Article Tools
ASCO SPECIAL ARTICLES
Article Tools
Use of Opioids for Adults With Pain From Cancer or Cancer Treatment: ASCO Guideline
, PhD, RN1; Kari Bohlke , ScD2; Debra Barton , PhD, RN3; David S. Craig, PharmD4; Areej El-Jawahri , MD5; Dawn L. Hershman , MD, MS6; Lynn R. Kong , MD7; Geana P. Kurita, PhD, MNSc8; Thomas W. LeBlanc , MD9; Sebastiano Mercadante , MD10; Kristina L. M. Novick, MD, MS11; Ramy Sedhom , MD12; Carole Seigel, MBA13; Joanna Stimmel, PhD14; and Eduardo Bruera , MD15 Show More
Abstract
To provide guidance on the use of opioids to manage pain from cancer or cancer treatment in adults.
A systematic review of the literature identified systematic reviews and randomized controlled trials of the efficacy and safety of opioid analgesics in people with cancer, approaches to opioid initiation and titration, and the prevention and management of opioid adverse events. PubMed and the Cochrane Library were searched from January 1, 2010, to February 17, 2022. American Society of Clinical Oncology convened an Expert Panel to review the evidence and formulate recommendations.
The evidence base consisted of 31 systematic reviews and 16 randomized controlled trials. Opioids have primarily been evaluated in patients with moderate-to-severe cancer pain, and they effectively reduce pain in this population, with well-characterized adverse effects. Evidence was limited for several of the questions of interest, and the Expert Panel relied on consensus for these recommendations or noted that no recommendation could be made at this time.
Opioids should be offered to patients with moderate-to-severe pain related to cancer or active cancer treatment unless contraindicated. Opioids should be initiated PRN (as needed) at the lowest possible dose to achieve acceptable analgesia and patient goals, with early assessment and frequent titration. For patients with a substance use disorder, clinicians should collaborate with a palliative care, pain, and/or substance use disorder specialist to determine the optimal approach to pain management. Opioid adverse effects should be monitored, and strategies are provided for prevention and management.
Additional information is available at www.asco.org/supportive-care-guidelines.
Pain remains a common consequence of cancer and its treatment. Approximately 55% of those undergoing active treatment experience pain, while the prevalence is > 66% in people with advanced disease.1 In most cases, moderate-to-severe cancer pain can be effectively managed with available medications, including opioids. Opioids have long been the foundation of cancer pain management, yet serious challenges to their use exist, including a striking lack of research to guide clinical practice in this population. Compounding an insufficient scientific foundation are interventions designed to combat the current epidemic of opioid misuse and related deaths.2 Access difficulties include reduced reimbursement, high patient copays, and a lack of availability of opioids at retail pharmacies. As a result of these and other challenges, patients with cancer report stigma and concern related to opioid use.3,4 Patients express greater fear of addiction along with guilt and a sense of moral failure that they require opioids, causing some to skip a dose or take a lower dose than prescribed.4-6 All of these barriers place people with cancer at great risk of suffering uncontrolled pain.
Use of Opioids for Adults With Pain From Cancer or Cancer Treatment: ASCO Guideline
In what circumstances should opioids be used to manage cancer pain in adults, how should opioids be administered, and how should opioid adverse effects be prevented or managed?
Adults with pain from cancer or active cancer treatment.
Clinicians who provide care to adults with cancer (physicians, nurses, advanced practice providers, oncology pharmacists, and others), adults with cancer, and family members and caregivers.
An Expert Panel was convened to develop clinical practice guideline recommendations on the basis of a systematic review of the medical literature.
Question 1: In what circumstances should opioids be offered?
Recommendation 1.1. Opioids should be offered to patients with moderate-to-severe pain related to cancer or active cancer treatment unless contraindicated (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate; Strength of recommendation: Strong).
Recommendation 1.2. Prior to initiating opioid therapy, clinicians, patients, and caregivers should discuss goals regarding functional outcomes, shared expectations, and pain intensity, as well as any concerns about opioids (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Question 2: Which opioids should be offered?
Recommendation 2.1. For patients who are candidates to begin opioid treatment (Recommendation 1.1), clinicians may offer any of the opioids approved by the US Food and Drug Administration or other regulatory agencies for pain treatment (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate to low; Strength of recommendation: Weak).
Qualifying statement. The decision of which opioid is most appropriate should be based on factors such as pharmacokinetic properties, including bioavailability, route of administration, half-life, neurotoxicity, and cost of the differing drugs. Tramadol and codeine have limitations that may make them less desirable than other opioids in this setting. Tramadol is a prodrug, has limitations in dose titration related to a low threshold for neurotoxicity, and has potential interactions with other drugs at the level of cytochrome P450 (CYP) 2D6, 2B6, and 3A4.11,12 Codeine is a prodrug, requiring CYP2D6 to allow it to be metabolized to morphine to achieve analgesic effects.12
Recommendation 2.2. Clinicians with limited experience with methadone prescribing should consult palliative care or pain specialists when initiating or rotating to methadone (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Question 3: How should opioids be initiated and titrated?
Recommendation 3.1. Opioids should be initiated at the lowest possible dose to achieve acceptable analgesia and patient goals (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Recommendation 3.2. Opioids should be initiated as immediate release and PRN (as needed) to establish an effective dose, with early assessment and frequent titration (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Recommendation 3.3. Patients who have been taking other analgesics, such as nonsteroidal anti-inflammatory drugs, may continue these analgesics after opioid initiation if these agents provide additional analgesia and are not contraindicated (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Weak).
Recommendation 3.4. Evidence remains insufficient to recommend for or against the use of genetic testing, such as for polymorphism of CYP2D6, to guide opioid dosing.
Recommendation 3.5. Evidence remains insufficient to recommend any single set of ranges for dose escalation in opioid titration.
Note: In general, the minimum dose increase is 25%-50%, but patient factors such as frailty, comorbidities, and organ function must be evaluated and considered when changing doses.
Recommendation 3.6. For patients with a substance use disorder, clinicians should collaborate with a palliative care, pain, and/or substance use disorder specialist to determine the optimal approach to pain management (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Question 4: How should opioid-related adverse events be prevented or managed?
Recommendation 4. Clinicians should proactively offer education and strategies to prevent known opioid-related adverse effects, monitor for the development of these adverse effects, and manage these effects when they occur (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Note: Strategies for the prevention and management of common opioid-induced adverse effects are provided in Table 1.
Question 5: How should opioid use be modified in patients with renal or hepatic impairment?
Recommendation 5.1. For patients with renal impairment currently treated with an opioid, clinicians may rotate to methadone, if not contraindicated, as this agent is excreted fecally. Opioids primarily eliminated in urine, such as fentanyl, oxycodone, and hydromorphone, should be carefully titrated and frequently monitored for risk or accumulation of the parent drug or active metabolites. Morphine, meperidine, codeine, and tramadol should be avoided in this population, unless there are no alternatives (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Recommendation 5.2. For patients with renal or hepatic impairment who receive opioids, clinicians should perform more frequent clinical observation and opioid dose adjustment (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Question 6: How should breakthrough pain be managed?
Recommendation 6.1. In patients receiving opioids around the clock, immediate-release opioids at a dose of 5%-20% of the daily regular morphine equivalent daily dose should be prescribed for breakthrough pain (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong for prescribing immediate-release opioids for breakthrough pain, weak for dosing).
Recommendation 6.2. Evidence remains insufficient to recommend a specific, short-acting opioid for breakthrough pain.
Question 7: When and how should opioids be switched (rotated)?
Recommendation 7. Opioid rotation should be offered to patients with pain that is refractory to dose titration of a given opioid, poorly managed side effects, logistical or cost concerns, or trouble with the route of opioid administration or absorption (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate; Strength of recommendation: Strong).
Definitions for the quality of the evidence and strength of recommendation ratings are available in Appendix Table A2 (online only). More information, including a supplement with additional evidence tables, slide sets, and clinical tools and resources, is available at www.asco.org/supportive-care-guidelines. The Methodology Manual (available at www.asco.org/guideline-methodology) provides additional information about the methods used to develop this guideline. Patient information is available at www.cancer.net.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
Evidence-based information is needed to direct the safe and effective use of opioids and counter misinformation. Clinical practice guidelines informed by systematic reviews of available evidence can provide recommendations to advance the best clinical care. Although guidelines exist for treating cancer-related pain,7-10 few are focused solely on opioid use in the patient with cancer. Given the current environment of apprehension regarding opioids, specific guidance is warranted to counteract misinformation while informing clinicians on how to effectively administer these medications, educate patients and loved ones regarding safe use, and advocate for appropriate access. To that end, American Society of Clinical Oncology (ASCO) convened a panel of experts to review the available evidence and develop recommendations to guide best practices regarding the use of opioids to relieve pain from cancer or cancer treatment.
This clinical practice guideline addresses seven clinical questions for adults with pain from cancer or active cancer treatment: (1) In what circumstances should opioids be offered? (2) Which opioids should be offered? (3) How should opioids be initiated and titrated? (4) How should opioid-related adverse events be prevented or managed? (5) How should opioid use be modified in patients with renal or hepatic impairment? (6) How should breakthrough pain be managed? (7) When and how should opioids be switched (rotated)?
This systematic review-based guideline was developed by a multidisciplinary Expert Panel, which included patient representatives and an ASCO guidelines staff member with health research methodology expertise (Appendix Table A1). The Expert Panel met via webinar and corresponded through e-mail. Based upon the consideration of the evidence, the authors were asked to contribute to the development of the guideline, provide critical review, and finalize the guideline recommendations. The guideline recommendations were sent for an open comment period of 2 weeks, allowing the public to review and comment on the recommendations after submitting a confidentiality agreement. These comments were taken into consideration while finalizing the recommendations. Members of the Expert Panel were responsible for reviewing and approving the penultimate version of the guideline, which was then circulated for external review, and submitted to the Journal of Clinical Oncology for editorial review and consideration for publication. All ASCO guidelines are ultimately reviewed and approved by the Expert Panel and the ASCO Evidence Based Medicine Committee before publication. All funding for the administration of the project was provided by ASCO.
The recommendations were developed using a systematic literature review and clinical experience. The systematic review involved online searches of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and systematic reviews published between January 1, 2010, and February 17, 2022. Articles were selected for inclusion in the systematic review on the basis of the following criteria:
Population: Adults with pain from cancer or active cancer treatment
Interventions: Opioid analgesics or interventions to manage opioid side effects
Comparisons: Placebo, different pharmacologic or nonpharmacologic approaches to pain management, different approaches to the management of opioid side effects
Outcomes: Pain, quality of life, function, and adverse events
Sample size: Minimum of 20 patients in total
Articles were excluded from the systematic review if they were (1) meeting abstracts not subsequently published in peer-reviewed journals; (2) editorials, commentaries, letters, news articles, case reports, or narrative reviews; or (3) published in a non-English language. The quality of included systematic reviews was assessed using the 11-item AMSTAR tool.13 Design and analysis elements such as blinding, adequate randomization, sufficient sample size, intention to treat, and funding sources were assessed for RCTs. The guideline recommendations were crafted, in part, using the Guidelines Into Decision Support methodology.14 Ratings for evidence quality and for type and strength of the recommendation are provided with each recommendation. Definitions for these ratings are provided in Appendix Table A2. When evidence was lacking, and the Expert Panel chose to make recommendations based on informal consensus, recommendations felt to be important for patient safety were labeled as strong recommendations.
The ASCO Expert Panel and guidelines staff will work with co-chairs to keep abreast of any substantive updates to the guideline. Based on a formal review of the emerging literature, ASCO will determine the need to update. The ASCO Guidelines Methodology Manual (available at www.asco.org/guideline-methodology) provides additional information about the guideline update process. This is the most recent information as of the publication date.
The Clinical Practice Guidelines and other guidance published herein are provided by ASCO to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations specify the level of confidence that the recommendation reflects the net effect of a given course of action. The use of words like “must,” “must not,” “should,” and “should not” indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO does not endorse third party drugs, devices, services, or therapies used to diagnose, treat, monitor, manage, or alleviate health conditions. Any use of a brand or trade name is for identification purposes only. ASCO provides this information on an “as is” basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions.
The Expert Panel was assembled in accordance with ASCO's Conflict of Interest Policy Implementation for Clinical Practice Guidelines (“Policy,” found at https://www.asco.org/guideline-methodology). All members of the Expert Panel completed ASCO's disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker's bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Policy, the majority of the members of the Expert Panel did not disclose any relationships constituting a conflict under the Policy.
A total of 820 publications were identified in the literature search. After applying the eligibility criteria, 31 systematic reviews15-45 and 16 RCTs46-61 remained, forming the evidentiary basis for the guideline recommendations.
The quality ratings of included systematic reviews varied greatly, with total AMSTAR scores ranging from 3 to 11 on the 11-item AMSTAR tool. A majority of included RCTs had an intermediate or high risk of bias. Quality results for each publication are provided in the Data Supplement (online only).
In what circumstances should opioids be offered?
Opioids should be offered to patients with moderate-to-severe pain related to cancer or active cancer treatment unless contraindicated (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate; Strength of recommendation: Strong).
Prior to initiating opioid therapy, clinicians, patients, and caregivers should discuss goals regarding functional outcomes, shared expectations, and pain intensity, as well as any concerns about opioids (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
RCTs of opioids for cancer pain have focused primarily on patients with moderate-to-severe cancer pain, and most used an active comparator (eg, another formulation, dose, or type of opioid).42 In a 2016 review of oral morphine, the results from 17 studies indicated that 96% of morphine-treated patients (362 of 377) achieved the outcome of no worse than mild pain.43 Several systematic reviews have focused on the relative efficacy of different opioids, with few reported differences but low to very low certainty of evidence.19,23,27,33,38,41 Opioid adverse events have been well characterized, including constipation, nausea, vomiting, drowsiness, and respiratory depression.42 A 2016 review of oral morphine for cancer pain reported that 7% of patients discontinued morphine due to adverse events.43
Opioids should be offered to patients with moderate-to-severe pain related to the primary or metastatic tumor, or acute painful treatment complications such as mucositis.62-65 Before prescribing opioids, it is useful to assess the mechanism for the pain syndrome (imaging may be required if unclear), the response to nonopioid analgesics (eg, acetaminophen or nonsteroidal anti-inflammatory drugs), and the presence of risk factors for nonmedical opioid use such as a history of misuse of alcohol, recreational substances, or prescription drugs. This can be done using simple tools such as the Cut down, Annoyed, Guilty, Eye-Opener Adapted to Include Drugs,66 the Opioid Risk Tool,67 or the Screener and Opioid Assessment for Patients in Pain.66 Approximately 15% of patients with cancer will score positive in these simple risk screening tools, and they should receive opioids in the same way as those who score negative, but will need closer follow-up and regular monitoring of behaviors related to nonmedical opioid use and the Prescription Drug Monitoring Program (PDMP) database64-66,68 (in some states, monitoring of PDMP each time before opioid prescription is mandatory). Random urinary drug tests can be positive in more than 20% of patients with cancer receiving opioids.69 There is no consensus regarding the usefulness of regularly monitoring urinary drug tests before or during opioid treatment among patients with cancer receiving opioids. For those patients who are no longer receiving active cancer treatment and do not have pain related to ongoing tumor burden, the authors refer readers to the ASCO Management of Chronic Pain in Survivors of Adult Cancer9 for guidance related to the use of opioids in this population.
When opioids are no longer indicated, they should be weaned or tapered. Patients with cancer and their caregivers can be reassured that this is feasible at the initiation of opioid therapy. For example, acute syndromes such as mucositis will resolve, and anticancer therapies or interventional treatments may lead to significant pain relief. Additionally, there may be situations when it is not safe to continue prolonged opioid therapy, usually in the setting of long-term cancer survivorship.9 Although there is little evidence regarding strategies for opioid tapering in the oncology population, clinical experience can be guided by tapering in those with persistent noncancer pain. Opioid doses can be reduced more rapidly for those on lower doses for short periods without precipitating abstinence syndrome. For patients on higher doses of opioids for longer periods, dose reduction must be conducted slowly (5%-20% per month) to avoid abstinence syndrome while optimizing nonopioid and nonpharmacologic pain interventions.70
Which opioids should be offered?
For patients who are candidates to begin opioid treatment (Recommendation 1.1), clinicians may offer any of the opioids approved by the US Food and Drug Administration or other regulatory agencies for pain treatment (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate to low; Strength of recommendation: Weak).
The decision of which opioid is most appropriate should be based on factors such as pharmacokinetic properties, including bioavailability, route of administration, half-life, neurotoxicity, and cost of the differing drugs. Tramadol and codeine have limitations that may make them less desirable than other opioids in this setting. Tramadol is a prodrug, has limitations in dose titration related to a low threshold for neurotoxicity, and has potential interactions with other drugs at the level of cytochrome P450 (CYP) 2D6, 2B6, and 3A4.11,12 Codeine is a prodrug, requiring CYP2D6 to allow it to be metabolized to morphine to achieve analgesic effects.12
Clinicians with limited experience with methadone prescribing should consult palliative care or pain specialists when initiating or rotating to methadone (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
As noted previously, systematic reviews have identified few differences in analgesic efficacy across opioids used for cancer pain. Comparisons have included hydromorphone in relation to oxycodone, morphine, and fentanyl23; methadone in relation to morphine27; transdermal fentanyl in relation to oral morphine or other active agents19,38; oxycodone in relation to morphine and other opioids33; oral tapentadol in relation to oxycodone and morphine41; and buprenorphine in relation to various active comparators.34 A 2017 systematic review of tramadol reported that it may be less effective than morphine, on the basis of very low certainty of evidence.40 This was based largely on a 2016 trial by Bandieri et al,71 which compared weak opioids (tramadol with or without acetaminophen or codeine with acetaminophen) to low-dose morphine in 240 patients with moderate cancer pain. A ≥ 20% reduction in pain intensity occurred in 88% of patients treated with low-dose morphine and 58% of patients treated with a weak opioid.
Systematic reviews have also compared adverse events across opioids.19,23,33,38 Some differences were reported in individual adverse events, but none of the investigated agents offered a clear advantage over others in terms of adverse event profiles.
Most patients who report unrelieved pain with nonopioids initially receive as-needed, immediate-release opioid agonists such as codeine, hydrocodone, or oxycodone combined with acetaminophen.62-65 These drugs were considered step 2 in the three-step opioid analgesic ladder by the WHO and a step required before starting strong immediate-release and extended-release opioids (step 3). A number of studies found no major advantage in using the step 2 drugs,71 and the most recent WHO guideline dropped the analgesic ladder as universally required for opioid initiation.63 However, these drugs are usually well tolerated and inexpensive. Moreover, it is possible to determine in just a few days if they will be able to control pain or if a strong regularly dosed opioid without acetaminophen will be needed.
As noted, tramadol and codeine have limitations in dose titration and drug interactions. Patients with genetic polymorphism of CYP2D6 (more common among Asians72) may have less response to codeine. Although tests for CYP2D6 polymorphism are available, there is insufficient evidence to recommend for or against their use in guiding opioid selection or dosing. In addition, drugs that inhibit or compete for CYP2D6 might reduce the analgesic effects of codeine.
Methadone has some potential clinical advantages, including potency, efficacy in neuropathic pain, use as a long-acting agent after crushing (for enteral feeding tube delivery), relative safety in those with renal impairment, and very low cost. However, because of very unique pharmacokinetic and pharmacodynamic properties, it should only be prescribed as a first- or second-line opioid by experienced clinicians.24
How should opioids be initiated and titrated?
Opioids should be initiated at the lowest possible dose to achieve acceptable analgesia and patient goals (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Opioids should be initiated as immediate release and PRN (as needed) to establish an effective dose, with early assessment and frequent titration (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Patients who have been taking other analgesics, such as nonsteroidal anti-inflammatory drugs, may continue these analgesics after opioid initiation if these agents provide additional analgesia and are not contraindicated (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Weak).
Evidence remains insufficient to recommend for or against the use of genetic testing, such as for polymorphism of CYP2D6, to guide opioid dosing.
Evidence remains insufficient to recommend any single set of ranges for dose escalation in opioid titration.
Note: In general, the minimum dose increase is 25%-50%, but patient factors such as frailty, comorbidities, and organ function must be evaluated and considered when changing doses.
For patients with a substance use disorder, clinicians should collaborate with a palliative care, pain, and/or substance use disorder specialist to determine the optimal approach to pain management (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Few included publications directly addressed these questions. Varying approaches to dose titration were evaluated.21,52,56 Genetic variation may contribute to opioid response and dosing requirements,44 but evidence remains insufficient for a recommendation.
The initial opioid dose is dictated by safety considerations rather than pain type or intensity, and it is a dose of approximately 30 mg of morphine equivalent (MME) per day.73-75 Opioids are usually initiated during a short course of an immediate-release formulation as needed to establish the effective dose. In the setting of stable pain, the effective dose can often be determined within a few days. The US Food and Drug Administration also recommends this practice of as-needed immediate-release opioids before starting regularly scheduled opioids.76 Once the effective dose has been determined, extended-release opioids are considered. Extended-release opioids can be administered by mouth every 12 or 24 hours, or transdermal every 72 hours (fentanyl) or every 7 days (buprenorphine). The main advantage of these formulations is the need for much less frequent administration compared with immediate-release opioids, while their main disadvantage is higher cost and frequent insurance company denials or elevated copayments. Immediate-release opioids are inexpensive but they need to be administered every 4 hours to maintain stable blood levels and analgesia. This requires patients to wake up in the middle of the night to take an opioid dose.77
Dose titration can be done a few days after each dose increase or reduction. Because of the wide variation in individual opioid dose response, the increase or decrease in opioid daily dose is calculated as a percentage of the total daily dose (usually approximately 25%-50%). A dose increase should occur when the patient reports persistent pain after being on a certain dose of a regular opioid for a few days, or when the pain is low but the patient needs to take multiple doses of a breakthrough opioid per day. A simple way to determine the new dose of an opioid administered around the clock is to add the total daily dose of the regular plus breakthrough opioids and increase this number by 20%-30%. It is also useful to update the dose of the breakthrough opioid to keep each dose at about 10% (5%-20%) of the regular daily opioid dose.
How should opioid-related adverse events be prevented or managed?
Clinicians should proactively offer education and strategies to prevent known opioid-related adverse effects, monitor for the development of these adverse effects, and manage these effects when they occur (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
Note: Strategies for the prevention and management of common opioid-induced adverse effects are provided in Table 1.
|
Studies designed to explore strategies to prevent opioid-induced constipation suggest that the stimulant laxative senna provides effective control without the addition of the softener docusate.61 Although prevention is crucial, at times, constipation as a result of opioid intake may occur. A 2018 systematic review by Candy et al16 addressed the efficacy and safety of mu-opioid antagonists for opioid-induced bowel dysfunction in patients with cancer and patients in palliative care (a majority of whom had cancer). There was moderate-quality evidence that naldemedine improved bowel function over 2 weeks in adults with cancer, with an increased risk of adverse events such as diarrhea compared with placebo. In patients receiving palliative care, methylnaltrexone was associated with more laxations in 24 hours than placebo, with moderate-quality evidence for efficacy and low-quality evidence of no increase in side effects.
A 2019 systematic review32 evaluated the management of opioid-induced nausea and vomiting in patients with cancer. Eight of the included RCTs reported on opioid switching, with no clear conclusions because of limitations of the evidence: nausea and vomiting was a secondary or tertiary outcome, interventions and comparison arms varied across the trials, and sample sizes tended to be small. Evidence regarding antiemetics or different routes of opioid administration was also limited. In a 2018 RCT not included in the 2019 review, 120 patients with cancer without prior opioid use who started to receive oral oxycodone were randomly assigned to prophylactic prochlorperazine (5 mg) or placebo, three times daily for 5 days. Complete response (no emetic episode and no rescue medication) occurred in 69.5% of patients in the prochlorperazine arm and 63.3% of patients in the placebo arm (P = .47).
There is also very little evidence to guide the management of other opioid side effects, such as cognitive impairment and sedation.36
Relatively little research has been conducted to explore the prevention and management of opioid-induced adverse effects. Guidelines exist for opioid-induced constipation and for constipation related to cancer, yet none specifically address opioid-induced constipation in the oncology population.78-80 As a result, clinicians must rely upon expert guidance on the basis of clinical experience. In Table 1, the ASCO Expert Panel provides consensus-based strategies for preventing and managing common opioid-induced adverse effects.
How should opioid use be modified in patients with renal or hepatic impairment?
For patients with renal impairment currently treated with an opioid, clinicians may rotate to methadone, if not contraindicated, as this agent is excreted fecally. Opioids primarily eliminated in urine, such as fentanyl, oxycodone, and hydromorphone, should be carefully titrated and frequently monitored for risk or accumulation of the parent drug or active metabolites. Morphine, meperidine, codeine, and tramadol should be avoided in this population, unless there are no alternatives (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
For patients with renal or hepatic impairment who receive opioids, clinicians should perform more frequent clinical observation and opioid dose adjustment (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong).
A 2021 systematic review of opioids for patients with cancer-related pain and hepatic impairment identified no RCTs and three prospective observational studies.20 The authors noted that no recommendations could be made regarding the preferred opioid in patients with hepatic impairment. A 2017 systematic review evaluated opioid side effects in patients with cancer pain and renal impairment.31 The review included 18 studies (no RCTs), with no clear evidence to identify a preferred opioid in the setting of renal impairment.
In patients with significant renal function impairment, morphine use may result in the accumulation of neurotoxic metabolites such as morphine-3-glucuronide and normorphine, and opioid-induced neurotoxicity.81-83 Other opioids such as hydromorphone or fentanyl are less likely to result in accumulation of active metabolites in renal failure. Methadone can also be a good alternative since it is primarily metabolized in the liver, but as previously mentioned, it should only be used by experienced clinicians.
How should breakthrough pain be managed?
In patients receiving opioids around the clock, immediate-release opioids at a dose of 5%-20% of the daily regular morphine equivalent daily dose should be prescribed for breakthrough pain (Type: Informal consensus, benefits outweigh harms; Strength of recommendation: Strong for prescribing immediate-release opioids for breakthrough pain, weak for dosing).
Evidence remains insufficient to recommend a specific, short-acting opioid for breakthrough pain.
A 2015 systematic review focused on oral or nasal fentanyl for breakthrough pain.30 The review included 11 RCTs with a total of 1,121 patients. No meta-analysis was possible. Fentanyl was reported to be effective compared with placebo, but evidence was limited regarding efficacy relative to other opioids. In a more recent, 2017 noninferiority trial of fentanyl sublingual tablet versus subcutaneous morphine in 114 patients, fentanyl was not noninferior to morphine at 30 minutes.60 By contrast, a 2015 crossover trial of fentanyl buccal tablet versus oral morphine in 68 patients favored fentanyl for pain reduction at 30 minutes.53
For many patients, the ideal prescription consists of an immediate-release or extended-release opioid administered regularly around the clock, plus an immediate-release opioid at a dose of approximately 10% (ranging from 5% to 20%) of the daily MME dose to be taken if there are episodes of breakthrough pain. Most people with cancer report good pain control with this combined approach.84
When and how should opioids be switched (rotated)?
Opioid rotation should be offered to patients with pain that is refractory to dose titration of a given opioid, poorly managed side effects, logistical or cost concerns, or trouble with the route of opioid administration or absorption (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate; Strength of recommendation: Strong).
Opioid rotation was evaluated in a 2018 systematic review among adults with chronic, cancer-related pain and regular use of oral or transdermal opioids.35 The review included three systematic reviews, four RCTs, and five prospective observational studies. The authors concluded that opioid rotation can improve pain relief and patient satisfaction. Dose escalation after rotation was necessary to achieve adequate pain relief in a majority of studies evaluated, with the exception of rotation to methadone.
Opioid rotation is common in the management of cancer pain, with one study demonstrating a frequency of close to one third of patients requiring a change.85 The goal of opioid rotation is to safely switch from one opioid, or one route, to an alternate agent. Unfortunately, there are few studies comparing the potency of one opioid or route to another, including in models of different types of pain (eg, acute v chronic, neuropathic v nociceptive). One exception is the work conducted by Reddy et al exploring conversion factors between a variety of opioids in clinical settings.86-88 Vigorous debate currently centers around the use of equianalgesic tables or conversion factors.89 Widely divergent information is available in the very large number of existing tools and online applications. Current equianalgesic tables assume fixed and bidirectional values and require more complicated mathematical formulas that may be prone to error. Yet, a very large number of conversion factors would be required to address all the potential permutations for rotating from one opioid to another or from one route to another. Additionally, none of these tools consider the clinical context that is crucial when converting opioids and/or routes. To address these concerns, ASCO has partnered with the Multinational Association of Supportive Care in Cancer and other organizations to develop an international opioid conversion guideline. Until there is greater evidence and consensus within the field, clinicians and teams should select one method to calculate a safe dose and use this consistently when switching from one opioid to another or from one route to another.
Regardless of the methodology used, opioid rotation should be personalized on the basis of the underlying reason to change the medication. The dose might be more conservative in those individuals experiencing significant adverse effects, particularly sedation or a history of falls. This is also true when rotating to a parenteral route of administration if there is any question about absorption of the drug when taken enterally (eg, possible loss through vomiting or rapid motility). Conversely, when patients are in severe pain, doses may be more liberal. Close monitoring and frequent follow-up with necessary dose titration are warranted.
Complicating the limited research related to opioid use in those with cancer are serious challenges in accessing these medications. Barriers include regulations that burden prescribers, such as frequent, mandatory review of the PDMP database. Additionally, limits on the daily dose of an opioid or the number of doses that can be dispensed greatly hinder availability.90 The 2016 Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain91 suggested maximum daily doses that explicitly excluded those with active cancer or those approaching the end of life, yet oncologists report that the guidelines are widely misinterpreted to include those with cancer.4 Compounding this misinterpretation, state laws often exempt cancer-related pain, yet are insufficiently clear to guide prescribers as they address the needs of diverse cancer populations.92
These regulations and other measures designed to mitigate the opioid misuse epidemic have been associated with decreased opioid prescribing in cancer and noncancer pain and have even been noted in those patients entering hospice.93-98 One study observed a correlation between decreased opioid prescribing and an increase in cancer pain–related emergency department visits.96 The most vulnerable patients remain the most affected, with reduced rates of opioid prescribing, along with lower doses, reported in people of color.99,100
When provided a prescription for an opioid, patients with cancer consistently recount problems obtaining the medication, with one quarter describing perceived difficulties during interactions with pharmacy staff.101 Some of these problems arise because of the complexities of medication dispensing in our current health care system. Is the drug available at the pharmacy, and if so, will insurance pay? Shortages of opioids have been noted as the US Drug Enforcement Administration has repeatedly reduced production quotas. Pharmacies are often unwilling to carry these crucial medications. Delays in access can occur because of increasing requirements by payors for prior authorizations, a cumbersome process that can take 3-7 business days. Many payors require step therapy, where a patient must undergo unnecessary trials of medications to demonstrate the failure of an agent, before obtaining approval for a requested opioid. As discussed previously, the WHO no longer supports a step-wise analgesic ladder for opioid initiation.63 Furthermore, although a prior authorization may eventually be approved, patients are frequently charged higher, onerous copays.102
The consequences of these burdensome regulatory and payment requirements include stigma and fear. People with cancer report stigma related to opioid use generated by their interactions with clinicians, pharmacists, and society.3,4 Patients express greater fear of addiction, along with guilt and a sense of moral failure that they require the use of opioids, causing some to skip a dose or take a lower dose than prescribed.4-6 Another broader consequence of these many obstacles is the pharmaceutical industry's disinterest in investment in research and development of new opioids, harboring little hope for future effective treatments for cancer pain.
The increasing number of substance-related deaths, including opioids, is a serious public health emergency that has only escalated during the COVID-19 pandemic.103,104 Because those with cancer are not exempt from substance use disorder and/or nonmedical opioid use, a thorough proactive assessment of pain, function, and risk is required, along with strategies to balance risk mitigation with effective pain control.105-107 It is imperative that we do not compound this crisis by undertreating cancer pain.
Safe and effective use of opioids requires clear communication among patients, caregivers, and clinicians. Clinicians can help patients and caregivers understand that early and effective pain management improves quality of life and is a key component of cancer care. Common patient concerns about opioids include fear of respiratory depression or addiction, along with stigma regarding the use of these drugs. To address these concerns, clinicians may assess patient and caregiver knowledge and attitudes regarding pain and the use of opioids. Education is needed, particularly as these drugs are often prescribed as needed, requiring the patient and their loved ones to decide when and how to take them. Additionally, web-based applications and electronic pill diaries can help remind patients when to take medications while recording this information to help clinicians determine optimal pain treatment strategies. Regular follow-up of patients is important to monitor opioid efficacy and safety, and to make timely changes to the treatment regimen when needed. Patients should be informed that inadequate pain relief or bothersome opioid side effects can be managed and should be reported. Especially in advanced disease, patients and caregivers should be aware that some symptoms, such as confusion or loss of mental clarity, may occur in part due to opioids, but also as a result of organ dysfunction and disease progression. In those circumstances, the benefits of relief need to be carefully considered while optimizing quality of life.
When opioids are prescribed, clinicians must educate patients and their caregivers about safe storage and disposal. Opioids should be stored in their original packaging in a locked container and not shared with others. Unused opioid medications and other controlled substances such as benzodiazepines should be safely disposed of, ideally through take-back programs or medication drop boxes.
For general recommendations and strategies to optimize patient-clinician communication, see Patient-Clinician Communication: American Society of Clinical Oncology Consensus Guideline.108
Although ASCO clinical practice guidelines represent expert recommendations on the best practices in disease management to provide the highest level of cancer care, it is important to note that many patients have limited access to medical care or receive fragmented care. Factors such as race and ethnicity, age, socioeconomic status, sexual orientation and gender identity, geographic location, and insurance access are known to affect cancer care outcomes.109 Racial and ethnic disparities in health care contribute significantly to this problem in the United States. Patients with cancer who are members of racial or ethnic minorities suffer disproportionately from comorbidities, experience more substantial obstacles to receiving care, are more likely to be uninsured, and are at greater risk of receiving fragmented or poor-quality care than other Americans.110,111 In the case of opioids, prescribing in the United States varies by age, sex, gender, race, and ethnicity.96,99,100,112 A 2020 analysis of linked Surveillance, Epidemiology, and End Results-Medicare data assessed opioid prescriptions among opioid-naive, older patients with nonmetastatic cancer.99 Compared with non-Hispanic White patients, the likelihood of a new opioid prescription was lower in non-Hispanic Black patients (odds ratio [OR], 0.75; 95% CI, 0.67 to 0.84), nonsignificantly higher in Hispanic patients (OR, 1.14; 95% CI, 0.99 to 1.30), and higher in Asian-Pacific Islander patients (OR, 2.15; 95% CI, 1.85 to 2.50). In addition, many patients lack access to care because of their geographic location and distance from appropriate treatment facilities. Awareness of these disparities in access to care should be considered in the context of this clinical practice guideline, and clinicians should strive to deliver the highest level of cancer care to these vulnerable populations. Additionally, stakeholders should work toward achieving health equity by ensuring equitable access to high-quality cancer care and research, and addressing the structural barriers that preserve health inequities.109
Creating evidence-based recommendations to inform the treatment of patients with additional chronic conditions, a situation in which the patient may have two or more such conditions—referred to as multiple chronic conditions (MCC)—is challenging. Patients with MCC are a complex and heterogeneous population, making it difficult to account for all possible permutations to develop specific recommendations for care. In addition, the best available evidence for treating index conditions, such as cancer, is often from clinical trials whose study selection criteria may exclude these patients to avoid potential interaction effects or confounding of results associated with MCC. As a result, the reliability of outcome data from these studies may be limited, thereby creating constraints for expert groups to make recommendations for care in this heterogeneous patient population.
A particularly challenging chronic condition in the oncology setting is persistent noncancer pain.113 Patients with noncancer pain who are now diagnosed with cancer after being treated with opioids for many years frequently experience difficulty obtaining relief. These obstacles are greatly exacerbated in these patients who also suffer from comorbid substance use disorder or mental health conditions. Primary care clinicians may be unwilling to continue prescribing these medications, deferring to the oncology team.114 If there is an additive effect of new cancer pain on top of persistent noncancer pain, dose escalation in the face of already high doses of opioids may be restricted by tolerance and toxicity along with access obstacles such as reduced reimbursement or limited availability of these medications at retail pharmacies. For cancer survivors, long-term opioid therapy may be detrimental,9 yet few oncology clinicians have been trained in tapering high-dose opioid therapy.
Oncology clinicians can collaborate with primary care clinicians and geriatricians so that once cancer treatment is completed, patients will resume pain care through these clinicians. During cancer treatment, complex pain may require referral to pain management, palliative care, mental health, and substance use experts. Abruptly discontinuing opioids after long-term use has been shown to increase illicit substance use, emergency department visits, and deaths from overdose or suicide.115-117 As a result, tapering opioid therapy must be conducted slowly, engaging patients throughout the process.118
As many patients for whom guideline recommendations apply present with MCC, any treatment plan needs to account for the complexity and uncertainty created by the presence of MCC and highlight the importance of shared decision making regarding guideline use and implementation. Therefore, in consideration of recommended care for the target index condition, clinicians should review all other chronic conditions present in the patient and take those conditions into account when formulating the treatment and follow-up plan.
Increasingly, patients with cancer are required to pay a larger proportion of their treatment costs through deductibles and coinsurance.119,120 Higher patient out-of-pocket costs are a barrier to initiating and adhering to recommended cancer treatments.121,122
Discussion of cost can be an important part of shared decision making.123 Clinicians should discuss with patients the use of less-expensive alternatives when it is practical and feasible for the treatment of the patient's disease and there are two or more treatment options that are comparable in terms of benefits and harms.123 Opioid costs can vary markedly by agent: morphine, methadone, and immediate-release hydrocodone tend to be the least expensive, while the cost for more recently introduced agents for which there is no available generic equivalent is typically higher. Patient out-of-pocket costs may vary depending on insurance coverage. Coverage may originate in the medical or pharmacy benefit, which may have different cost-sharing arrangements. Patients should be aware that different products may be preferred or covered by their particular insurance plan. Even with the same insurance plan, the price may vary between different pharmacies. When discussing financial issues and concerns, patients should be informed of any financial counseling services available to address this complex, heterogeneous, and ever-changing landscape.123
The draft recommendations were released to the public for open comment from July 8 through July 22, 2022. Response categories of “Agree as written,” “Agree with suggested modifications,” and “Disagree. See comments” were captured for every proposed recommendation, with 34 written comments received. For each recommendation, the proportion of respondents who agreed or agreed with slight modifications ranged from 88% to 100%. Expert Panel members reviewed the comments and determined whether to maintain original draft recommendations, revise with minor language changes, or consider major recommendation revisions. All changes were incorporated before Evidence Based Medicine Committee review and approval.
ASCO guidelines are developed for implementation across health settings. Each ASCO guideline includes a member from ASCO's Practice Guideline Implementation Network (PGIN) on the panel. The additional role of this PGIN representative on the guideline panel is to assess the suitability of the recommendations for implementation in the community setting, but also to identify any other barrier to implementation of which a reader should be aware. Barriers to implementation include the need to increase awareness of the guideline recommendations among frontline practitioners and survivors of cancer and caregivers, and also to provide adequate services in the face of limited resources. The guideline Bottom Line Box was designed to facilitate the implementation of recommendations. This guideline will be distributed widely through the ASCO PGIN. ASCO guidelines are posted on the ASCO website and most often published in the Journal of Clinical Oncology.
Despite the prevalence and impact of cancer pain, many questions remain about the optimal use of opioids in this setting. Priorities for future research include the following:
What are the clinically meaningful differences between opioids in patients with cancer?
What are the clinically meaningful differences between scheduling an immediate-release opioid with as-needed opioid dosing versus extended-release opioid administration with as-needed immediate-release opioids for breakthrough pain?
Which is the preferred opioid for breakthrough pain?
What is the optimal increase or decrease when modifying the opioid dose in response to changes in pain?
What is the clinical impact of renal dysfunction on the absorption, distribution, metabolism, and excretion of each opioid?
What is the clinical impact of hepatic dysfunction on the absorption, distribution, metabolism, and excretion of each opioid?
What are the conversion factors for different opioids and routes, and do these vary based upon dose (low dose v high dose)?
What is the optimal strategy for opioid switching?
What are the most effective strategies for preventing and managing opioid-induced adverse effects?
What is the real-world role of genetic testing in guiding opioid dosing?
What are the safest and most effective strategies for treating cancer pain in patients with opioid use disorders or nonmedical opioid use?
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
More information, including a supplement with additional evidence tables, slide sets, and clinical tools and resources, is available at www.asco.org/supportive-care-guidelines. Patient information is available at www.cancer.net.
Management of Chronic Pain in Survivors of Adult Cancers9 (https://ascopubs.org/doi/pdf/10.1200/JCO.2016.68.5206)
Integration of Palliative Care Into Standard Oncology Care124 (http://ascopubs.org/doi/10.1200/JCO.2016.70.1474)
Patient-Clinician Communication108 (http://ascopubs.org/doi/10.1200/JCO.2017.75.2311)
Integrative Medicine for Pain Management in Oncology: SIO-ASCO Guideline125 (https://ascopubs.org/doi/10.1200/JCO.22.01357)
J.A.P. and E.B. were Expert Panel co-chairs.
This American Society of Clinical Oncology (ASCO) Clinical Practice Guideline provides recommendations, with comprehensive review and analyses of the relevant literature for each recommendation. Additional information, including a supplement with additional evidence tables, slide sets, clinical tools and resources, and links to patient information at www.cancer.net, is available at www.asco.org/supportive-care-guidelines.
Conception and design: All authors
Administrative support: All authors
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Debra Barton
Research Funding: Merck
David S. Craig
Employment: Delta Care Rx
Consulting or Advisory Role: Trevena, Inc, Meter Health, Inc
Areej El-Jawahri
Leadership: Elevate Therapeutics
Stock and Other Ownership Interests: Elevate Therapeutics
Consulting or Advisory Role: AIM Specialty Health, Novartis, GlaxoSmithKline, Incyte
Research Funding: Blue Note Therapeutics
Dawn L. Hershman
Consulting or Advisory Role: AIM Specialty Health
Geana P. Kurita
Research Funding: Novo Nordisk (Inst)
Thomas W. LeBlanc
Honoraria: Agilix
Consulting or Advisory Role: Pfizer, AbbVie/Genentech, Flatiron Health, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Astellas Pharma, Blue Note Therapeutics, Agios/Servier, Novartis, BeiGene
Speakers' Bureau: Agios, AbbVie, Bristol Myers Squibb/Celgene, SERVIER
Research Funding: Jazz Pharmaceuticals (Inst), Bristol Myers Squibb (Inst)
Patents, Royalties, Other Intellectual Property: UpToDate Inc, Royalty
Travel, Accommodations, Expenses: Agios, AbbVie/Genentech, Bristol Myers Squibb/Celgene
Eduardo Bruera
Research Funding: PharmaCann (Inst)
No other potential conflicts of interest were reported.
ACKNOWLEDGMENT
The Expert Panel wishes to thank Eric Roeland, MD, Elizabeth Shaw, NP, and the Evidence Based Medicine Committee for their thoughtful reviews and insightful comments on this guideline. T.W.L., MD, and AE.-J., MD, are each supported by a Scholar in Clinical Research Award from the Leukemia and Lymphoma Society.
| 1. | van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, et al: Update on prevalence of pain in patients with cancer: Systematic review and meta-analysis. J Pain Symptom Manage 51:1070-1090.e9, 2016 Crossref, Medline, Google Scholar |
| 2. | Paice JA: Cancer pain management and the opioid crisis in America: How to preserve hard-earned gains in improving the quality of cancer pain management. Cancer 124:2491-2497, 2018 Crossref, Medline, Google Scholar |
| 3. | Bulls HW, Chu E, Goodin BR, et al: Framework for opioid stigma in cancer pain. Pain 163:e182-e189, 2022 Crossref, Medline, Google Scholar |
| 4. | Schenker Y, Hamm M, Bulls HW, et al: This is a different patient population: Opioid prescribing challenges for patients with cancer-related pain. JCO Oncol Pract 17:e1030-e1037, 2021 Link, Google Scholar |
| 5. | Wright EM, El-Jawahri A, Temel JS, et al: Patient patterns and perspectives on using opioid regimens for chronic cancer pain. J Pain Symptom Manage 57:1062-1070, 2019 Crossref, Medline, Google Scholar |
| 6. | Azizoddin DR, Knoerl R, Adam R, et al: Cancer pain self-management in the context of a national opioid epidemic: Experiences of patients with advanced cancer using opioids. Cancer 127:3239-3245, 2021 Crossref, Medline, Google Scholar |
| 7. | World Health Organization: WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents. Geneva, World Health Organization, 2018. https://apps.who.int/iris/handle/10665/279700 Google Scholar |
| 8. | Swarm RA, Paice JA, Anghelescu DL, et al: Adult cancer pain, version 3.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 17:977-1007, 2019 Crossref, Medline, Google Scholar |
| 9. | Paice JA, Portenoy R, Lacchetti C, et al: Management of chronic pain in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 34:3325-3345, 2016 Link, Google Scholar |
| 10. | Fallon M, Giusti R, Aielli F, et al: Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Ann Oncol 29:iv166-iv191, 2018 (suppl 4) Crossref, Medline, Google Scholar |
| 11. | Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet 43:879-923, 2004 Crossref, Medline, Google Scholar |
| 12. | Crews KR, Monte AA, Huddart R, et al: Clinical pharmacogenetics implementation consortium guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy. Clin Pharmacol Ther 110:888-896, 2021 Crossref, Medline, Google Scholar |
| 13. | Shea BJ, Grimshaw JM, Wells GA, et al: Development of AMSTAR: A measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol 7:10, 2007 Crossref, Medline, Google Scholar |
| 14. | Shiffman RN, Michel G, Rosenfeld RM, et al: Building better guidelines with BRIDGE-Wiz: Development and evaluation of a software assistant to promote clarity, transparency, and implementability. J Am Med Inform Assoc 19:94-101, 2012 Crossref, Medline, Google Scholar |
| 15. | Boland JW, Ziegler L, Boland EG, et al: Is regular systemic opioid analgesia associated with shorter survival in adult patients with cancer? A systematic literature review. Pain 156:2152-2163, 2015 Crossref, Medline, Google Scholar |
| 16. | Candy B, Jones L, Vickerstaff V, et al: Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care. Cochrane Database Syst Rev 6:CD006332, 2018 Medline, Google Scholar |
| 17. | Colson J, Koyyalagunta D, Falco FJ, et al: A systematic review of observational studies on the effectiveness of opioid therapy for cancer pain. Pain Physician 14:E85-E102, 2011 Crossref, Medline, Google Scholar |
| 18. | Fallon MT, Laird BJ: A systematic review of combination step III opioid therapy in cancer pain: An EPCRC opioid guideline project. Palliat Med 25:597-603, 2011 Crossref, Medline, Google Scholar |
| 19. | Hadley G, Derry S, Moore RA, et al: Transdermal fentanyl for cancer pain. Cochrane Database Syst Rev 2013:CD010270, 2013 Medline, Google Scholar |
| 20. | Hughes LT, Raftery D, Coulter P, et al: Use of opioids in patients with cancer with hepatic impairment—A systematic review. BMJ Support Palliat Care 12:152-157, 2021 Crossref, Medline, Google Scholar |
| 21. | Klepstad P, Kaasa S, Borchgrevink PC: Starting step III opioids for moderate to severe pain in cancer patients: Dose titration: A systematic review. Palliat Med 25:424-430, 2011 Crossref, Medline, Google Scholar |
| 22. | Koyyalagunta D, Bruera E, Solanki DR, et al: A systematic review of randomized trials on the effectiveness of opioids for cancer pain. Pain Physician 15:ES39-ES58, 2012 Crossref, Medline, Google Scholar |
| 23. | Li Y, Ma J, Lu G, et al: Hydromorphone for cancer pain. Cochrane Database Syst Rev 8:CD011108, 2021 Medline, Google Scholar |
| 24. | Mercadante S, Bruera E: Methadone as a first-line opioid in cancer pain management: A systematic review. J Pain Symptom Manage 55:998-1003, 2018 Crossref, Medline, Google Scholar |
| 25. | Mercadante S, Caraceni A: Conversion ratios for opioid switching in the treatment of cancer pain: A systematic review. Palliat Med 25:504-515, 2011 Crossref, Medline, Google Scholar |
| 26. | Mesgarpour B, Griebler U, Glechner A, et al: Extended-release opioids in the management of cancer pain: A systematic review of efficacy and safety. Eur J Pain 18:605-616, 2014 Crossref, Medline, Google Scholar |
| 27. | Nicholson AB, Watson GR, Derry S, et al: Methadone for cancer pain. Cochrane Database Syst Rev 2:CD003971, 2017 Medline, Google Scholar |
| 28. | Pask S, Dell'Olio M, Murtagh FEM, et al: The effects of opioids on cognition in older adults with cancer and chronic noncancer pain: A systematic review. J Pain Symptom Manage 59:871-893.e1, 2020 Crossref, Medline, Google Scholar |
| 29. | Radbruch L, Trottenberg P, Elsner F, et al: Systematic review of the role of alternative application routes for opioid treatment for moderate to severe cancer pain: An EPCRC opioid guidelines project. Palliat Med 25:578-596, 2011 Crossref, Medline, Google Scholar |
| 30. | Rogríguez D, Urrutia G, Escobar Y, et al: Efficacy and safety of oral or nasal fentanyl for treatment of breakthrough pain in cancer patients: A systematic review. J Pain Palliat Care Pharmacother 29:228-246, 2015 Crossref, Medline, Google Scholar |
| 31. | Sande TA, Laird BJ, Fallon MT: The use of opioids in cancer patients with renal impairment—A systematic review. Support Care Cancer 25:661-675, 2017 Crossref, Medline, Google Scholar |
| 32. | Sande TA, Laird BJA, Fallon MT: The management of opioid-induced nausea and vomiting in patients with cancer: A systematic review. J Palliat Med 22:90-97, 2019 Crossref, Medline, Google Scholar |
| 33. | Schmidt-Hansen M, Bennett MI, Arnold S, et al: Oxycodone for cancer-related pain. Cochrane Database Syst Rev 8:CD003870, 2017 Medline, Google Scholar |
| 34. | Schmidt-Hansen M, Bromham N, Taubert M, et al: Buprenorphine for treating cancer pain. Cochrane Database Syst Rev 2015:CD009596, 2015 Medline, Google Scholar |
| 35. | Schuster M, Bayer O, Heid F, et al: Opioid rotation in cancer pain treatment. Dtsch Arztebl Int 115:135-142, 2018 Medline, Google Scholar |
| 36. | Stone P, Minton O: European Palliative Care Research collaborative pain guidelines: Central side-effects management: What is the evidence to support best practice in the management of sedation, cognitive impairment and myoclonus? Palliat Med 25:431-441, 2011 Crossref, Medline, Google Scholar |
| 37. | Straube C, Derry S, Jackson KC, et al: Codeine, alone and with paracetamol (acetaminophen), for cancer pain. Cochrane Database Syst Rev 2014:CD006601, 2014 Medline, Google Scholar |
| 38. | Wang DD, Ma TT, Zhu HD, et al: Transdermal fentanyl for cancer pain: Trial sequential analysis of 3406 patients from 35 randomized controlled trials. J Cancer Res Ther 14:S14-S21, 2018 Crossref, Medline, Google Scholar |
| 39. | Wiffen PJ, Derry S, Moore RA: Impact of morphine, fentanyl, oxycodone or codeine on patient consciousness, appetite and thirst when used to treat cancer pain. Cochrane Database Syst Rev 2014:CD011056, 2014 Medline, Google Scholar |
| 40. | Wiffen PJ, Derry S, Moore RA: Tramadol with or without paracetamol (acetaminophen) for cancer pain. Cochrane Database Syst Rev 5:CD012508, 2017 Medline, Google Scholar |
| 41. | Wiffen PJ, Derry S, Naessens K, et al: Oral tapentadol for cancer pain. Cochrane Database Syst Rev 2015:CD011460, 2015 Medline, Google Scholar |
| 42. | Wiffen PJ, Wee B, Derry S, et al: Opioids for cancer pain—An overview of Cochrane reviews. Cochrane Database Syst Rev 7:CD012592, 2017 Medline, Google Scholar |
| 43. | Wiffen PJ, Wee B, Moore RA: Oral morphine for cancer pain. Cochrane Database Syst Rev 4:CD003868, 2016 Medline, Google Scholar |
| 44. | Zhang X, Liang Y, Zhang N, et al: The relevance of the OPRM1 118A>G genetic variant for opioid requirement in pain treatment: A meta-analysis. Pain Physician 22:331-340, 2019 Medline, Google Scholar |
| 45. | Zhou J, Wang Y, Jiang G: Oxycodone versus morphine for cancer pain titration: A systematic review and pharmacoeconomic evaluation. PLoS One 15:e0231763, 2020 Medline, Google Scholar |
| 46. | Currow DC, Clark K, Louw S, et al: A randomized, double-blind, crossover, dose ranging study to determine the optimal dose of oral opioid to treat breakthrough pain for patients with advanced cancer already established on regular opioids. Eur J Pain 24:983-991, 2020 Crossref, Medline, Google Scholar |
| 47. | Haumann J, van Kuijk SMJ, Geurts JW, et al: Methadone versus fentanyl in patients with radiation-induced nociceptive pain with head and neck cancer: A randomized controlled noninferiority trial. Pain Pract 18:331-340, 2018 Crossref, Medline, Google Scholar |
| 48. | Inoue S, Saito Y, Tsuneto S, et al: A double-blind, randomized comparative study to investigate the morphine to hydromorphone conversion ratio in Japanese cancer patients. Jpn J Clin Oncol 48:442-449, 2018 Crossref, Medline, Google Scholar |
| 49. | Kleeberg UR, Davies A, Jarosz J, et al: Pan-European, open-label dose titration study of fentanyl buccal tablet in patients with breakthrough cancer pain. Eur J Pain 19:528-537, 2015 Crossref, Medline, Google Scholar |
| 50. | Kosugi T, Hamada S, Takigawa C, et al: A randomized, double-blind, placebo-controlled study of fentanyl buccal tablets for breakthrough pain: Efficacy and safety in Japanese cancer patients. J Pain Symptom Manage 47:990-1000, 2014 Crossref, Medline, Google Scholar |
| 51. | Lee KH, Kim TW, Kang JH, et al: Efficacy and safety of controlled-release oxycodone/naloxone versus controlled-release oxycodone in Korean patients with cancer-related pain: A randomized controlled trial. Chin J Cancer 36:74, 2017 Crossref, Medline, Google Scholar |
| 52. | Liang J, Chen L, Yang S, et al: A 12-hour rapid titration method for cancer pain: A randomized, controlled, open-label study. Ann Palliat Med 10:88-96, 2021 Crossref, Medline, Google Scholar |
| 53. | Mercadante S, Adile C, Cuomo A, et al: Fentanyl buccal tablet vs. oral morphine in doses proportional to the basal opioid regimen for the management of breakthrough cancer pain: A randomized, crossover, comparison study. J Pain Symptom Manage 50:579-586, 2015 Crossref, Medline, Google Scholar |
| 54. | Mercadante S, Gatti A, Porzio G, et al: Dosing fentanyl buccal tablet for breakthrough cancer pain: Dose titration versus proportional doses. Curr Med Res Opin 28:963-968, 2012 Crossref, Medline, Google Scholar |
| 55. | Pan H, Shen P, Shu Q, et al: Efficacy and safety of sustained-release oxycodone compared with immediate-release morphine for pain titration in cancer patients: A multicenter, open-label, randomized controlled trial (SOCIAL). Medicine (Baltimore) 98:e15505, 2019 Crossref, Medline, Google Scholar |
| 56. | Poulain P, Berleur MP, Lefki S, et al: Efficacy and safety of two methadone titration methods for the treatment of cancer-related pain: The EQUIMETH2 trial (methadone for cancer-related pain). J Pain Symptom Manage 52:626-636.e1, 2016 Crossref, Medline, Google Scholar |
| 57. | Raptis E, Vadalouca A, Stavropoulou E, et al: Pregabalin vs. opioids for the treatment of neuropathic cancer pain: A prospective, head-to-head, randomized, open-label study. Pain Pract 14:32-42, 2014 Crossref, Medline, Google Scholar |
| 58. | Rauck R, Reynolds L, Geach J, et al: Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: A randomized, double-blind, placebo-controlled study. Curr Med Res Opin 28:859-870, 2012 Crossref, Medline, Google Scholar |
| 59. | Tsukuura H, Miyazaki M, Morita T, et al: Efficacy of prophylactic treatment for oxycodone-induced nausea and vomiting among patients with cancer pain (POINT): A randomized, placebo-controlled, double-blind trial. Oncologist 23:367-374, 2018 Crossref, Medline, Google Scholar |
| 60. | Zecca E, Brunelli C, Centurioni F, et al: Fentanyl sublingual tablets versus subcutaneous morphine for the management of severe cancer pain episodes in patients receiving opioid treatment: A double-blind, randomized, noninferiority trial. J Clin Oncol 35:759-765, 2017 Link, Google Scholar |
| 61. | Tarumi Y, Wilson MP, Szafran O, et al: Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients. J Pain Symptom Manage 45:2-13, 2013 Crossref, Medline, Google Scholar |
| 62. | Dalal S, Bruera E: Pain management for patients with advanced cancer in the opioid epidemic era. Am Soc Clin Oncol Educ Book 39:24-35, 2019 Link, Google Scholar |
| 63. | World Health Organization: WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents. Geneva, World Health Organization, 2018 Google Scholar |
| 64. | Bruera E: Cancer Pain Treatment Selection. ASCO Education, Alexandria, VA, American Society of Clinical Oncology, 2022. https://education.asco.org/product-details/cancer-pain-treatment-selection Google Scholar |
| 65. | Paice JA: Opioid Management. ASCO Education, Alexandria, VA, American Society of Clinical Oncology, 2022. https://education.asco.org/product-details/opioid-management Google Scholar |
| 66. | Arthur J, Bruera E: Balancing opioid analgesia with the risk of nonmedical opioid use in patients with cancer. Nat Rev Clin Oncol 16:213-226, 2019 Crossref, Medline, Google Scholar |
| 67. | Webster LR, Webster RM: Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the Opioid Risk Tool. Pain Med 6:432-442, 2005 Crossref, Medline, Google Scholar |
| 68. | Berlin J: The PMP requirement begins. Tex Med 116:29-30, 2020 Medline, Google Scholar |
| 69. | Arthur JA, Tang M, Lu Z, et al: Random urine drug testing among patients receiving opioid therapy for cancer pain. Cancer 127:968-975, 2021 Crossref, Medline, Google Scholar |
| 70. | US Department of Veterans Affairs: Opioid Taper Decision Tool. Washington, DC, US Department of Veterans Affairs, 2016. https://www.pbm.va.gov/PBM/AcademicDetailingService/Documents/Pain_Opioid_Taper_Tool_IB_10_939_P96820.pdf Google Scholar |
| 71. | Bandieri E, Romero M, Ripamonti CI, et al: Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol 34:436-442, 2016 Link, Google Scholar |
| 72. | Bradford LD: CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3:229-243, 2002 Crossref, Medline, Google Scholar |
| 73. | De Conno F, Ripamonti C, Fagnoni E, et al: The MERITO study: A multicentre trial of the analgesic effect and tolerability of normal-release oral morphine during 'titration phase' in patients with cancer pain. Palliat Med 22:214-221, 2008 Crossref, Medline, Google Scholar |
| 74. | Ripamonti CI, Campa T, Fagnoni E, et al: Normal-release oral morphine starting dose in cancer patients with pain. Clin J Pain 25:386-390, 2009 Crossref, Medline, Google Scholar |
| 75. | Mercadante S, Porzio G, Ferrera P, et al: Low morphine doses in opioid-naive cancer patients with pain. J Pain Symptom Manage 31:242-247, 2006 Crossref, Medline, Google Scholar |
| 76. | US Food and Drug Administration: Letter to Application Holders: ER/LA Opioid Analgesic Class Labeling Changes and Postmarketing Requirements. Silver Spring, MD, US Food and Drug Administration, 2013. http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM367697.pdf Google Scholar |
| 77. | Mazzotta M, Filetti M, Piras M, et al: Patients' satisfaction with breakthrough cancer pain therapy: A secondary analysis of IOPS-MS study. Cancer Manag Res 14:1237-1245, 2022 Crossref, Medline, Google Scholar |
| 78. | Crockett SD, Greer KB, Heidelbaugh JJ, et al: American Gastroenterological Association Institute guideline on the medical management of opioid-induced constipation. Gastroenterology 156:218-226, 2019 Crossref, Medline, Google Scholar |
| 79. | Davies A, Leach C, Caponero R, et al: MASCC recommendations on the management of constipation in patients with advanced cancer. Support Care Cancer 28:23-33, 2020 Crossref, Medline, Google Scholar |
| 80. | Larkin PJ, Cherny NI, La Carpia D, et al: Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines. Ann Oncol 29:iv111-iv125, 2018 (suppl 4) Crossref, Medline, Google Scholar |
| 81. | Franken LG, Masman AD, de Winter BC, et al: Pharmacokinetics of morphine, morphine-3-glucuronide and morphine-6-glucuronide in terminally ill adult patients. Clin Pharmacokinet 55:697-709, 2016 Crossref, Medline, Google Scholar |
| 82. | Portenoy RK, Foley KM, Stulman J, et al: Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: Plasma profiles, steady-state concentrations and the consequences of renal failure. Pain 47:13-19, 1991 Crossref, Medline, Google Scholar |
| 83. | Tiseo PJ, Thaler HT, Lapin J, et al: Morphine-6-glucuronide concentrations and opioid-related side effects: A survey in cancer patients. Pain 61:47-54, 1995 Crossref, Medline, Google Scholar |
| 84. | Azhar A, Kim YJ, Haider A, et al: Response to oral immediate-release opioids for breakthrough pain in patients with advanced cancer with adequately controlled background pain. Oncologist 24:125-131, 2019 Crossref, Medline, Google Scholar |
| 85. | Reddy A, Yennurajalingam S, Pulivarthi K, et al: Frequency, outcome, and predictors of success within 6 weeks of an opioid rotation among outpatients with cancer receiving strong opioids. Oncologist 18:212-220, 2013 Crossref, Medline, Google Scholar |
| 86. | Reddy A, Tayjasanant S, Haider A, et al: The opioid rotation ratio of strong opioids to transdermal fentanyl in cancer patients. Cancer 122:149-156, 2016 Crossref, Medline, Google Scholar |
| 87. | Reddy A, Vidal M, Stephen S, et al: The conversion ratio from intravenous hydromorphone to oral opioids in cancer patients. J Pain Symptom Manage 54:280-288, 2017 Crossref, Medline, Google Scholar |
| 88. | Reddy A, Yennurajalingam S, Desai H, et al: The opioid rotation ratio of hydrocodone to strong opioids in cancer patients. Oncologist 19:1186-1193, 2014 Crossref, Medline, Google Scholar |
| 89. | Rosielle D: Opioid Equianalgesic Tables Are Broken, Pallimed: A Hospice & Palliative Medicine Blog. Pallimed, 2022. https://www.pallimed.org/2022/03/opioid-equianalgesic-tables-are-broken.html Google Scholar |
| 90. | Stone EM, Rutkow L, Bicket MC, et al: Implementation and enforcement of state opioid prescribing laws. Drug Alcohol Depend 213:108107, 2020 Crossref, Medline, Google Scholar |
| 91. | Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep 65:1-49, 2016 Crossref, Medline, Google Scholar |
| 92. | Bulls HW, Bell LF, Orris SR, et al: Exemptions to state laws regulating opioid prescribing for patients with cancer-related pain: A summary. Cancer 127:3137-3144, 2021 Crossref, Medline, Google Scholar |
| 93. | Townsend TN, Salz T, Haffajee RL, et al: Has declining opioid dispensing to cancer patients been tailored to risk of opioid harms? J Pain Symptom Manage 63:179-188, 2022 Crossref, Medline, Google Scholar |
| 94. | Zhang H, Paice J, Portenoy R, et al: Prescription opioids dispensed to patients with cancer with bone metastasis: 2011-2017. Oncologist 26:e1890-e1892, 2021 Crossref, Medline, Google Scholar |
| 95. | Woods C, Chai G, Meyer T, et al: Patterns of opioid analgesic use in the US, 2009 to 2018. Pain 162:1060-1067, 2021 Crossref, Medline, Google Scholar |
| 96. | Enzinger AC, Ghosh K, Keating NL, et al: US trends in opioid access among patients with poor prognosis cancer near the end-of-life. J Clin Oncol 39:2948-2958, 2021 Link, Google Scholar |
| 97. | Agarwal A, Roberts A, Dusetzina SB, et al: Changes in opioid prescribing patterns among generalists and oncologists for Medicare Part D beneficiaries from 2013 to 2017. JAMA Oncol 6:1271-1274, 2020 Crossref, Medline, Google Scholar |
| 98. | Furuno JP, Noble BN, Fromme EK, et al: Decreasing trends in opioid prescribing on discharge to hospice care. J Pain Symptom Manage 62:1026-1033, 2021 Crossref, Medline, Google Scholar |
| 99. | Vitzthum LK, Nalawade V, Riviere P, et al: Racial, ethnic, and socioeconomic discrepancies in opioid prescriptions among older patients with cancer. JCO Oncol Pract 17:e703-e713, 2021 Link, Google Scholar |
| 100. | Morden NE, Chyn D, Wood A, et al: Racial inequality in prescription opioid receipt—Role of individual health systems. N Engl J Med 385:342-351, 2021 Crossref, Medline, Google Scholar |
| 101. | Brown JH, Torres HP, Maddi RD, et al: Cancer patients' perceived difficulties filling opioid prescriptions after receiving outpatient supportive care. J Pain Symptom Manage 60:915-922, 2020 Crossref, Medline, Google Scholar |
| 102. | Vidal M, Reddy A, Rodriguez E, et al: Challenges to opioid prescription access among patients with advanced cancer. J Palliat Med 22:121-122, 2019 Crossref, Medline, Google Scholar |
| 103. | White AM, Castle IP, Powell PA, et al: Alcohol-related deaths during the COVID-19 pandemic. JAMA 327:1704-1706, 2022 Crossref, Medline, Google Scholar |
| 104. | Centers for Disease Control: Drug Overdose Deaths in the US Top 100,000 Annually. Hyattsville, MD, CDC, National Center for Health Statistics, 2021 Google Scholar |
| 105. | Yennurajalingam S, Arthur J, Reddy S, et al: Frequency of and factors associated with nonmedical opioid use behavior among patients with cancer receiving opioids for cancer pain. JAMA Oncol 7:404-411, 2021 Crossref, Medline, Google Scholar |
| 106. | Leap KE, Chen GH, Lee J, et al: Identifying prevalence of and risk factors for abnormal urine drug tests in cancer pain patients. J Pain Symptom Manage 62:355-363, 2021 Crossref, Medline, Google Scholar |
| 107. | Vitzthum LK, Riviere P, Sheridan P, et al: Predicting persistent opioid use, abuse, and toxicity among cancer survivors. J Natl Cancer Inst 112:720-727, 2020 Crossref, Medline, Google Scholar |
| 108. | Gilligan T, Coyle N, Frankel RM, et al: Patient-clinician communication: American Society of Clinical Oncology consensus guideline. J Clin Oncol 35:3618-3632, 2017 Link, Google Scholar |
| 109. | Patel MI, Lopez AM, Blackstock W, et al: Cancer disparities and health equity: A policy statement from the American Society of Clinical Oncology. J Clin Oncol 38:3439-3448, 2020 Link, Google Scholar |
| 110. | American Cancer Society: Cancer Facts & Figures for African American/Black People 2022-2024. Atlanta, American Cancer Society, 2022 Google Scholar |
| 111. | American Cancer Society: Cancer Facts & Figures for Hispanic/Latino People 2021-2023. Atlanta, American Cancer Society, 2021 Google Scholar |
| 112. | Fisch MJ, Lee JW, Weiss M, et al: Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer. J Clin Oncol 30:1980-1988, 2012 Link, Google Scholar |
| 113. | Hui D, Abdelghani E, Chen J, et al: Chronic non-malignant pain in patients with cancer seen at a timely outpatient palliative care clinic. Cancers (Basel) 12:214, 2020 Crossref, Medline, Google Scholar |
| 114. | Page R, Blanchard E: Opioids and cancer pain: Patients' needs and access challenges. J Oncol Pract 15:229-231, 2019 Link, Google Scholar |
| 115. | Agnoli A, Xing G, Tancredi DJ, et al: Association of dose tapering with overdose or mental health crisis among patients prescribed long-term opioids. JAMA 326:411-419, 2021 Crossref, Medline, Google Scholar |
| 116. | Oliva EM, Bowe T, Manhapra A, et al: Associations between stopping prescriptions for opioids, length of opioid treatment, and overdose or suicide deaths in US veterans: Observational evaluation. BMJ 368:m283, 2020 Crossref, Medline, Google Scholar |
| 117. | DiPrete BL, Ranapurwala SI, Maierhofer CN, et al: Association of opioid dose reduction with opioid overdose and opioid use disorder among patients receiving high-dose, long-term opioid therapy in North Carolina. JAMA Netw Open 5:e229191, 2022 Crossref, Medline, Google Scholar |
| 118. | Coffin PO, Barreveld AM: Inherited patients taking opioids for chronic pain—Considerations for primary care. N Engl J Med 386:611-613, 2022 Crossref, Medline, Google Scholar |
| 119. | Schnipper LE, Davidson NE, Wollins DS, et al: American Society of Clinical Oncology statement: A conceptual framework to assess the value of cancer treatment options. J Clin Oncol 33:2563-2577, 2015 Link, Google Scholar |
| 120. | Schnipper LE, Davidson NE, Wollins DS, et al: Updating the American Society of Clinical Oncology value framework: Revisions and reflections in response to comments received. J Clin Oncol 34:2925-2934, 2016 Link, Google Scholar |
| 121. | Streeter SB, Schwartzberg L, Husain N, et al: Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract 7:46s-51s, 2011 Link, Google Scholar |
| 122. | Dusetzina SB, Winn AN, Abel GA, et al: Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 32:306-311, 2014 Link, Google Scholar |
| 123. | Meropol NJ, Schrag D, Smith TJ, et al: American Society of Clinical Oncology guidance statement: The cost of cancer care. J Clin Oncol 27:3868-3874, 2009 Link, Google Scholar |
| 124. | Ferrell BR, Temel JS, Temin S, et al: Integration of palliative care into standard oncology care: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 35:96-112, 2017 Link, Google Scholar |
| 125. | Mao JJ, Ismaila N, Bao T, et al: Integrative medicine for pain management in oncology: Society for Integrative Oncology–ASCO guideline. J Clin Oncol 40:3998-4024, 2022 Link, Google Scholar |
| 126. | Davies A, Leach C, Butler C, et al: Opioid-induced constipation in patients with cancer: A "real-world," multicentre, observational study of diagnostic criteria and clinical features. Pain 162:309-318, 2021 Crossref, Medline, Google Scholar |
| 127. | Rao VL, Micic D, Davis AM: Medical management of opioid-induced constipation. JAMA 322:2241-2242, 2019 Crossref, Medline, Google Scholar |
| 128. | Birthi P, Nagar VR, Nickerson R, et al: Hypogonadism associated with long-term opioid therapy: A systematic review. J Opioid Manag 11:255-278, 2015 Crossref, Medline, Google Scholar |
| 129. | Marudhai S, Patel M, Valaiyaduppu Subas S, et al: Long-term opioids linked to hypogonadism and the role of testosterone supplementation therapy. Cureus 12:e10813, 2020 Medline, Google Scholar |
| 130. | Davis M, Hui D, Davies A, et al: MASCC antiemetics in advanced cancer updated guideline. Support Care Cancer 29:8097-8107, 2021 Crossref, Medline, Google Scholar |
| 131. | Benson JL, Campbell HE, Phillips CN: Opioid-induced pruritus. Consult Pharm 30:221-227, 2015 Crossref, Medline, Google Scholar |
| 132. | Rashid S, Trivedi DD, Al-Shathir M, et al: Is there a role for 5-HT3 receptor antagonists in the treatment of opioid-induced pruritus? Am J Hosp Palliat Care 35:740-744, 2018 Crossref, Medline, Google Scholar |
| 133. | Gammel LB, Leonard M, Wheeler H, et al: Controlled substance use and clinical outcomes of elderly patients after a fall. Cureus 14:e22356, 2022 Medline, Google Scholar |
| 134. | Gomes T, Greaves S, van den Brink W, et al: Pregabalin and the risk for opioid-related death: A nested case-control study. Ann Intern Med 169:732-734, 2018 Crossref, Medline, Google Scholar |
| 135. | Gomes T, Juurlink DN, Antoniou T, et al: Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med 14:e1002396, 2017 Crossref, Medline, Google Scholar |
| 136. | Prommer E: Methylphenidate: Established and expanding roles in symptom management. Am J Hosp Palliat Care 29:483-490, 2012 Crossref, Medline, Google Scholar |
| 137. | Mercadante S, Ferrera P, Casuccio A: Prevalence of opioid-related dysuria in patients with advanced cancer having pain. Am J Hosp Palliat Care 28:27-30, 2011 Crossref, Medline, Google Scholar |
