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Overview

Opioid agonists are recommended for moderate-to-severe pain refractory to other analgesics.¹ While the potency of opioid analgesics varies, available evidence suggests similar efficacy amongst products when compared at equianalgesic doses.² However, due to the large interindividual variability in pain response to analgesic agents, the choice of treatment and associated monitoring requires an individualized approach that includes consideration of patient-specific needs related to pain management and risk of treatment-related toxicities.^1-3 Since many opioid-related adverse events (AEs) are dose-related, the analgesic potential of a particular opioid is likely to be limited by its safety profile; therefore, patient tolerability becomes an important factor in treatment choice.⁴

All full opioid agonists are Schedule II controlled substances (CSs) due to their potential for abuse that may lead to severe physical or psychological dependence.⁵ Tapentadol, a weak opioid agonist and norepinephrine (NE) reuptake inhibitor is also a Schedule II CS, while tramadol, an opioid agonist and NE and serotonin reuptake inhibitor is a Schedule IV CS.^3,5 As of 2017, all opioid analgesics are also included in the Food and Drug Administration’s (FDA’s) Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS), which has a goal of helping to ensure health care provider familiarity with the treatment and monitoring of patients with pain, including the benefits and risks of opioids in the treatment paradigm.⁶ Certain risk factors increase an individual’s susceptibility to opioid-related harms (see Box 1).⁴ Therefore, therapeutic success with opioid analgesia will depend on proper candidate selection, assessment before selecting and administering therapy, and close monitoring throughout treatment. Education for providers and patients focused on principles of pain management are recognized as an important strategy in promoting the safe use of opioids and are a primary component of the Opioid Analgesic REMS.^4,6

Contraindications, warnings, and precautions

Boxed warnings and contraindications for clinically employed opioid analgesics are summarized in Table 1.^7,8 Formulation and product-specific safety concerns are applicable throughout this drug class, and the prescribing information for a particular product should be consulted for a complete safety profile for that agent. The mixed opioid agonist-antagonist agents (buprenorphine, etc) may cause opioid withdrawal in opioid-tolerant patients. Since these agents are not commonly used in practice for analgesic indications, they are not included in the table.^2,3

In general, opioids are contraindicated in patients with hypersensitivity to any component or the active ingredient.^7,8 They should not be administered to patients with significant respiratory depression, acute or severe bronchial asthma, or suspected or documented gastrointestinal obstruction or paralytic ileus. Numerous warnings and precautions are also applicable to opioid analgesics including:

• Abuse potential
• Respiratory depression
• Central nervous system (CNS) depression
• Unintentional pediatric exposure
• Neonatal opioid withdrawal syndrome (NOWS)
• Adrenal insufficiency
• Risk of opioid withdrawal with abrupt discontinuation of treatment
• Hepatitis and hepatic events
• Hypersensitivity reactions
• Precipitation of opioid withdrawal signs and symptoms
• Use in patients with impaired hepatic function
• Impairment of the ability to drive or operate machinery
• Orthostatic hypotension
• Elevation of cerebrospinal fluid pressure
• Elevation of intracholedochal pressure
• Effects in acute abdominal conditions

Opioids that are co-formulated with nonopioid analgesics such as acetaminophen and ibuprofen also carry contraindications, warnings, and precautions applicable to those agents.

Adverse effects

All opioids have similar AE profiles at equianalgesic doses.² Opioid-related AEs may limit dose increases and represent an important barrier to the analgesic potential of a product. In some cases, AEs reflect the presence of high peak serum concentrations. Clinicians may mitigate AEs related to this situation by changing to an extended-release (ER) opioid formulation if appropriate, giving smaller doses more frequently, or rotating to another opioid. Key opioid-related AEs and their management (as appropriate) are discussed further in this section.

Tolerance and dependence

Tolerance to both the analgesic and unfavorable effects of opioids develops with prolonged or repeated exposure to opioid analgesics.³ Tolerance refers to the need for escalating doses of an opioid to achieve the same level of pain control. Patients may also develop tolerance to opioid-related AEs, and experience less AEs as opioid therapy is continued. The development of tolerance is highly variable and may occur at different rates and times for patients and AEs. Constipation and miosis are an exception, as tolerance to these AEs does not occur to a clinically significant degree.⁹ The decrease in the analgesic effectiveness of an opioid over time may warrant switching to alternate opioid therapy (ie, “opioid rotation”) to maintain adequate analgesia.² When rotating between opioids, the current 24-hour opioid analgesic dose is converted to the total daily oral morphine equivalent and then converted to the estimated 24-hour requirement of the new opioid therapy. A 25% to 50% decrease in this daily dose should be instituted to account for incomplete cross-tolerance between different opioids.

Dependence is a state of adaptation to a drug where sudden discontinuation or rapid dose reduction may result in serious withdrawal symptoms, uncontrolled pain, psychological distress, and, potentially, suicide.³ In patients who become physically dependent on opioids, dose reductions or discontinuation of therapy should be done gradually using an individualized approach.

Misuse, abuse, and addiction

Opioid tolerance and dependence, which are eventually seen in all patients who use opioids chronically, are not synonymous with misuse, abuse, or addiction.¹⁰ Unlike tolerance and dependence, which are physiologic responses to prolonged opioid exposure, opioid addiction is a disease characterized by drug-seeking behaviors, including impaired control over drug use, cravings, compulsive use, or continued use despite harm.^4,10 The positive and rewarding effects of opioids are considered to be the driving component for addiction, and avoidance or alleviation of withdrawal symptoms may also become a primary motivation for compulsive drug use.³ Opioid abuse involves intentional self-administration of opioids for nonmedical purposes, while misuse involves the willful or unintentional use of an opioid other than as directed or indicated.¹¹ A diagnosis of opioid use disorder (OUD) is generally used to characterize a problematic pattern of opioid use that leads to serious impairment or distress.

Misuse, abuse, and addiction can occur in anyone who uses opioids.¹⁰ In 2016, upwards of 11 million Americans reported misusing prescription opioids in the past year. Risk factors for opioid misuse, abuse, and OUD are summarized in Boxes 2 and 3.¹¹ Opioid misuse and addiction increase the risk of opioid-related harms and death due to overdose. Per the CDC, hydrocodone, oxycodone, and methadone are the most common drugs involved in prescription opioid overdose deaths.

Systems-based review of key adverse effects

Neurological

Drowsiness, sedation, and cognitive impairment are common with all opioid analgesics, and increasing sedation is a key indicator of impending opioid-induced respiratory depression (OIRD) and death due to overdose.³ Opioids may also precipitate seizures, especially when used at high doses. Other neurotoxicities, including muscle twitches, tremors, and delirium, have also been reported, especially with meperidine use.

Respiratory

Respiratory depression is a relatively uncommon, but severe AE of opioid therapy.³ All opioid analgesics have the potential to cause respiratory depression when given in large enough doses, especially in at-risk populations (see Box 4). ER, long-acting (LA), and transdermal products are also more likely to lead to OIRD and death if titrated too rapidly or if there is a loss of integrity of their dosage form (eg, a tablet is crushed or patch is cut), as these products commonly contain more opioid than indicated on the labeling. Periods of greater OIRD risk include at treatment initiation and after a dose increase.²

Cardiovascular

Bradycardia and hypotension (particularly orthostatic hypotension) have been reported with opioid use.³ Prolongation of the QT interval has been reported with methadone.¹² Methadone safety guidelines from the American Pain Society (APS), in collaboration with the College on Problems of Drug Dependence (CPDD) and Heart Rhythm Society (HRS), provide recommendations for baseline and continued monitoring of electrocardiogram (ECG) for patients requiring methadone therapy (see Box 5). methadone should be avoided in patients with a baseline QT interval > 500 milliseconds (ms). Patients who develop a QT interval ≥ 500 ms while receiving methadone should immediately have their dose lowered, or be switched to an alternative opioid therapy. In patients with a QT interval ≥ 450 ms but < 500 ms, switching to an alternative opioid or lowering the methadone dose should be considered. Clinicians should also evaluate for, and correct reversible causes of, QT interval prolongation in all cases.

Gastrointestinal

Constipation is one of the most common side effects of opioids and experienced to some degree by nearly all patients who receive opioid-containing analgesia.¹³ Unlike most other opioid-induced AEs, tolerance to constipation does not develop. Therefore, patients receiving chronic opioid therapy should always receive a concurrent bowel regimen and counseling on nonpharmacologic strategies to manage constipation.

According to the 2019 American Gastroenterological Association (AGA) guideline on the medical management of opioid-induced constipation (OIC), lifestyle modifications including appropriate fluid intake, regular exercise, and toileting as soon as possible when there is an urge to defecate are essential initial steps in constipation management.¹³ Patients with OIC may also benefit from switching to an equianalgesic dose of an opioid associated with less constipation. If a nonpharmacologic approach does not relieve OIC, there are a variety of pharmacologic classes available including traditional laxatives (eg, lactulose, magnesium citrate, bisacodyl, docusate, mineral oil, and senna), peripherally acting m-opioid receptor antagonists (PAMORAs), intestinal secretagogues, and selective 5-hydroxytrypamine agonists.¹³ For first-line treatment of OIC, the AGA guideline recommends administration of a traditional laxative. With regard to the more recently available medications for OIC, a summary of AGA recommendations is presented in Table 2.

Other common gastrointestinal AEs with opioid agonists include including nausea and vomiting.³ Antiemetics may help to reduce these symptoms as tolerance to them develops.

Dermatologic

Dermatological AEs are common with transdermal opioids and include mild rash and pruritus. Morphine and meperidine have also been reported to cause pruritus, with a higher probability of occurrence when administered by epidural or intraspinal injection.³ Relief of itching in these cases may be achieved with antihistamines such as diphenhydramine. Morphine has also been shown to cause transient flushing of the skin of the face, neck, and upper thorax.

Endocrine

Opioids may modulate the hypothalamic-pituitary-adrenal (HPA) axis and impair the release of vital HPA hormones, including cortisol and sex hormones.³ The resulting clinical effects include adrenal insufficiency and sexual dysfunction.¹⁴ Symptoms of adrenal insufficiency include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure. Low levels of sex hormones may present as low libido, impotence, erectile dysfunction, lack of menstruation, or infertility. Clinicians should perform diagnostic testing if there are concerns about HPA axis suppression in patients taking opioids. Adrenal insufficiency can be treated with corticosteroids. Weaning off opioids should also be considered, if appropriate.

Drug interactions

Patients who require opioid medications generally have other comorbidities that require drug therapy.¹⁵ Polypharmacy, even when appropriate, increases the risk for clinically significant drug interactions. Therefore, patients receiving opioids concurrently with other therapies should be closely monitored for the development of AEs secondary to drug interactions.

Table 3 lists the major drug interactions with opioid analgesics.^7,8 Similar to other drug classes, drug interactions with opioids can occur through pharmacokinetic and pharmacodynamic pathways.⁹ The hepatic cytochrome P450 system is responsible for a large portion of opioid-metabolism. Therefore, substrates, inhibitors, and inducers of CYP enzymes, mainly CYP3A4 and CYP2D6, can significantly alter the serum concentrations of opioids. Genetic and phenotypic variation in CYP enzymes may also alter how individuals metabolize certain opioids.³ For example, codeine and tramadol are converted to their active metabolites (morphine and n-desmethyltramadol, respectively) much quicker than average in patients who are ultra-rapid metabolizers of CYP2D6 substrates.^2,3 A higher than expected rate of metabolism of these agents may lead to elevated concentrations of their active metabolites, which increases the risk for opioid-related AEs including overdose and respiratory depression. Conversely, poor metabolizers may experience a lack of efficacy with these agents, as the resulting serum concentration of active metabolites may be inefficient to produce analgesia.³ Since children may also metabolize opioids at rates similar to ultra-metabolizers, both codeine and tramadol are contraindicated for use in children < 12 years of age. Caution should also be applied when using codeine in adolescents, and codeine should not be used in patients < 18 years after a tonsillectomy and/or adenoidectomy.

Pharmacodynamic interactions with opioids occur when they are coadministered with other drugs or substances that yield synergistic or antagonistic pharmacological effects.⁹ Concurrent use of opioids with other CNS depressants like benzodiazepines and alcohol, for example, increases the risk for sedation, respiratory depression, coma, and death. On the other hand, the combined use of opioid agonists with mixed opioid agonists/antagonists may result in reduced analgesic effects of the opioid agonists or possible precipitation of withdrawal symptoms.

Serotonin syndrome

Serotonin syndrome may occur within hours to days of taking an opioid with another serotonergic agent, but may also occur without concurrent serotonergic therapy.^9,14 Symptoms of serotonin syndrome include agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.⁹ If serotonin syndrome is suspected, either the opioid and/or the other serotonergic therapy should be discontinued.¹⁴

Special populations

Children and older adults may be more sensitive to the effects of opioids due to alterations in drug metabolism.² Since most opioids are metabolized and eliminated via hepatic and renal routes, respectively, patients with these organ impairments may also experience alterations in serum concentrations of opioids. Caution should be exercised when administering opioids to these populations.

While the use of opioids is not contraindicated in pregnancy, these agents can lead to respiratory depression and physical dependence in neonates due to their ability to cross the placenta.⁷ Furthermore, prolonged use of opioids during pregnancy may lead to NOWS, which can be life-threatening to the newborn if not recognized and treated. Similarly, infants exposed to opioid agonists through breast milk may experience withdrawal symptoms when maternal opioid use or breastfeeding is stopped. Infants exposed to opioids through breast milk should be monitored for excessive sedation and respiratory depression. Mother’s administered codeine and tramadol are recommended to avoid breastfeeding, since ultra-rapid metabolism and increase in drug concentrations may lead to life-threatening respiratory depression in the infant.

Medication errors

Medication therapy management of opioids is complicated by the variety of available agents and the need to convert between different formulations and routes of administration.³ The dose of a prescription opioid can vary by a factor of 10 to 100 depending on the product and how it is administered; therefore, significant changes in the patient’s clinical response or toxicity can result from inappropriate use of these drugs. Many points in the medication use process for opioids are susceptible to medication errors, including at the point of prescribing, dispensing, and administration.¹⁶ A misunderstanding in the directions for use can result in patients receiving more or less of the drug than intended. Fentanyl patches, in particular, have been linked to serious injuries due to medication errors, included prescribing errors, inappropriate placement of patches by patients, replacement of patches at wrong time intervals, and accidental exposure to patches in children, resulting in death.¹⁷

All formulations of opioids appear on the Institute for Safe Medication Practices (ISMP) lists of high-alert medications that are used in the acute care, community/ambulatory, and long-term care settings.^18-20

Many solid oral dosage forms of opioid-containing products also appear on ISMP’s Oral Dosage Forms that Should Not Be Crushed List, and several opioids appear on ISMP’s List of Confused Drug Names due to “look-alike” or “sound-alike” characteristics between drug names.^21,22 These lists may be helpful to consult when designing safeguards to reduce the risk of medication errors and minimize harm relevant to certain opioids.

Improving patient safety

Frequent assessments of analgesic efficacy and the emergence of AEs should be performed to optimize pain management in patients requiring opioids.⁴ Opioid analgesics, while effective for a variety of pain syndromes, present serious risks, including addiction, overdose, and death. From 1999 to 2017, there were more than 400,000 deaths due to opioid overdose.²³ To encourage responsible opioid prescribing particularly among primary care providers, the Centers for Disease Control and Prevention (CDC) issued a guideline for prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care.⁴ This 2016 guideline addresses when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing risks and addressing harms of opioid use. A summary of the CDC’s recommendations is provided in Box 6.

Risk Evaluation and Mitigation Strategy

On September 18, 2018, an existing long-acting opioid REMS program was modified to include all IR opioids as well.⁶ This program, now known as the Opioid Analgesic REMS program, encourages health care providers (including nurses and pharmacists) to complete an approved training program focused on the treatment and monitoring of patients with pain. Education under this program is intended to assist health care providers in reducing opioid-related harms, including addiction, unintentional overdose, and death resulting from inappropriate prescribing, abuse, and misuse. Drug-specific REMS programs are also available for transmucosal IR fentanyl products and sublingual sufentanil tablets to encourage judicious use of these therapies.^24,25

Patient counseling and education

Patient counseling and education surrounding opioid therapy can greatly mitigate opioid-related harms. The Opioid Analgesic REMS includes a patient counseling guide that can be used to facilitate discussions about the risks of opioid therapy and what to do in the event of over-sedation and OIRD.²⁶ Key counseling points from this guide are summarized in Box 7.

Storage and disposal of unused opioids

Accidental or intentional consumption of an opioid by someone for whom the drug was not intended may cause significant harms including death.²⁷ Therefore, counseling patients on proper storage and disposal of opioids may help to reduce the risk of accidental exposure and ingestion by household contacts and reduce the risk of theft. Opioid medications should be stored in a secure place and out of reach of others. Specific environmental storage requirements related to temperature, packaging, and light exposure are often found in the prescribing information and medication guide for a particular product. In general, products should be stored in their original containers and placed in a locked cabinet, lockbox, or other location that is not easily accessible by others. To proactively identify theft, patients are encouraged to keep track of how much medication they have left each time they open the packaging.

Community- and pharmacy-driven drug take-back programs are the recommended strategy for safe disposal of unused drugs, including prescription opioids.²⁸ Registered sites that collect old, unused, unneeded, or expired controlled substances and other medicines are available on the FDA’s website. Authorized mail-back programs and drop off boxes may also be available.

If a medication take-back program is not available, the FDA maintains a “flush list” that includes drugs that can be flushed down the toilet, including instructions on doing so safely.²⁹ Medications found on this list are harmful, even in small quantities, when used by someone for which the drug was not intended. Therefore, the immediate disposal of these substances reduces the risk of harm from accidental ingestion or intentional misuse. Opioids, including transdermal formulations such as fentanyl, comprise most of the drugs on this list. Immediate disposal of fentanyl patches is especially critical, as this product can be extremely harmful if misused by adults, children, or pets. The following steps should be used to discard used or leftover fentanyl patches:³⁰

1. Fold the patch in half so that the sticky side sticks to itself. Removing the patch from its protective pouch and removing the liner may be required. Take care to minimize handling of the patch as much as possible, as there can still be medication leftover after use.
2. Immediately flush down the toilet

Due to environmental concerns with flushing, this strategy of drug disposal should only be performed when other take-back options are not available at the time disposal is needed, and only for medicines on the “flush list.”²⁹

Emergency treatment of opioid overdose

Almost 70% of the 67,000 drug overdose deaths in 2018 involved an opioid, and opioid-involved overdoses continue to be a major public health problem in the United States.²³ Timely administration of naloxone, an opioid antagonist, in conjunction with emergency medical care, is the standard of care for the prevention of death following an opioid overdose.³¹ Naloxone works by displacing opioids from receptor sites in the brain and reverses respiratory depression, sedation, and hypotension. Naloxone dosing depends upon the amount, type, and route of administration of the opioid being antagonized. Key information related to naloxone is summarized in Table 4.^7,31 The World Health Organization (WHO) recommends selecting a route of naloxone administration based on the formulation available, skills in administration, the setting, and local context.³¹

In December 2018, the United States Department of Health & Human Services (HHS) recommended prescribing or co-prescribing naloxone to all patients who are at risk for opioid overdose (Box 8).³² Recommendations for providing naloxone to those likely to witness an overdose are also available from this organization. Naloxone is provided to patients through the regular course of medical care, or via community-based opioid overdose prevention programs.³¹ Most states have passed laws and changed regulations authorizing prescribers to provide naloxone through standing orders and/or to potential overdose witnesses, as well as protecting those who administer naloxone from penalties for practicing medicine without a license. People who are likely to witness an overdose are encouraged to have access to and be trained in the use of naloxone.³² Importantly, bystanders and providers should be aware that forcefully trying to stimulate a person who has overdosed, or making them vomit, should be avoided as it may cause further injury.

Interdisciplinary collaboration

Interdisciplinary pain management programs have been shown to reduce the use of analgesics while improving patient functioning.^33,34 These programs involve collaboration between patients and nurses, pharmacists, physicians, psychiatrists, amongst other clinicians, to optimize therapeutic outcomes related to analgesia. Pain specialists also play an important role in the interdisciplinary care of patients requiring pain management, and consultation with these providers is recommended for those with complex pain syndromes or requiring opioid doses exceeding 90 OME/d.⁴ In patients with active or history of substance use disorder or opioid overdose, a substance use disorder specialist, in conjunction with a pain specialist, is recommended for pain management.

Conclusion

The Opioid Analgesic REMS has a goal of helping to ensure health care provider familiarity with the treatment and monitoring of patients with pain, including the benefits and risks of opioids in the treatment paradigm.⁶ The large interindividual variability in toxicity to opioid analgesics means that the associated monitoring of these therapies requires an individualized approach.^1-3 All opioids contain warnings regarding addiction, abuse, and misuse of these products.⁷ Opioid-involved overdoses also continue to be a major public health concern in the United States, and have led to recommendations for prescribing or co-prescribing naloxone to at-risk patients.^23,32 To mitigate the risk of opioid-related harms, patients prescribed opioid analgesics should receive comprehensive counseling and education on how to administer opioid therapy, the risks of treatment, guidance for the use of naloxone, and proper storage and disposal of opioid analgesics.²⁶

References

1. Herndon CM, RJ, Kominek CM. Pain management. In: DiPiro JT, Yee GC, Posey LM, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. New York, NY: McGraw Hill; 2019. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577§ionid=219306022. Accessed April 24, 2020.
2. Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J Clin Pharmacol. 2018;58(9):1111-1122.
3. Yaksh T, Wallace M. Opioids, analgesia, and pain management. In: Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill Education; 2018. https://accessanesthesiology.mhmedical.com/content.aspx?bookid=2189§ionid=165936845. Accessed April 24, 2020.
4. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain-United States, 2016.2016;315(15):1624-1645.
5. Drug Enforcement Administration (DEA). Lists of: scheduling actions, controlled substances, and regulated chemicals. DEA website. https://www.deadiversion.usdoj.gov/schedules/. Updated February 2020. Accessed April 24, 2020.
6. Food and Drug Administration (FDA) Approved Risk Evaluation and Mitigation Strategies (REMS). Opioid Analgesic REMS. FDA website. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&REMS=17. November 14, 2019. Accessed April 24, 2020.
7. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2020. http://www.clinicalpharmacology-ip.com/default.aspx. Accessed March 20, 2020.
8. Micromedex Solutions [database online]. Greenwood Village, CO: Truven Health Analytics;
   http://www.micromedexsolutions.com/micromedex2/librarian/. Accessed March 20, 2020.
9. Schumancher MA, Basbaum AI, Naidu RK. Opioid agonists & antagonists. In: Weitz M, Boyle P, eds. Basic & Clinical Pharmacology. 14th ed. New York, NY: McGraw-Hill; 2018. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2249&sectionid=175215158. Accessed March 20, 2020.
10. Centers for Disease Control and Prevention (CDC). Opioid basics. CDC website. https://www.cdc.gov/drugoverdose/opioids/index.html. Updated March 19, 2020. Accessed April 24, 2020.
11. Webster LR. Risk factors for opioid-use disorder and overdose. Anesth Analg. 2017;125(5):1741-1748.
12. Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15(4):321-337.
13. Crockett SD, Greer KB, Heidelbaugh JJ, et al; American Gastroenterological Association (AGA) Institute Clinical Guidelines Committee. AGA Institute guideline on the medical management of opioid-induced constipation. 2019;156(1):218-226.
14. Food and Drug Administration (FDA). FDA Drug Safety Communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. FDA website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-several-safety-issues-opioid-pain-medicines-requires. Published March 22, 2016. Accessed April 24, 2020.
15. Peabody J, Acelajado MC, Robert T, et al. Drug-drug interaction assessment and identification in the primary care setting. J Clin Med Res.2018;10(11):806-814.
16. Substance Abuse and Mental Health Services Administration (SAMHSA). Opioid overdose prevention toolkit. SAMHSA website. https://store.samhsa.gov/product/Opioid-Overdose-Prevention-Toolkit/SMA18-4742. Accessed April 24, 2020.
17. Institute for Safe Medication Practices (ISMP). Quarter Watch. ISMP website. https://www.ismp.org/quarterwatch/pdfs/2012Q4.pdf. Updated October 17, 2013. Accessed April 24, 2020.
18. Institute for Safe Medication Practices (ISMP). High-alert medications in the acute care setting. ISMP website. https://www.ismp.org/recommendations/high-alert-medications-acute-list. Updated August 23, 2018. Accessed April 24, 2020.
19. Institute for Safe Medication Practices (ISMP). High-alert medications in community/ambulatory care settings. ISMP website. https://www.ismp.org/recommendations/high-alert-medications-community-ambulatory-list. Updated January 31, 2011. Accessed April 24, 2020.
20. Institute for Safe Medication Practices (ISMP). High-alert medications in long-term care (LTC) settings. ISMP website. https://www.ismp.org/recommendations/high-alert-medications-long-term-care-list. Updated November 20, 2017. Accessed April 24, 2020.
21. Institute for Safe Medication Practices (ISMP). Oral dosage forms that should not be crushed. ISMP website. https://www.ismp.org/recommendations/do-not-crush. Updated February 21, 2020. Accessed April 24, 2020.
22. Institute for Safe Medication Practices (ISMP). List of confused drug names. ISMP website. https://www.ismp.org/recommendations/confused-drug-names-list. February 28, 2019. Accessed April 24, 2020.
23. Centers for Disease Control and Prevention (CDC). Opioid overdose. CDC website. https://www.cdc.gov/drugoverdose/. Updated March 4, 2020. Accessed April 24, 2020.
24. Food and Drug Administration (FDA) Approved Risk Evaluation and Mitigation Strategies (REMS). Transmucosal immediate-release fentanyl (TIRF) products. FDA website. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&REMS=60. Updated September 7, 2017. Accessed March 20, 2020.
25. Food and Drug Administration (FDA) Approved Risk Evaluation and Mitigation Strategies (REMS). Dsuvia (sufentanil). FDA website. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=384. Updated November 2, 2018. Accessed April 24, 2020.
26. What you need to know about opioid pain medicines. Opioid Analgesic REMS website. https://opioidanalgesicrems.com/RpcUI/rems/pdf/resources/patient_counseling_document.pdf. Accessed April 24, 2020.
27. Centers for Disease Control and Prevention (CDC). Your prescription medicine: tips for safe storage and disposal. CDC website. https://www.cdc.gov/wtc/prescriptionsafety.html. Updated April 18, 2019. Accessed April 24, 2020.
28. Food and Drug Administration (FDA). Where and how to dispose of unused medications. FDA website. https://www.fda.gov/consumers/consumer-updates/where-and-how-dispose-unused-medicines. Updated March 11, 2020. Accessed April 24, 2020.
29. Food and Drug Administration (FDA). Drug disposal: flush potentially dangerous medications. FDA website. https://www.fda.gov/drugs/disposal-unused-medicines-what-you-should-know/drug-disposal-flush-potentially-dangerous-medicine#FlushList. Updated December 19, 2018. Accessed April 24, 2020.
30. Duragesic [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2019.
31. World Health Organization (WHO). Community management of opioid overdose. WHO website. http://www.who.int/substance_abuse/publications/management_opioid_overdose/en/. Published November 2014. Accessed April 24, 2020.
32. US Department of Health & Human Services (HHS). Naloxone: the opioid reversal drug that saves lives. HHS website. https://www.hhs.gov/opioids/sites/default/files/2018-12/naloxone-coprescribing-guidance.pdf. Published December 2018. Accessed April 24, 2020.
33. Giannitrapani KF, Glassman PA, Vang D, et al. Expanding the role of clinical pharmacists on interdisciplinary primary care teams for chronic pain and opioid management. BMC Fam Pract. 2018;19(1):107.
34. Guildford BJ, Daly-Eichenhardt A, Hill B, Sanderson K, McCracken LM. Analgesic reduction during an interdisciplinary pain management programme: treatment effects and processes of change. Br J Pain. 2018;12(2):72-86.

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