Case Objectives

• Appreciate the challenges of managing acute pain in hospitalized patients on chronic opioids.
• Describe the importance of understanding the nature of the acute pain and its relationship to the chronic pain.
• List key principles in safe prescribing of opioids in the hospital.
• List patient-related and prescribing-related risk factors for opioid-related adverse events.
• Describe steps to improve prescribing and monitoring of patients on opioids in the hospital.
• Describe the Prescription Drug Monitoring Program and how it may improve prescribing.

Case & Commentary—Part 1

A 58-year-old man was admitted to the hospital with a non-healing foot ulcer related to severe peripheral vascular disease. He also had a history of chronic obstructive disease and chronic pain. His pain was long-standing and related to multiple prior neck and back surgeries. For years he had been treated with long-acting morphine (extended-release 40 mg twice daily) as well as additional opioids for breakthrough pain. On admission, he reported 8/10 pain, despite receiving his home opioid regimen. After a surgical amputation to treat the ulcer, his pain worsened to 10/10.

Rates of opioid use, and long-term use for chronic non-cancer pain, have markedly increased over the last 2–3 decades.(1,2) Although data regarding the prevalence of chronic opioid use in hospitalized patients are sparse, one recent study found that more than 25% of patients hospitalized at Veterans Administration Hospitals were receiving chronic opioid therapy, defined as 90 days or more of opioids prescribed in the 6 months prior to hospitalization.(3) Furthermore, patients receiving chronic opioid therapy consume a disproportionate share of health care resources, including significantly more emergency room visits and days in the hospital.(4) The issue faced by providers caring for the patient in the case, therefore, is quite common: How should management of acute pain in hospitalized patients receiving chronic opioid therapy be approached? Embedded in this question are issues relating to efficacy and safety; specifically, finding the right balance between achieving adequate analgesia and avoiding adverse effects or problems with opioid misuse and/or addiction.

Achieving adequate analgesia in patients on chronic opioid therapy is challenging. There are well-described pharmacodynamic issues that make pain control more difficult to achieve in patients on chronic opioids, including tolerance (higher doses of opioids are required to maintain the same level of analgesia) and opioid-induced hyperalgesia (patients experience greater pain with less noxious stimuli). Thus, not only are patients on chronic opioids more likely to be hospitalized, but they may be more likely to experience acute pain while in the hospital. Physicians, on the other hand, may be reluctant to provide additional opioids due to concerns over adverse effects, particularly while prescribing the higher doses often required in this patient population. Physicians and other providers may also have concerns about abuse or contributing to addiction. All of these factors can result in under-treatment of pain in this patient population.(5)

When evaluating a patient on chronic opioids for acute pain, a thorough understanding of the nature or quality of the pain and its relationship to the patient's chronic pain complaint is crucial. We are told that the patient in this case experienced a "worsening" of his pain after his surgery, but it is not clear whether this was worsening of his chronic neck and back pain or worsening of his foot pain. This information would be essential in assessing response to therapy. Opioid escalation for acute foot pain in the setting of a surgical amputation should be identified as such, and opioid requirements should be expected to gradually decrease with passage of time after the operation. Lack of improvement with time could indicate a post-operative complication, tolerance, or possible addiction. Additionally, a better understanding of the nature or quality of the pain could assist in identifying the optimal treatment strategy. For example, inflammatory pain is optimally treated with nonsteroidal anti-inflammatory drugs (NSAIDs), while neuropathic pain may respond well to the addition of gabapentin or pregabalin, or consultation with a pain management specialist for consideration of a nerve block.(6) These non-opioid medications, when combined with opioids, have been demonstrated to improve pain control and lower opioid requirements in the acute care setting.(6) Accordingly, the American Society of Anesthesiologists recommends a multimodal approach to pain management, using at least two different classes of analgesics.(6)

Once a decision has been made to use opioid analgesics to manage acute post-operative pain, identifying the optimal drug, dose, route, and regimen are important in assuring a favorable risk-to-benefit ratio. Guidance on these decisions comes mostly from expert opinion.(6,7) The patient's previous long-acting opioid should be continued, if possible, to deliver the patient's usual baseline analgesia and avoid precipitating withdrawal. When adding additional opioids for acute pain, immediate-release opioids should be used to facilitate dose titration. The oral route of administration is preferred when possible to maximize duration of action and reduce addiction potential. If pain is severe and immediate control is necessary, intravenous opioids may be initially required, and consideration should be given to patient-controlled analgesia in an alert patient. If possible, the immediate-release opioid chosen for management of acute pain should be the same type as that used for chronic pain, to minimize chances of side effects and adverse effects due to incomplete cross-tolerance and facilitate ease of dose calculations. The patient's total daily opioid consumption prior to hospitalization should be ascertained as accurately as possible and converted to a baseline daily oral morphine equivalent—several online or handheld device calculators are available for this conversion. In general, an initial dose of 10%–20% of the baseline total daily dose should be used, with an as-needed frequency based on the estimated duration of action—approximately 4 hours for oral, and 3 hours for intravenous.(8,9)

In the event that adverse effects or other considerations necessitate changing to a different opioid than the chronic medication, guidelines advise starting with a dose 25%–50% lower than the calculated equianalgesic dose, to avoid unintentional overdose in the setting of incomplete cross-tolerance.(10) In selecting an alternate opioid, there are a few key considerations. Due to their metabolism, morphine and hydromorphone have fewer drug–drug interactions than other opioids.(11) However, most opioids, including morphine and hydromorphone, are eliminated primarily in the urine, necessitating dosage adjustment in the presence of renal failure.(11)

With respect to the patient in the case, his outpatient dose of 40 mg extended-release morphine twice daily should be confirmed and continued. For his superimposed acute pain, since his primary outpatient opioid is morphine, immediate-release morphine would be an appropriate choice. The recommended dose would be 10%–20% of his baseline of 80 mg daily, which is 8–16 mg orally, every 4 hours as needed, with adjustment based on response. Given the inflammatory nature of his pain, an NSAID should be administered as well, assuming there is no contraindication.

Case & Commentary—Part 2

In addition to post-operative surgical pain and his chronic pain, he also began having diffuse severe muscle spasms. Over the next 48 hours he was given increasing doses of extended-release morphine (up to a dose of morphine 165 mg orally three times a day), as well as intravenous and oral hydromorphone for breakthrough pain. In the afternoon on post-operative day 3, he was found to be somnolent, with an oxygen saturation of 87% on room air. His other vital signs were unremarkable and his oxygen saturation improved to 92% on 2 liters of oxygen by nasal cannula. His afternoon dose of extended-release morphine was held by the primary nurse who notified the surgical resident on duty.

The patient did well until 3 hours after the dose had been held, when he became more alert but complained of 10/10 pain in his post-surgical leg and had tremors and diffuse muscle spasms. The nurse treated his symptoms with hydromorphone 6 mg orally and 1 mg intravenously per the prescribing orders.

The surgical resident was contacted to evaluate the patient and requested the extended-release morphine be given for the ongoing severe pain. The nurse, reluctant to administer this medication in light of the recent episode of somnolence, attempted to explain his reasoning for withholding it but the resident insisted on having him administer the medication. In addition, the patient was writhing in bed with muscle spasms so the resident prescribed diazepam 5 mg intravenously (a muscle relaxant the patient had not been previously prescribed).

Approximately 5 minutes after the diazepam was given, the patient turned pale and became minimally responsive. He was found to have a respiratory rate of 5 breaths per minute. A code blue was called for opioid and benzodiazepine overdose. Fortunately, the patient responded well to intravenous naloxone (an agent that acutely reverses the effects of opioids) and increased oxygen by non-rebreather mask.

He was transferred to the intensive care unit for ongoing monitoring and treatment with naloxone. He was found to have new acute renal insufficiency, which likely had contributed to a build-up of opioids, enhancing their effects. He recovered well and was transferred back to the surgical unit 3 days later. He was ultimately discharged without any long-term effects.

Opioids are among the top causes of drug-related adverse outcomes in hospitalized patients.(12) The most severe adverse event, opioid overdose, is difficult to estimate owing to varied definitions of this endpoint and varied patient populations; however, estimates range from 0.2%–4% of those exposed in the inpatient setting.(13-15) Predictors of opioid-related adverse events include patient-related factors such as age (15,16), obesity (15,16), renal or hepatic failure (11), sleep apnea (16), chronic obstructive pulmonary disease (16), and prescribing-related factors, such as high doses—particularly doses of more than 100 mg oral morphine equivalents per day (16,17) and co-prescription of other sedating medications.(17) Thus, the patient in this case had several factors associated with heightened risk of an opioid-related adverse event, including opioid doses in excess of 100 mg daily, use of multiple opioid drugs with likely incomplete cross-tolerance, co-prescription of other sedating medications, and renal failure.

Studies demonstrate that among the phases of the medication-use process, the prescribing phase contributes most to confirmed opioid overdoses.(18) Improper monitoring is the second most common contributor.(18) This would suggest that multimodal initiatives (as opposed to a single simple solution) aimed at improving prescribing and monitoring practices may have the highest yield in preventing opioid-related overdose in the inpatient setting. However, limited guidance exists on the best methods for achieving these aims in the inpatient setting, and most recommendations are based on expert opinion rather than implementation studies.

In 2012, The Joint Commission issued recommendations for safe use of opioids in hospitals.(18) Although many of these recommendations are based solely on the opinion of experts in the field, they make intuitive sense and provide guidance where few data exist. With respect to improving prescribing, they recommend a combination of education, information technology, and oversight and consultation with pain management specialists. Education should include advising clinicians to use both pharmacologic and non-pharmacologic methods of pain management. In addition, clinicians should be educated on the use of non-narcotic analgesics either as first-line therapy or in combination with opioids. Information technology can be used to support desired prescribing practices, build alerts for unsafe prescribing, and provide conversion support to calculate correct doses of opioids. Institutions are encouraged to create policies and procedures that allow for second-level review and/or consultation by a pain management specialist or pharmacist when doing the following: (i) converting from one opioid to another, (ii) changing the route of administration (i.e., from oral to intravenous or transdermal), or (iii) using high-risk opioids such as methadone, fentanyl, and intravenous hydromorphone.(18) Beyond these recommendations, there are no additional guidelines regarding a threshold at which providers should consult a pain service or other expert. However, most would agree that uncertainty about opioid prescribing decisions, difficulty achieving adequate analgesia, suspected addiction, and managing opioids in a patient with risk factors for adverse events (see above) should all prompt consideration of consultation.

The Prescription Drug Monitoring Program (PDMP) is an additional resource that can improve opioid prescribing by assisting with outpatient opioid dose confirmation and identification of potential addiction, misuse, or diversion. PDMPs, presently available in 49 states, are state-run electronic databases used to track pharmacy dispensing of controlled substances to patients. Studies have demonstrated that PDMPs can influence prescribing in primary care and emergency department settings (19), and it seems logical that they would similarly improve prescribing practices in the inpatient setting. Hospitals should work toward linking PDMPs to electronic health records so that PDMP information is available at the point of care, as recommended by the Centers for Disease Control and Prevention.(20)

With respect to improving monitoring of patients receiving opioid medications in the inpatient setting, The Joint Commission recommends performing serial assessments of respiration and the depth of sedation, particularly when increasing the opioid dose or changing from one opioid to another.(18) However, the method and frequency of such assessments is not specified. They also suggest using continuous pulse oximetry to monitor oxygen saturation. It is important to keep in mind that oxygen saturation can be falsely normal in the setting of supplemental oxygen, and pulse oximetry, therefore, cannot be relied upon as the sole monitoring approach in this setting. Since continuous pulse oximetry is presently a limited resource at most hospitals, future research is necessary to determine which patients may benefit most from this monitoring strategy. In the absence of such data, consider continuous pulse oximetry when increasing the opioid dose, changing from one opioid to another, or in patients with risk factors for adverse events.

Although the patient described ultimately did well, the case illustrates many of the common errors in opioid prescribing for acute pain in a hospitalized patient on chronic opioids. A distinction should have been made between the patient's chronic pain, for which continuation of his usual dose of extended-release morphine would have been appropriate, and his acute postoperative pain, for which immediate-release opioids are more appropriate. Incomplete cross-tolerance to hydromorphone likely played a role, and using intravenous hydromorphone in addition to oral is not only unnecessary, but makes total dosage calculations more difficult, thereby increasing risk of overdose. Morphine and hydromorphone should be dose reduced in the setting of renal failure, and benzodiazepines should generally be avoided in patients on opioids. Consultation with a pain management specialist would likely have prevented these prescribing errors and the associated adverse outcome.

Take-Home Points

• Taking a thorough history regarding the nature of the pain, and differentiating acute from chronic pain, is crucial in directing optimal treatment and optimal monitoring of response.
• Always combine opioid and non-opioid analgesics to maximize analgesia and reduce opioid requirements. For acute pain, use immediate-release opioids to allow dose titration, preferably via the oral route, starting at a dose of approximately 10%–20% of the patient's total baseline opioid requirement. If changing to a different opioid, use a dose 25%–50% lower than the calculated equianalgesic dose.
• Most opioids, with the exception of fentanyl, need to be dose reduced in the setting of renal failure.
• Avoid co-prescription of other medications with sedating properties—particularly benzodiazepines.
• Consider consultation with a pain management specialist for patients at high risk of an opioid-related adverse event, or in situations of uncertainty or suspected addiction.
• Hospitals should work toward integrating Prescription Drug Monitoring Program information into physician workflow when prescribing opioids.

Shoshana J. Herzig, MD, MPH

Instructor in Medicine, Harvard Medical School

Division of General Medicine, Beth Israel Deaconess Medical Center

Boston, MA

Faculty Disclosure: Dr. Herzig has declared that neither she, nor any immediate member of her family, have a financial arrangement or other relationship with the manufacturers of any commercial products discussed in this continuing medical education activity. In addition, the commentary does not include information regarding investigational or off-label use of pharmaceutical products or medical devices.

References

1. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep. 2011;60:1487-1492. [go to PubMed]

2. Boudreau D, Von Korff M, Rutter CM, et al. Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiol Drug Saf. 2009;18:1166-1175. [go to PubMed]

3. Mosher HJ, Jiang L, Vaughan Sarrazin MS, Cram P, Kaboli PJ, Vander Weg MW. Prevalence and characteristics of hospitalized adults on chronic opioid therapy. J Hosp Med. 2014;9:82-87. [go to PubMed]

4. Cicero TJ, Wong G, Tian Y, Lynskey M, Todorov A, Isenberg K. Co-morbidity and utilization of medical services by pain patients receiving opioid medications: data from an insurance claims database. Pain. 2009;144:20-27. [go to PubMed]

5. Huxtable CA, Roberts LJ, Somogyi AA, MacIntyre PE. Acute pain management in opioid-tolerant patients: a growing challenge. Anaesth Intensive Care. 2011;39:804-823. [go to PubMed]

6. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116:248-273. [go to PubMed]

7. Chou R, Fanciullo GJ, Fine PG, et al; American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10:113-130. [go to PubMed]

8. Gammaitoni AR, Fine P, Alvarez N, McPherson ML, Bergmark S. Clinical application of opioid equianalgesic data. Clin J Pain. 2003;19:286-297. [go to PubMed]

9. Levy MH. Pharmacologic treatment of cancer pain. N Engl J Med. 1996;335:1124-1132. [go to PubMed]

10. Fine PG, Portenoy RK; Ad Hoc Expert Panel on Evidence Review and Guidelines for Opioid Rotation. Establishing "best practices" for opioid rotation: conclusions of an expert panel. J Pain Symptom Manage. 2009;38:418-425. [go to PubMed]

11. Smith H, Bruckenthal P. Implications of opioid analgesia for medically complicated patients. Drugs Aging. 2010;27:417-433. [go to PubMed]

12. Lucado J, Paez K, Elixhauser A. Medication-Related Adverse Outcomes in U.S. Hospitals and Emergency Departments, 2008. HCUP Statistical Brief #109. Rockville, MD: Agency for Healthcare Research and Quality; April 2011. [Available at]

13. Eckstrand JA, Habib AS, Williamson A, et al. Computerized surveillance of opioid-related adverse drug events in perioperative care: a cross-sectional study. Patient Saf Surg. 2009;3:18. [go to PubMed]

14. Whipple JK, Ausman RK, Quebbeman EJ. Narcotic use in the hospital: reasonably safe? Ann Pharmacother. 1992;26:897-901. [go to PubMed]

15. Kessler ER, Shah M, Gruschkus SK, Raju A. Cost and quality implications of opioid-based postsurgical pain control using administrative claims data from a large health system: opioid-related adverse events and their impact on clinical and economic outcomes. Pharmacotherapy. 2013;33:383-391. [go to PubMed]

16. Oderda G. Challenges in the management of acute postsurgical pain. Pharmacotherapy. 2012;32(suppl 9):6S-11S. [go to PubMed]

17. Nuckols TK, Anderson L, Popescu I, et al. Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med. 2014;160:38-47. [go to PubMed]

18. Sentinel Event Alert. Safe use of opioids in hospitals. August 8, 2012;(49):1-5. [Available at]

19. Cobaugh DJ, Gainor C, Gaston CL, et al. The opioid abuse and misuse epidemic: implications for pharmacists in hospitals and health systems. Am J Health Syst Pharm. 2014;71:1539-1554. [go to PubMed]

20. Policy Impact: Prescription Painkiller Overdoses. Atlanta, GA: National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. [Available at]