who are able to provide careful monitoring. Referral to a pain specialist or a palliative care team may be indicated.

Methadone is metabolized by CYP3A4 and CYP2D6. CYP3A4 inducers (e.g., certain anticonvulsants and antiretroviral agents) can potentially reduce its analgesic effect.[28] In contrast, substrates/inhibitors of CYP3A4 may increase methadone’s activity, including side effects. For clinicians, the potential for significant drug-drug interactions may mean that some medications need to be replaced and that patients need extra monitoring. Furthermore, because methadone is a substrate of P-glycoprotein, medications that inhibit the activity of this transporter, such as verapamil and quinidine, may increase methadone’s bioavailability.

Methadone is associated with QT prolongation. This risk increases in patients receiving high doses (especially >100 mg/day) or with preexisting risk factors, including treatment with some anticancer agents. For patients with risk factors for QT prolongation, it is important to conduct a baseline electrocardiogram (ECG) before treatment with methadone. A follow-up ECG is recommended at 2 to 4 weeks after methadone initiation if the patient has known risk factors, with the occurrence of new risk factor(s) for all patients, and when the doses of methadone reach 30 to 40 mg/day and 100 mg/day for all patients regardless of risk.[29]

One group of investigators reported that the conversion ratio for switching from oral morphine to methadone varied between 2.5 and 14.3, with greater potency as the MEDD increased.[30] In a small retrospective study, other investigators found that the equianalgesic ratio for switching from methadone to oral morphine was 4.7 for oral methadone and 13.5 for intravenous methadone.[31]

A systematic review has highlighted three approaches to methadone conversion in the literature;[32,33] however, the evidence was low, making it difficult to conclude which approach was superior. Rapid titration of methadone may result in delayed respiratory depression because of its long half-life.[34]

Adverse effects

Adverse effects from opioids are common and may interfere with achieving adequate pain control. However, not all adverse effects are caused by opioids, and other etiologies also need to be evaluated. Examples of relevant factors include symptoms from disease progression, comorbid health conditions, drug interactions (including adjuvant analgesics), and clinical conditions such as dehydration or malnutrition.[35] In general, options for addressing adverse effects associated with opioids include aggressive management of the adverse effects, opioid rotation, or dose reduction. In most instances, definitive recommendations are not possible.

Table 5. Relative Prevalence of Opioid Adverse Effects by Duration of Usea

Adverse Effect	Relative Prevalenceb		Comments
	Acute Usec	Chronic Used
aThe reported prevalence may differ on the basis of opioid choice, dose, route, and duration of use.
bRelative prevalence: (–) absent; (+) rare; (++) less common; (+++) common.
cAcute use defined as use for ≤2 weeks, as-needed use, and upon significant dose increase.
dChronic use defined as consistent use for >2–3 months at stable doses.
Cardiovascular
Hypotension	+	+	Mostly with intravenous opioids.
Central nervous system
Sedation	+++	+	More common upon opioid initiation and dose increase.[36]
Dizziness	++	+	[10]
Delirium/hallucinations	+	+	[10]
Impaired cognitive status	++	+	[10]
Sleep disturbances	++	+	[10]
Gastrointestinal
Nausea	+++	+	Slow upward dose titration reduces risk. Lower rates with hydromorphone vs. morphine.[36,37]
Vomiting	++	+	[10]
Constipation	+++	+++	[38]
Autonomic nervous system
Xerostomia	+++	+	[10]
Bladder dysfunction/urinary retention	+	+	[10]
Respiratory
Respiratory depression	+	–	Extremely rare if used appropriately.[36]
Dermatologic
Pruritus	++	–	More common with spinal analgesia.[36]
Miscellaneous
Hyperalgesia	–	+	Observed more commonly with opioid-induced neurotoxicity. May be more common with morphine and hydromorphone.[39]
Opioid endocrinopathy/hypogonadism	–	+	[40,41]
Hypoglycemia	+	+	May be observed among patients on tramadol or methadone. More common among diabetics.

Central nervous system (CNS) effects

Adverse effects on the CNS may be attributed to opioids’ anticholinergic activity or direct effect on neurons.[42,43] Sedation and drowsiness are common but typically transient adverse effects. Patients who have persistent problems may benefit from opioid rotation. Methylphenidate has been proposed as an intervention to reduce opioid-induced sedation.[44,45] The effects of opioids on cognitive or psychomotor functioning are not well established. Given the incidence of sedation, caution is exercised when an opioid is initiated or when dose escalation is required. There is less evidence, however, that patients on chronic stable doses exhibit cognitive or motor impairment.[46]

Delirium is associated with opioids but is typically multifactorial in origin.[47] In one retrospective study, 80% of the delirium cases were not related to opioids.[48] (Refer to the Delirium section in the PDQ summary on Last Days of Life for more information about the management of delirium.)

Respiratory depression

Opioid-induced respiratory depression may be caused by a blunting of the chemoreceptive response to carbon dioxide and oxygen levels and altered mechanical function of the lung necessary for efficient ventilation and gas exchange.[49] Opioid-induced respiratory depression may manifest through decreased respiratory rate, hypoxemia, or increases in total exhaled carbon dioxide.[50] The prevalence of respiratory depression is not known but rarely occurs with proper opioid use and titration.[51-54]

If respiratory depression is thought to be related to opioids (e.g., in conjunction with pinpoint pupils and sedation), naloxone, a nonselective competitive opioid antagonist, may be useful; however, careful titration should be considered because it may compromise pain control, and may precipitate withdrawal in opioid-dependent individuals. Because of methadone’s long half-life, naloxone infusion may be required for respiratory depression caused by methadone.

Nausea and vomiting

Opioid-induced nausea occurs in up to two-thirds of patients receiving opioids, and half of those patients will experience vomiting.[55] Opioids cause nausea and vomiting via enhanced vestibular sensitivity, via direct effects on the chemoreceptor trigger zone, and by causing delayed gastric emptying.[56] Antiemetics may be started up front in patients at risk of developing nausea, or instituted once symptoms occur. Tolerance to opioid-induced nausea and vomiting (OINV) may develop, and symptoms should resolve within 1 week. If symptoms persist despite treatment with antiemetics, opioid rotation can be considered, or other causes of nausea can be investigated.

OINV is treated with many of the same antiemetic drugs that are used for chemotherapy-induced nausea and vomiting. Although many antiemetic regimens have been proposed for OINV, there is no current standard.[56] The chemoreceptor trigger zone is stimulated by dopamine, serotonin, and histamine. Metoclopramide may be a particularly attractive option because of its dual antiemetic and prokinetic effects. Other dopamine antagonists such as prochlorperazine, promethazine, and olanzapine have been used to treat OINV. For patients whose nausea worsens with positional changes, a scopolamine patch has been found effective. Serotonin antagonists such as ondansetron may be used; however, they could worsen constipation among patients already taking opioids.

Constipation

Constipation is the most common adverse effect of opioid treatment, occurring in 40% to 95% of patients.[57] It can develop after a single dose of morphine, and patients generally do not develop tolerance to opioid-induced constipation. Chronic constipation can result in hemorrhoid formation, rectal pain, bowel obstruction, and fecal impaction.

Opioids cause constipation by decreasing peristalsis, which occurs by reducing gastric secretions and relaxing longitudinal muscle contractions, and results in dry, hardened stool.[58] Constipation is exacerbated by dehydration, inactivity, and comorbid conditions such as spinal cord compression. Patients are encouraged to maintain adequate hydration, fiber intake, and regular exercise, in addition to taking laxatives.

A scheduled stimulant laxative is started with opioid initiation. The addition of a stool softener offers no further benefit.[59,60] Laxatives are titrated to a goal of one unforced bowel movement every 1 to 2 days. If constipation persists despite prophylactic measures, then additional assessment of the cause and severity of constipation is performed. After obstruction and impaction are ruled out, other causes of constipation (such as hypercalcemia) are treated.

There is no evidence to recommend one laxative class over another in this setting. Appropriate drugs include bisacodyl, polyethylene glycol, magnesium hydroxide, lactulose, sorbitol, and magnesium citrate. Suppositories are generally avoided in the setting of neutropenia or thrombocytopenia.

Methylnaltrexone and naloxegol are peripherally acting opioid antagonists approved for the treatment of opioid-induced constipation in patients who have had inadequate response to conventional laxative regimens. Laxatives are discontinued before peripherally acting opioid antagonists are initiated. These agents are not used if postoperative ileus or mechanical bowel obstruction is suspected.[61,62]

Hyperalgesia

Defined as “the need for increasingly high levels of opioids to maintain pain inhibition after repeated drug exposure,” opioid-induced hyperalgesia (OIH) is a clinical phenomenon that has been differentiated from opioid tolerance in the research literature.[39,63-66]

The clinical relevance needs to be further studied, and this issue may be underappreciated in clinical practice.

A thorough history and physical are appropriate if OIH is suspected. Changes in pain perception and increasing opioid requirements may be caused by OIH, opioid tolerance, or disease progression. There is no standard recommendation for the diagnosis and treatment of OIH. A trial of incremental opioid dose reductions may lead to an improvement in pain from OIH. However, this may be psychologically distressing to oncology patients who require opioid treatment. Opioid rotation is a strategy frequently employed if opioid tolerance has occurred. Methadone is an ideal opioid to switch to, given its mechanism of action as an opioid receptor agonist and NMDA receptor antagonist. Given the similarities between OIH and neuropathic pain, the addition of an adjunctive medication such as pregabalin has been recommended.[39]

Opioid endocrinopathy

Opioid endocrinopathy (OE) is the effect of opioids on the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis over the long term. Opioids act on opioid receptors in the hypothalamus, decreasing the release of gonadotropin-releasing hormone.[67] This results in a decreased release of luteinizing hormone and follicle-stimulating hormone, and finally a reduction of testosterone and estradiol released from the gonads. These effects occur in both men and women.[41] Patients may present with symptoms of hypogonadism such as decreased libido, erectile dysfunction, amenorrhea or irregular menses, galactorrhea, depression, and hot flashes.

Treatment for OE is not well established. One group of investigators performed a 24-week, open-label pilot study of a testosterone patch in 23 men with opioid-induced androgen deficiency and reported an improvement in androgen deficiency symptoms, sexual function, mood, depression, and hematocrit levels.[68] There was no change in opioid use. Men and women with OE may be offered hormone replacement therapy after a thorough risk-benefit discussion. Testosterone replacement is contraindicated in men with prostate cancer; estrogen replacement therapy may be contraindicated in patients with breast and ovarian cancer and has serious associated health risks.

Opioid-induced immunological changes

Opioids have immunomodulatory effects through neuroendocrine mechanisms and by direct effects on opioid receptors on immune cells.[69] Opioids can alter the development, differentiation, and function of immune cells, causing immunosuppression.[40] Different opioids cause varying effects on the immune system. In mouse and rat models, methadone is less immunosuppressive than morphine. In contrast, tramadol improves natural killer cell activity. Further research is needed to determine the true clinical significance of opioid-induced immunosuppression, such as the risk of infections.

Opioid rotation

Opioid rotation or switching may be needed when one of the following occurs:[70,71]

• The patient is experiencing side effects beyond what can be managed with simple measures. For example, the presence of opioid-induced neurotoxicity (e.g., myoclonus, hallucinations, vivid dreams, hyperalgesia, or delirium) almost always warrants opioid rotation.
• Pain control remains suboptimal despite an active effort to titrate the opioid dose. Ideally, the opioid is increased to the highest tolerable level for the patient before switching occurs, to avoid abandoning an opioid prematurely.
• A switch is needed for logistical reasons, such as change of the route of administration (e.g., from intravenous to oral in preparation for discharge or from oral to transdermal due to severe odynophagia); the need to minimize toxicities with the onset of renal/hepatic failure (e.g., from morphine to fentanyl or methadone); and cost considerations (e.g., long-acting oxycodone to methadone).

The selection of a target opioid depends on the reason for rotation. All strong opioids have similar efficacy and side effect profiles at equianalgesic doses. Because of the lack of predictors for specific opioids, empiric trials are needed to identify the ideal opioid. If opioid-induced neurotoxicity is the reason for switching, it may not matter which opioid is switched to, as long as it is a different agent. Importantly, patient preference, history of opioid use, route of administration, and cost are necessary considerations before the final choice is made.

A study of opioid rotation in the outpatient palliative care setting revealed that approximately one-third of 385 consecutive patients needed an opioid rotation, mostly for uncontrolled pain (83%) and opioid-induced neurotoxicity (12%).[72] The success rate was 65%, with a median pain improvement of two points out of ten (minimal clinically important difference is one point).[73]

Barriers related to opioid use

The barriers to appropriate use of opioids in the treatment of cancer pain include misunderstandings or misapprehensions about opioids by health care providers, patients, and society. One group of investigators surveyed 93 patients with cancer cared for in an academic practice in Australia to understand patient-level barriers to the use of opioids.[74] One-third of the patients reported high levels of pain that adversely affected activity, mood, sleep, and enjoyment of life. High percentages of patients reported concerns about addiction (76%) or side-effects (67%). In addition, patients expressed concerns that the pain represented disease progression (71%), that they were distracting the doctor (49%), or that they would not be seen as a “good patient” (46%).[74] Patients with more severe pain were more likely to express concerns about side effects and were less likely to use unconventional approaches to pain control. Results were similar to those of a survey of American patients from the previous decade.[75]

Physician-perceived barriers to opioid prescribing tend to parallel those of the patient.[76] Physicians and other health care providers have beliefs about addiction, for example, that inhibit prescribing. In addition, there are significant knowledge deficits that lead to inadequate dosing of opioids and unaddressed side effects.

Other barriers to opioid prescribing and compliance are the costs of abuse and misuse of opioids, which are estimated to be in the tens of billions of dollars and include increased mortality rates.[77] As a consequence, many states have developed prescription drug monitoring programs, and the FDA requires REMS for certain opioids (such as rapid-onset fentanyl products), which could serve as an additional barrier to opioid prescribing. Other barriers include poor or limited formulary and reimbursement for opioids.

Liver disease

The liver plays a major role in the metabolism and pharmacokinetics of opioids and most drugs. The liver produces enzymes involved in two forms of metabolism: phase 1 metabolism (modification reactions, CYP) and phase 2 metabolism (conjugation reactions, glucuronidation).[28]

Methadone and fentanyl are unaffected by liver disease and are drugs of choice in patients with hepatic failure.[78,79]

Morphine, oxymorphone, and hydromorphone undergo glucuronidation exclusively. CYP2D6 metabolizes codeine, hydrocodone, and oxycodone; CYP3A4 and CYP2D6 metabolize methadone; and CYP3A4 metabolizes fentanyl.[28] Hepatic impairment affects both CYP enzymes and glucuronidation processes. Prescribing information recommends caution when prescribing opioids for patients with hepatic impairment.

In cirrhosis, the elimination half-life and peak concentrations of morphine are increased.[80] Moderate to severe liver disease increases peak levels and the area under the curve (AUC) for both oxycodone and its chief metabolite, noroxycodone.[81] Peak plasma concentrations and AUC of another active metabolite, oxymorphone, are decreased by 30% and 40%, respectively.[81]

Although oxymorphone itself does not undergo CYP-mediated metabolism, a portion of the oxycodone dose is metabolized to oxymorphone by CYP2D6. Failure to convert oxycodone to oxymorphone may result in accumulation of oxycodone and noroxycodone, with an associated increase in adverse events. Hepatic disease increases the bioavailability of oxymorphone as liver function worsens.[82]

Renal insufficiency

Renal insufficiency affects the excretion of morphine, oxycodone, hydromorphone, oxymorphone, and hydrocodone. Methadone and fentanyl are safe to use in patients with renal failure, although there is some evidence that the hepatic extraction of fentanyl is affected by uremia.[83]

When patients with renal insufficiency receive hydromorphone and morphine, both hydromorphone and morphine metabolites accumulate, with the potential to cause neuro-excitatory adverse effects. Morphine, which has a higher risk of drug and metabolite accumulation, may be used in patients with mild renal failure but requires dosing at less-frequent intervals or at a lower daily dose to provide benefit with adequate safety.[81] In patients with stage III to stage IV chronic kidney disease (glomerular filtration rate <59 cc/min), morphine may not be desirable.[81]

There are conflicting reports about the safety of hydromorphone in patients with renal failure. One case series suggests adverse effects increasing when hydromorphone is given by continuous infusion to patients with renal failure.[84] Other series suggest that it is safe to use.[85] Although renal impairment affects oxycodone more than it does morphine, there is no critical accumulation of an active metabolite that produces adverse events.[81]

Opioids and risk of addiction

In the United States, the number of opioid prescriptions and deaths from painkillers quadrupled between 1999 and 2013.[86] In 2013 alone, two million Americans were estimated to have either abused or been dependent on opioids, with 22,767 deaths related to prescription drug overdose. Although most cancer patients prescribed opioids are using them safely, one study estimated that up to 8% of cancer patients may be addicted to opioids.[87] Thus, it is important for clinicians treating cancer patients for pain to provide careful monitoring and to adopt safe opioid-prescribing practices.[88]

Most patients begin opioid therapy after an acute event such as a pain crisis from cancer progression or surgery.[89] Sometimes cancer treatment and its effects will lead to increased opioid use, with approximately 10% of patients continuing to take the equivalent of 30 mg of hydrocodone per day at 1 year post–curative surgery.[90] All patients taking opioids require assessment for risk of abuse or addiction.[89]

Addiction is defined as continued, compulsive use of a drug despite harm. Many other conditions may be misidentified as addiction, and it is important that clinicians distinguish between the two.[91] These conditions include:[92,93]

• Aberrant behavior: a behavior outside the boundaries of the agreed-on treatment plan that is established as early as possible in the doctor-patient relationship.[94]
• Chemical coping: the use of opioids to cope with emotional distress, characterized by inappropriate and/or excessive opioid use.[93]
• Diversion: redirection of a prescription drug from its intended user to another individual.
• Misuse: inappropriate use of a drug, whether deliberate or unintentional.
• Physical dependence: condition in which abrupt termination of drug use causes withdrawal syndrome.
• Pseudo-addiction: condition characterized by behaviors such as drug hoarding that mimic addiction but are driven by a desire for pain relief; usually signals undertreated pain or anxiety that future pain will be untreated.
• Self-medication: use of a drug without consulting a health care professional to alleviate stressors or disorders such as depression or anxiety.
• Substance abuse: maladaptive pattern of substance use leading to considerable impairment or distress.
• Tolerance: phenomenon in which analgesia decreases as the body grows tolerant to a given dosage of a drug, requiring an increased dose to achieve the same analgesic effect.[92]

The following aberrant behaviors may suggest addiction or abuse; further assessment is required to make the diagnosis:

• Aggressive complaining about the need for more drugs.
• Drug hoarding during periods of reduced symptoms.
• Acquiring similar drugs from other medical sources.
• Requesting specific drugs.
• Reporting psychic effects not intended by the physician.
• Resistance to a change in therapy associated with tolerable adverse effects accompanied by expressions of anxiety related to the return of severe symptoms.
• Resistance to referral to a mental health professional.
• Unapproved use of the drug to treat another symptom or use of the drug for a minor symptom (e.g., use of fentanyl for mild headache pain).
• Unsanctioned dose escalation or other nonadherence to therapy on one or two occasions.
• Unconfirmed multiple allergies to multiple opioids.

Table 6. Risk Mitigation Tools for Evaluating Opioid Misusea

Tool	Description	Comments
aAdapted from DiScala SL, Lesé MD: Chronic pain. In Murphy JE, Lee MW, eds.: Pharmacotherapy Self-Assessment Program. Book 2: CNS/Pharmacy Practice. Lenexa, Kan: American College of Clinical Pharmacy, 2015, p. 102.
Current Opioid Misuse Measure (COMM)	17-item self-assessment tool for patients	Identifies aberrant behaviors; for those with chronic pain who are already on opioids.
Diagnosis, Intractability, Risk, Efficacy (DIRE)	8-item tool	Determines risk of long-term opioid use in those with chronic pain; evaluates regimen efficacy.
Opioid Risk Tool (ORT)	5-item tool	Predicts aberrant or drug-related behaviors.
Prescription Drug Use Questionnaire (Self-Report) (PDUQp)	31-item self-assessment tool	Evaluates and predicts opioid misuse in those with chronic pain.
Pain Medication Questionnaire (PMQ)	26-item tool	Evaluates risk of opioid misuse in those with chronic pain.
Screening Instrument for Substance Abuse Potential (SISAP)	5-item tool	Evaluates those with history of substance abuse and risk of opioid misuse; used in primary care setting.
Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1.0	24-item self-assessment	Evaluates risk of long-term opioid therapy in those with chronic pain.
Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R)	24-item self-assessment	Evaluates those already taking opioids, or those about to begin (before initiation of therapy).

Risk factors for opioid abuse include smoking, psychiatric disorders, history of childhood sexual abuse, and personal or family history of substance abuse.[91] Screening tools help in risk assessment. Common tools include the Opioid Risk Tool (ORT),[95] the Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R),[96] and the Screening Instrument for Substance Abuse Potential (SISAP).[92,97] The choice of which tool to use depends on the type of practice. The ORT is short and useful for busy practices.[92]

Risk assessment determines the structure of therapy, which can range from minimal structure to more structure. Highly structured opioid therapy requires approaches such as frequent visits, limiting pills per prescription, use of other specialists, and urine drug testing.[91] Opioid agreements outline what is expected of the patient, educate about drug storage, and delineate acceptable and unacceptable behavior.[98] Patients are taught that they must safeguard their medications “like their wallets” to protect against diversion. In addition, state guidelines for chronic opioid use, state prescription monitoring, and the use of pharmacists may reduce the potential for worsening addictive behavior.[99]

Random urine drug testing is used for patients with an inadequate response to opioid therapy and those receiving opioids long term.[100] A urine drug test demonstrating absence of prescribed opioid can be useful because it suggests either diversion or stockpiling; a urine drug test revealing concurrent use of other nonprescribed medications or illicit substances can also be informative. Because many different types of urine drug tests are available, clinicians may want to become familiar with the types and interpretation of tests available locally. A clinician’s laboratory can identify the substance in question. Clinicians use urine drug testing differently, with some requiring it at the initiation of therapy, episodically, or at the transition to long-term opioid therapy. Risk assessment helps to determine frequency of urine drug testing.[100]

Pharmacologic deterrence has emerged as another option designed to dissuade misuse and abuse by making it difficult to obtain euphoric effects from opioid use.[100] Creating barriers to increasing the bioavailability of opioids is one method of pharmacologic deterrence. Approaches have included adding an opioid antagonist to the formulation [101] or adding niacin to create a bad taste in the mouth if too many pills are taken.[102] Embedding opioid into a matrix that cannot be obtained by crushing or chemical extraction is another pharmacologic deterrent.[103]

Gabapentin and Pregabalin

Gabapentin and pregabalin are structurally related to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) but have no effect on GABA binding. Instead, they bind to the alpha2delta-1 subunit of voltage-gated calcium channels, which may result in decreased neuronal excitability in pain-associated sensory neurons. These drugs have been widely studied in the treatment of neuropathic pain syndromes (refer to the Approach to Neuropathic Pain section of this summary for more information) and as adjunctive agents with opioids.

These medications may cause sedation, dizziness, peripheral edema, nausea, ataxia, and dry mouth. Gradual upward titration of gabapentin to a maximum of 3,600 mg per day and pregabalin to 300 mg per day can help with dose-dependent sedation and dizziness. In addition, starting doses of gabapentin may be given at bedtime to assist with tolerating any sedation. Doses of both agents need to be adjusted for patients with renal dysfunction.[10,104]

Venlafaxine and Duloxetine

The antidepressant medications venlafaxine and duloxetine have demonstrated some efficacy in the treatment of neuropathic pain syndromes. Venlafaxine and duloxetine are serotonin and norepinephrine reuptake inhibitors (SNRIs) originally approved for depression; however, both are used off-label for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Both serotonin and norepinephrine have important roles in analgesia.

Common dosing for duloxetine ranges from 30 mg to 60 mg per day. Side effects include nausea, headache, fatigue, dry mouth, and constipation.[105] Duloxetine is avoided in patients with hepatic impairment and severe renal impairment, and it carries an increased risk of bleeding.

Venlafaxine inhibits serotonin reuptake more intensely at low doses, and norepinephrine more intensely at higher doses; higher doses may be necessary for relief of CIPN.[106]

Venlafaxine can be started at 37.5 mg, with a maximum dose of 225 mg per day. Adverse effects include nausea, vomiting, headache, somnolence, and hypertension at higher doses. These effects decrease with the use of the long-acting formulations. Venlafaxine is used with caution in patients with bipolar disorder or a history of seizures and is dose-adjusted for patients with renal or hepatic insufficiency. If the decision is made to discontinue venlafaxine, a slow tapering course may help to minimize withdrawal symptoms.

Tricyclic Antidepressants (TCAs)

The TCAs amitriptyline, desipramine, and nortriptyline are used to treat many neuropathic pain syndromes. These drugs enhance pain inhibitory pathways by blocking serotonin and norepinephrine reuptake.

TCAs have anticholinergic, antihistaminic, and antiadrenergic effects that result in dry mouth, drowsiness, weight gain, and orthostatic hypotension. Significant drug interactions are a concern, including interactions with anticholinergics, psychoactive medications, class IC antiarrhythmics, and selective serotonin reuptake inhibitors (SSRIs). Because of these adverse effects and drug interactions, TCAs are used with caution in elderly patients, patients with seizure disorders, and those with preexisting cardiac disease.

Corticosteroids

There is a lack of high-quality data demonstrating the efficacy of corticosteroids in treating cancer pain. A systematic review of the literature resulted in four randomized controlled trials and concluded that there is low-grade evidence to suggest corticosteroids have moderate activity in the treatment of cancer pain.[107] A small but well-designed study showed no benefit to adding corticosteroids to opioid analgesia in the short term (7 days).[108]

Despite the lack of good evidence, corticosteroids are often used in the clinical setting. Corticosteroids (dexamethasone, methylprednisolone, and prednisone) may be used as adjuvant analgesics for cancer pain originating in bone, neuropathy, and malignant intestinal obstruction. Mechanisms of analgesic action include decreased inflammation, decreased peritumoral edema, and modulation of neural activity and plasticity.[109]

Although there is no established corticosteroid dose in this setting, recommendations range from a trial of low-dose therapy such as dexamethasone 1 mg to 2 mg or prednisone 5 mg to 10 mg once or twice daily,[110] to dexamethasone 10 mg twice daily.[111] A randomized trial demonstrated that dexamethasone (8 mg on day of radiation therapy and daily for the following 4 days) reduces the incidence of pain flares, compared with placebo.[112] (Refer to the External-Beam Radiation Therapy section of this summary for more information.) Immediate side effects include hyperglycemia, insomnia, immunosuppression, and psychiatric disorders. Serious long-term effects of myopathy, peptic ulceration, osteoporosis, and Cushing syndrome encourage short-term use. If taken for more than 3 weeks, corticosteroids are tapered upon improvement in pain, if possible. If corticosteroids are to be continued long term, anti-infective prophylaxis can be considered. Dexamethasone is preferred because it has reduced mineralocorticoid effects, resulting in reduced fluid retention; however, it does exhibit cytochrome P450–mediated drug interactions.

Bisphosphonates and Denosumab

The bisphosphonate class of drugs inhibits osteoclastic bone resorption, decreasing bone pain and skeletal-related events associated with cancer that has metastasized to the bone. Pamidronate and zoledronic acid decrease cancer-related bone pain, decrease analgesic use, and improve quality of life in patients with bone metastases.[113-116] American Society of Clinical Oncology (ASCO) guidelines for the use of these bone-modifying agents in patients with breast cancer and myeloma specify they should be used not as monotherapy but as part of a treatment regimen that includes analgesics and nonpharmacologic interventions.[117,118] Bisphosphonates can cause an acute phase reaction characterized by fever, flu-like symptoms, arthralgia, and myalgia that may last for up to 3 days after administration. Additional adverse effects include renal toxicity, electrolyte imbalances, and osteonecrosis of the jaw.[119-121] Doses are adjusted for patients with renal dysfunction.

A single dose of ibandronate 6 mg was compared with a single fraction of radiation for localized metastatic bone pain in 470 prostate cancer patients.[122] Patients were allowed to cross over if they failed to respond at 4 weeks. Pain was assessed at 4, 8, 12, 26, and 52 weeks. Pain response was not statistically different between the two groups at 4 or 12 weeks; however, a faster onset of pain response was seen in the radiation therapy group. Interestingly, patients who crossed over and received both treatments had a longer overall survival than did patients who did not cross over. The authors concluded that ibandronate provides a feasible alternative to radiation therapy for the treatment of metastatic bone pain when radiation therapy is not an option.

Denosumab is a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL), prevents osteoclast precursor activation, and is primarily used in the treatment of bone metastases. A review of six trials comparing zoledronic acid with denosumab demonstrated a greater delay in time to worsening pain for denosumab (relative risk, 0.84; 95% confidence interval, 0.77–0.91).[123]

Compared with zoledronic acid, denosumab has similar adverse effects with less nephrotoxicity and increased hypocalcemia. There is no adjustment for renal dysfunction; however, patients with a creatinine clearance lower than 30 mL/min are at a higher risk of developing hypocalcemia. Denosumab may be more convenient than zoledronic acid because it is a subcutaneous injection and not an intravenous infusion; however, it is significantly less cost-effective.[124]

Ketamine

Ketamine is an FDA-approved dissociative general anesthetic that has been used off-label in subanesthetic doses to treat opioid-refractory cancer pain. A 2012 Cochrane review of ketamine used as an adjuvant to opioids in the treatment of cancer pain concluded there is insufficient evidence to evaluate its efficacy in this setting.[125]

Lack of demonstrated clinical benefit, significant adverse events, and CYP3A4-associated drug interactions limit ketamine’s utility in the treatment of cancer pain. It is an NMDA receptor antagonist that, at low doses, produces analgesia, modulates central sensitization, and circumvents opioid tolerance. However, a randomized placebo-controlled trial of subcutaneous ketamine in patients with chronic uncontrolled cancer pain failed to show a net clinical benefit when ketamine was added to the patients’ opioid regimen.[126] Adverse drug reactions include hypertension, tachycardia, psychotomimetic effects, increased intracranial and intraocular pressure, sedation, delirium, and impaired bladder function.

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