The United States is facing an opioid crisis as the rate of opioid overdoses has roughly tripled since 1999, and continues to climb.1 At present, the most commonly prescribed opioids, oxycodone and hydrocodone, are also the most commonly involved opioids in overdose deaths.1 Opioid prescribing has quadrupled since 1999 and has risen in parallel with the number of overdoses from the most commonly prescribed opioids.1 The economic cost of prescription opioid-related overdose, abuse, and dependence exceeds $78.5 billion annually with the majority of costs related to health care, substance abuse treatment, and lost productivity.2 To address this opioid crisis, a collaborative effort of stakeholders including law enforcement, the general public, and health care providers is needed to encourage appropriate opioid prescribing and monitoring for misuse, abuse, and diversion; expand prescription drug monitoring programs; and widen access to rescue naloxone and opioid use disorder treatment programs.
A particularly difficult aspect of this crisis is the use of opioids among surgical patients. Approximately 51 million Americans undergo inpatient surgery annually, and opioids remain a primary modality for postoperative acute pain management.3–8 Over 80% of patients receive opioids after low-risk surgery, and over 80% of these prescriptions involve oxycodone or hydrocodone.8 Thus, surgical patients routinely receive the most commonly prescribed opioids that are also most commonly implicated in drug overdose deaths. In the inpatient setting, patients undergoing operations most often receive a variety of opioids administered through multiple routes, and the majority of patients prescribed opioids at hospital discharge have had surgery.9,10 Surgery represents a critical event where the majority of patients are exposed to opioids regardless of whether or not they have had a prior opioid-related adverse event including overdose.1,11 Opioid-tolerant patients typically require higher doses over extended postoperative periods further compounding the risks of persistent opioid use, misuse, addiction, and overdose.12–17 Thus, tangible risks exist for both opioid-naive and opioid-tolerant patients undergoing surgery.
The perioperative care team, including anesthesiologists, now face the challenge of optimizing perioperative pain management while limiting the impact of prescription opioid exposure both in the hospital and long after discharge. Through interdisciplinary collaboration with primary care providers, surgeons, and other specialists, anesthesiologists now have the opportunity to provide the bridge between acute inpatient care and remote outpatient recovery, which will serve a critical role to optimize the safety of all surgical patients who are exposed to prescription opioids.
RISKS ASSOCIATED WITH OPIOID USE AFTER SURGERY
The adverse effects of prescription opioids are well documented. The presence of tolerance and physical dependence can occur even at prescribed doses.18–23 Opioids are associated with immunosuppression and opioid-induced endocrinopathy (sexual dysfunction, depression, and decreased energy).24–30 Opioids are implicated in opioid-induced hyperalgesia or increased pain sensitivity despite increasing doses of opioids. This hyperalgesia has been demonstrated with exposure to both short- and long-term opioids.31–33
Opioid-related adverse effects can manifest as a multitude of symptoms after surgery ranging from sedation, respiratory depression, delirium, and ileus to the paradoxical worsening of pain with higher opioid doses. The significance of these opioid-related adverse effects cannot be understated. The primary mechanism of opioid fatality involves opioid-induced respiratory depression and subsequent hypoxia, hypercapnia, and cardiorespiratory arrest.34–36 Pulmonary conditions, such as chronic obstructive pulmonary disease, and concurrent use of central nervous system depressants including benzodiazepines or antidepressants potentiate the risk of opioid-induced respiratory depression and overdose after surgery.37–40Postoperative opioid–induced respiratory depression often occurs within the first 24 hours and leads to death or severe brain damage in the majority of patients.41 Thus, measures to limit postoperative opioid use may help to decrease the morbidity and mortality resulting from opioid-related adverse events. These adverse effects are likely to accumulate as patients take opioids for longer lengths of time after surgery.
Particularly concerning is the association between preoperative opioid use and increased postoperative morbidity and mortality. In a cohort of 200,005 patients undergoing elective surgery, 8.8% of patients were using opioids before surgery42; preoperative opioid use was associated with longer hospital stays, a higher rate of 30-day readmission, and increased health care expenditures at 90, 180, and 365 days after surgery.42 Similarly, long-term opioid use was associated with an increased risk of knee revision in the first year after total knee arthroplasty in a cohort of veterans.43 As patients taking opioids before surgery often require higher postoperative doses for extended periods of time, it is possible that these heightened postoperative opioid requirements increase vulnerability to a multitude of opioid-related adverse effects. Alternatively, chronic opioid use may be associated with a number of psychosocial characteristics that impede physical function and recovery after surgery.
Concerns regarding persistent opioid use after surgery include misuse, abuse, addiction, and diversion. Of patients surveyed in outpatient neurosurgery or orthopedic clinics of a tertiary academic medical center, 14.7% reported using opioids without a prescription, in greater amounts, or longer than prescribed, far exceeding the national prevalence of opioid misuse of 1.9% among US adults.44 The potential for misuse and diversion is highlighted by research reporting that the majority of patients keep their unused opioids rather than disposing them after surgery.45–47 As provider overprescribing for acute pain is a primary source of diversion in America,48 efforts to limit excess perioperative opioid prescribing may be warranted.
Serious consequences of perioperative opioid misuse and dependence include increased inpatient mortality (odds ratio [OR], 3.7; 95% confidence interval [CI], 2.7–5.1), aggregate morbidity (OR, 2.3; 95% CI, 2.2–2.4), and resource utilization.49 In a cohort of patients scheduled for a variety of operations (thoracotomy, total knee replacement, total hip replacement, radical mastectomy, and lumpectomy), preoperative opioid use was associated with an increased risk for opioid misuse after surgery.50 Future work to characterize risks factors for the transition from therapeutic use to misuse is warranted in patients undergoing surgery given the increased morbidity, mortality, and health care costs associated with perioperative opioid misuse.
PERSISTENT OR CHRONIC OPIOID USE AFTER SURGERY
Opioids prescribed during and after surgery may trigger long-term use in patients regardless of whether or not they are opioid tolerant, taking opioids regularly before surgery, or ever been exposed to opioids in the past.44,47,51–54 Even opioids prescribed for low-pain, outpatient, or short-stay surgeries increase the risk of persistent opioid use,51,52 and over 60% of people receiving 90 days of continuous opioid therapy remain on opioid years later.55 Patients receiving an opioid prescription after short-stay surgeries have a 44% increased risk of long-term opioid use.52 Even prescribing opioids at hospital discharge to previously opioid-naive patients is a risk factor for chronic opioid use 1 year after discharge (adjusted OR, 4.9; 95% CI, 3.22–7.45).10 Surgery is an important stimulus for chronic opioid use even among those who are opioid naive before surgery.56 Given the likely transition from acute to long-term opioid use after surgery, measures to curb the duration of postoperative opioid use may be necessary to limit the risks of perioperative opioid exposure.
The incidence of prolonged opioid use after surgery varies based on preoperative patient characteristics and the type of surgery a patient undergoes. In a retrospective analysis of 641,941 opioid-naive patients undergoing surgery, and 18,011,137 opioid-naive nonsurgical patients, the incidence of chronic opioid use among nonsurgical patients was 0.136% (95% CI, 0.134%–0.137%).56 The highest incidence of chronic opioid use occurred after total knee arthroplasty (1.41%; 95% CI, 1.29%–1.53%).56 After controlling for age, sex, and preoperative medication use (antidepressants, antipsychotics, and benzodiazepines), patients undergoing total knee arthroplasty, open cholecystectomy, total hip arthroplasty, simple mastectomy, laparoscopic cholecystectomy, open appendectomy, and cesarean delivery were at significantly increased risk for chronic opioid use after surgery.56 Risk factors for chronic opioid use after surgery among opioid-naive patients included male sex, age >50 years, preoperative use of benzodiazepines, preoperative use of antidepressants, depression history, alcohol abuse history, and drug abuse history.56 Similarly, in a retrospective cohort of 36,177 opioid-naive patients undergoing minor (eg, varicose vein removal, laparoscopic cholecystectomy, laparoscopic appendectomy, hemorrhoidectomy, thyroidectomy, transurethral prostate surgery, parathyroidectomy, and carpal tunnel surgery) or major (eg, ventral incisional hernia repair, colectomy, reflux surgery, bariatric surgery, and hysterectomy) operations, the rates of new persistent opioid use varied between 5.9% and 6.5%.57 The incidence in a nonoperative control cohort was only 0.4%. Risks factors for new persistent opioid use after surgery included preoperative tobacco use, alcohol and substance abuse disorders, mood disorders, anxiety, and preoperative pain disorders.57 The higher incidence of new persistent opioid use noted in this second study may relate to defining the outcome as any opioid prescription filled between 90 and 180 days after the surgical procedure,57 whereas the first study defined chronic opioid use as 10 or more prescriptions, or more than a 120-day supply of an opioid within the first year after surgery excluding the first 90 days.56
Regardless of whether or not patients are taking opioids before surgery, undergoing surgery in and of itself is a risk factor for instigating persistent and chronic opioid use after surgery. When examining the surgical population as a whole, including patients taking opioids before surgery, postoperative chronic opioid use ranges from 9.2% to 13%.58,59 In the context of the current opioid crisis, measures to decrease the overall prevalence of chronic opioid use after surgery will decrease opioid-related adverse events including opioid misuse, abuse, addiction, diversion, respiratory depression, and overdose.
PREDICTORS OF CHRONIC OPIOID USE AFTER SURGERY
Preoperative opioid use is an important risk factor for persistent or chronic opioid use after surgery. In a national, population-based study of patients undergoing upper extremity surgery, opioid use before surgery was associated with longer opioid prescriptions, and more refills after surgery.60 Patients using opioids before operations including bariatric surgery, lumbar fusion, total joint arthroplasty, and kidney transplantation are at increased risk for chronic postoperative opioid use.61–65 Between 64% and 77% of chronic opioid users before surgery continue chronic opioid use after surgery.62,63 In a perioperative model of time to postoperative opioid and pain cessation using Cox regression, legitimate preoperative opioid use was a risk factor for persistent opioid use in a mixed surgical cohort.66 Higher preoperative opioid doses lead to an incremental risk of chronic use after surgery. Patients taking >60-mg oral morphine equivalents preoperatively have an 80% likelihood of chronic use 6 months after total knee or hip arthroplasty.67
Additional risk factors for postoperative chronic opioid use include lower socioeconomic status, preoperative pain, medical comorbidities (eg, pulmonary disease, heart failure), depression, and a history of drug, alcohol, or tobacco abuse.56,59 Use of specific medications including preoperative benzodiazepines and antidepressants are also associated with persistent opioid use after surgery.54,56,59
Prior research highlights preoperative depression and use of antidepressants as important risk factors for chronic opioid use after surgery.56,59 Clinically diagnosed depression (rather than anxiety or adjustment disorders) increases the odds of chronic opioid therapy after lumbar fusion (OR, 2.34; P < .001), and 77% of patients with depression receive chronic opioid therapy after lumbar fusion compared to 50% without a depression diagnosis.64 Similarly, depression is a risk factor for new chronic opioid use after total hip arthroplasty rather than anxiety or psychoses.68 This mirrors trends in long-term opioid therapy for noncancer pain, as patients with a history of depression are more likely to receive chronic opioid therapy at higher daily doses, and for extended durations.69 In a mixed surgical cohort, elevated preoperative Beck Depression Inventory-II scores were a significant predictor of prolonged opioid use independent of pain in a mixed surgical cohort.66 Further factor analysis identified self-loathing symptoms of the Beck Depression Inventory-II as a significant predictor of prolonged opioid use rather than somatic symptoms, which could be confounded by pain and other medical comorbidities in a surgical cohort.70–72 The primary determinants of postoperative opioid cessation appear unrelated to the duration of postoperative pain and preoperative pain intensity both at the future surgical site and elsewhere over the entire body.66 Thus, specific efforts to promote opioid cessation are warranted aside from focusing solely on optimizing pain management in the postoperative period.
STRATEGIES TO PROMOTE OPIOID CESSATION AFTER SURGERY
Regional and Neuraxial Anesthesia
Nerve blockade of peripheral nerves (regional anesthesia) or the central nervous system (neuraxial anesthesia) has been proposed as a possible way of reducing the risk of persistent opioid use after surgery. Nerve blockade could reduce the risk of persistent postoperative opioid use through one of 2 mechanisms. The first, a theory known as preventative analgesia73–75 suggests that nerve blockade can prevent the transition from acute to chronic pain by directly blocking transmission of pain impulses during the perioperative period and thereby preventing central sensitization and chronic neuropathic pain. Second, nerve blocks are a well-established modality for treating acute postoperative pain, which when severe, is predictive of the development of chronic pain.76
Despite these theoretical benefits and several studies showing that nerve blockade is associated with reduced opioid requirements in the immediate postoperative period,77–79 whether nerve blockade reduces long-term opioid use following in practice remains unclear. A meta-analysis of 23 randomized control trials found that epidural anesthesia was associated with decreased persistent postoperative pain for patients undergoing thoracotomy and that paravertebral blocks were associated with decreased persistent postoperative pain for breast cancer surgery.80 However, while these studies suggest that nerve blocks are associated with a decreased risk for persistent postoperative pain, whether nerve blocks decrease persistent postoperative opioid use itself remains an open question. Indeed, recent observational studies have found no association between nerve blockade and the risk of persistent postoperative opioid use for patients undergoing abdominal surgery,81 total knee arthroplasty,82 or shoulder arthroplasty.83
Intravenous Local Anesthetic
There is increasing interest in the intraoperative use of intravenous local anesthetics—typically lidocaine—for the purpose of reducing perioperative opioid consumption. When given as part of a nerve block, local anesthetics exert an analgesic effect by blocking the sodium channels responsible for neural transmission of pain impulses. The effect of intravenous local anesthetics on opioid consumption is thought to occur via the blockade of proinflammatory responses to surgery.84–86 A recent review found that intravenous lidocaine was associated with decreased opioid requirements in the immediate perioperative period for a variety of surgeries (eg, abdominal and thoracic procedures), although the literature suggested no benefit in some others (eg, total hip arthroplasty).84 With regard to long-term outcomes, 2 studies found that intraoperative lidocaine use was associated with decreased chronic pain at 387 and 6 months88 after the procedure for patients undergoing mastectomy, while another study found improved quality of life scores at 3 months after spine surgery.89 The duration of follow-up for all 3 studies was fairly short (maximum 6 months after procedure), and while the 3 studies examined the incidence of persistent postoperative pain, none of the 3 studies directly measured opioid use itself. More research is needed to characterize the extent to which the perioperative use of intravenous local anesthetics can reduce persistent opioid use after surgery.
Other Nonopioid Medications
Numerous studies have examined whether the intraoperative use of nonopioid medications with analgesic properties is associated with decreased opioid consumption after surgery. Ketamine is an N-methyl-d-aspartate receptor antagonist frequently used for induction. Its analgesic properties as an N-methyl-d-aspartate receptor antagonist have led researchers to examine whether its intraoperative use is associated with reduced opioid consumption. While studies have generally found intraoperative ketamine to be associated with decreased opioid consumption in the immediate postoperative period and for up to 6 weeks after procedure,90–92 to date no studies have examined its effect on opioid consumption at longer time windows after surgery.
Acetaminophen is frequently used for pain management or as part of multimodal analgesia protocols. As with ketamine, while numerous studies suggest that it is associated with decreased opioid consumption in the immediate perioperative period,93,94 there is a lack of research examining its effectiveness at reducing opioid use in the longer term.
Perioperative gabapentin appears to reduce the incidence and intensity of postoperative pain up to 6 months after otolaryngology, orthopedic, mastectomy, and abdominal/pelvic operations.95–98 Furthermore, perioperative gabapentin is often cited as a component of multimodal analgesia,99 but results have been mixed regarding gabapentin’s efficacy to reduce acute pain in the context of multimodal analgesia. Usual care varies across operations and hospitals nationwide.100–104 Previous trials examining gabapentin’s effect on opioid consumption have reported immediate reductions in 24–72 hours postoperative use during hospital admission.101,102,105 In contrast, a meta-analysis of 9498 patients found a negligible reduction in 24-hour morphine consumption with use of gabapentin, with an even more diminished effect in the context of multimodal analgesia.106 These findings were limited by low-quality evidence due to small study sizes and inconsistency.106 Studies examining the utility of perioperative gabapentin for remote postoperative opioid cessation are needed to fully understand the utility of gabapentin alone or as part of multimodal analgesia protocols.
Multimodal analgesia consists of 2 or more medications or nonpharmacologic interventions (eg, transcutaneous electrical nerve stimulation) with varying mechanisms of action for postoperative pain relief.99 Components of multimodal analgesia often include gabapentenoids, acetaminophen, ketamine, nonsteroidal anti-inflammatory drugs (NSAIDs), and regional anesthesia.107 It is thought that the combination of treatments is likely to have an additive or synergistic effect on opioid sparing as well. In a meta-analysis of 52 randomized trials including 4893 adults, acetaminophen, NSAIDs, or selective cyclooxygenase-2 inhibitors significantly reduced 24-hour morphine consumption after surgery.108 Similarly, a systematic review found that coadministration of paracetamol, NSAIDs, and cyclooxygenase-2 inhibitors with opioids decreases 24-hour postoperative morphine consumption without a clear benefit of one category versus another in terms of adverse effects.109 Future studies examining extended multimodal analgesic techniques with postoperative follow-up long after hospital discharge are needed to determine the utility of multimodal analgesia in preventing chronic opioid use after surgery. Furthermore, given the significant variation in implementing multimodal analgesia techniques across the United States, randomized trials are needed to inform best practices for clinical care.104
Multiple professional societies have focused efforts on reducing prescription opioid exposure after surgery. Guidelines now strongly recommend instituting a plan for opioid tapering after surgery. For example, the Agency Medical Directors’ Group Interagency Guidelines on Prescribing Opioids for Pain recommend tapering opioids by 6 weeks after most major surgeries to preoperative doses or lower in the absence of clinically meaningful improvements in function and pain, with 20% weekly dose reductions.110 However, the standard of care is to advise patients to discontinue opioids when they no longer have pain, and patients usually self-taper their opioids with minimal instructions after surgery.
There are efforts focused on providers’ prescribing patterns. This is being done by providing recommendations on number of pills or limiting the number prescribed. Currently, a disconnect exists between opioids prescribed and opioids used after surgery. The amount prescribed does not influence patients’ decisions to continue or discontinue opioid use, and patients exhibit wide variability in opioid needs after similar procedures.2,47,59,60 Research is needed to address a critical knowledge gap regarding optimal mechanisms for postoperative opioid weaning with supportive psychosocial interventions in the form of randomized controlled trials to support expert opinion.111 Evidence and evaluation of new programs are required to ensure the best balance of pain control with minimal opioid exposure.
In addition, a targeted approach is needed for vulnerable subset of patients who are at elevated risk for chronic opioid use after surgery. For example, patients with elevated preoperative depressive symptoms may benefit from preoperative and ongoing postoperative cognitive–behavioral therapy, to help curb postoperative opioid use and improve functional outcomes after surgery. Similarly, future studies examining extended multimodal analgesic techniques with postoperative follow-up long after hospital discharge are needed to determine the utility of multimodal analgesia in preventing chronic opioid use after surgery. With the advent of novel regional anesthetic techniques and medications, perioperative research must extend beyond hospital discharge to characterize the efficacy of these strategies in promoting opioid cessation.
Another vulnerable group of patients is those taking opioids before surgery. Given the association between preoperative opioid use and increased postoperative morbidity and mortality, research is needed to understand the mechanisms driving these worse outcomes. It is not entirely clear whether additional confounding patient characteristics are driving these prior research findings. In addition, interventions such as preoperative opioid tapering should be studied in the context of surgical outcomes and opioid use after surgery. If effective, the ideal time frame for opioid tapering before surgery would also need to be identified.
With continued opioid use after surgery, the risk of postoperative opioid–induced respiratory depression remains. Given the significant morbidity and mortality associated with opioid-induced respiratory depression, measures are needed to limit its occurrence. Opioid overdose education and naloxone distribution provide patients with education on opioid overdose prevention, recognition of opioid overdose, and training on the rescue response, including provision of naloxone.112 In conjunction with measures to limit the duration and dosages of opioids prescribed after surgery, future work to study the implementation of perioperative opioid overdose education and naloxone distribution to high-risk surgical patients may promote safer opioid use and prevent significant opioid-related adverse effects.
Although persistent opioid use after surgery may lead to misuse, abuse, addiction, and diversion, more perioperative research is needed to characterize the transition from postoperative therapeutic use to misuse of prescription opioids. The potential to improve patient outcomes is apparent as perioperative opioid misuse is associated with increase morbidity, mortality, and health care costs. Furthermore, longitudinal follow-up to examine the initiation of illicit heroin or fentanyl in patients misusing prescription opioids is needed to understand the contribution of perioperative opioid misuse to the ongoing opioid epidemic. Given the potential for overprescribing and diversion, patient education and measures to promote safe storage and disposal of prescription opioids must be further implemented after surgery.
In the context of the current opioid epidemic in the United States, health care providers are now faced with the challenge of simultaneously optimizing postoperative pain management and limiting opioid use after surgery. Emerging data suggest that persistent and chronic opioid use after surgery is a rising complication among both opioid-naive patients and those taking opioids preoperatively. Modifiable risk factors for chronic opioid use after surgery should be clearly delineated and targeted with novel interventions. In addition, existing interventions exhibiting opioid-sparing effects within the immediate postoperative period should be examined in randomized trials with follow-up long after hospital discharge to determine their utility in promoting definitive opioid cessation after surgery. Evidence-based strategies for opioid tapering are needed to complement the burgeoning guidelines and expert opinions advocating for postoperative opioid tapering to optimize patient success, prevent underprescribing of opioids to patients, and prevent opioid misuse and diversion.
Name: Jennifer M. Hah, MD, MS.
Contribution: This author helped in conception of the work, drafting, and revising the manuscript.
Conflicts of Interest: None.
Name: Brian T. Bateman, MD, MSc.
Contribution: This author helped in conception of the work and revising the manuscript.
Conflicts of Interest: None.
Name: John Ratliff, MD.
Contribution: This author helped in conception of the work and revising the manuscript.
Conflicts of Interest: None.
Name: Catherine Curtin, MD.
Contribution: This author helped in conception of the work and revising the manuscript.
Conflicts of Interest: None.
Name: Eric Sun, MD, PhD.
Contribution: This author helped in conception of the work, drafting, and revising the manuscript.
Conflicts of Interest: Eric Sun has a consulting arrangement with Egalet, Inc.
This manuscript was handled by: Honorio T. Benzon, MD.
1. Rudd RA, Aleshire N, Zibbell JE, et al. Increases in drug and opioid overdose deaths—United States, 2000–2014. MMWR Morb Mortal Wkly Rep. 2016;64:1378–1382.
2. Florence CS, Zhou C, Luo F, et al. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care.2016;54:901–906.
3. de Beer Jde V, Winemaker MJ, Donnelly GA, et al. Efficacy and safety of controlled-release oxycodone and standard therapies for postoperative pain after knee or hip replacement. Can J Surg. 2005;48:277–283.
4. Lindenhovius AL, Helmerhorst GT, Schnellen AC, et al. Differences in prescription of narcotic pain medication after operative treatment of hip and ankle fractures in the United States and the Netherlands. J Trauma. 2009;67:160–164.
5. Fischer HB, Simanski CJ. A procedure-specific systematic review and consensus recommendations for analgesia after total hip replacement. Anaesthesia. 2005;60:1189–1202.
6. Joshi GP, Rawal N, Kehlet H, et al.; PROSPECT Collaboration. Evidence-based management of postoperative pain in adults undergoing open inguinal hernia surgery. Br J Surg. 2012;99:168–185.
7. Roberts M, Brodribb W, Mitchell G. Reducing the pain: a systematic review of postdischarge analgesia following elective orthopedic surgery. Pain Med. 2012;13:711–727.
8. Wunsch H, Wijeysundera DN, Passarella MA, et al. Opioids prescribed after low-risk surgical procedures in the United States, 2004–2012. JAMA.2016;315:1654–1657.
9. Hooten WM, St Sauver JL, McGree ME, Jacobson DJ, Warner DO. Incidence and risk factors for progression from short-term to episodic or long-term opioid prescribing: a population-based study. Mayo Clin Proc. 2015;90:850–856.
10. Calcaterra SL, Yamashita TE, Min SJ, Keniston A, Frank JW, Binswanger IA. Opioid prescribing at hospital discharge contributes to chronic opioid use. J Gen Intern Med. 2016;31:478–485.
11. Larochelle MR, Liebschutz JM, Zhang F, Ross-Degnan D, Wharam JF. Opioid prescribing after nonfatal overdose and association with repeated overdose: a cohort study. Ann Intern Med. 2016;164:1–9.
12. Maxwell JC. The prescription drug epidemic in the United States: a perfect storm. Drug Alcohol Rev. 2011;30:264–270.
13. Hays L, Kirsh KL, Passik SD. Seeking drug treatment for OxyContin abuse: a chart review of consecutive admissions to a substance abuse treatment facility in Kentucky. J Natl Compr Canc Netw. 2003;1:423–428.
14. Passik SD, Hays L, Eisner N, Kirsh KL. Psychiatric and pain characteristics of prescription drug abusers entering drug rehabilitation. J Pain Palliat Care Pharmacother. 2006;20:5–13.
15. Potter JS, Hennessy G, Borrow JA, Greenfield SF, Weiss RD. Substance use histories in patients seeking treatment for controlled-release oxycodone dependence. Drug Alcohol Depend. 2004;76:213–215.
16. Ling W, Mooney L, Hillhouse M. Prescription opioid abuse, pain and addiction: clinical issues and implications. Drug Alcohol Rev. 2011;30:300–305.
17. Mudumbai SC, Oliva EM, Lewis ET, et al. Time-to-cessation of postoperative opioids: a population-level analysis of the veterans affairs health care system. Pain Med. 2016;17:1732–1743.
18. Joseph EK, Reichling DB, Levine JD. Shared mechanisms for opioid tolerance and a transition to chronic pain. J Neurosci. 2010;30:4660–4666.
19. Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg. 1998;86:1307–1311.
20. Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth. 1999;46:872–877.
21. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000;93:409–417.
22. Wright C, Bigelow GE, Stitzer ML, Liebson IA. Acute physical dependence in humans: repeated naloxone-precipitated withdrawal after a single dose of methadone. Drug Alcohol Depend. 1991;27:139–148.
23. Athanasos P, Smith CS, White JM, Somogyi AA, Bochner F, Ling W. Methadone maintenance patients are cross-tolerant to the antinociceptive effects of very high plasma morphine concentrations. Pain. 2006;120:267–275.
24. Mojadadi S, Jamali A, Khansarinejad B, Soleimanjahi H, Bamdad T. Acute morphine administration reduces cell-mediated immunity and induces reactivation of latent herpes simplex virus type 1 in BALB/c mice. Cell Mol Immunol. 2009;6:111–116.
25. Wan Q, Wang X, Wang YJ, Song L, Wang SH, Ho WZ. Morphine suppresses intracellular interferon-alpha expression in neuronal cells. J Neuroimmunol. 2008;199:1–9.
26. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377–384.
27. Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain. 2008;9:28–36.
28. Daniell HW. DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production. J Pain. 2006;7:901–907.
29. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Hypogonadism and sexual dysfunction in male cancer survivors receiving chronic opioid therapy. J Pain Symptom Manage. 2003;26:1055–1061.
30. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;112 supplS105–S120.
31. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003;106:49–57.
32. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain. 2006;7:43–48.
33. Chen L, Malarick C, Seefeld L, Wang S, Houghton M, Mao J. Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain. 2009;143:65–70.
34. White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction. 1999;94:961–972.
35. Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology. 2010;112:226–238.
36. Davies EC, Green CF, Taylor S, Williamson PR, Mottram DR, Pirmohamed M. Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes. PLoS One. 2009;4:e4439.
37. Macintyre PE, Loadsman JA, Scott DA. Opioids, ventilation and acute pain management. Anaesth Intensive Care. 2011;39:545–558.
38. Overdyk F, Dahan A, Roozekrans M, van der Schrier R, Aarts L, Niesters M. Opioid-induced respiratory depression in the acute care setting: a compendium of case reports. Pain Manag. 2014;4:317–325.
39. Zedler B, Xie L, Wang L, et al. Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients. Pain Med. 2014;15:1911–1929.
40. Overdyk FJ, Dowling O, Marino J, et al. Association of opioids and sedatives with increased risk of in-hospital cardiopulmonary arrest from an administrative database. PLoS One. 2016;11:e0150214.
41. Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology. 2015;122:659–665.
42. Waljee JF, Cron DC, Steiger RM, Zhong L, Englesbe MJ, Brummett CM. Effect of preoperative opioid exposure on healthcare utilization and expenditures following elective abdominal surgery. Ann Surg. 2017;265:715–721.
43. Ben-Ari A, Chansky H, Rozet I. Preoperative opioid use is associated with early revision after total knee arthroplasty: a study of male patients treated in the veterans affairs system. J Bone Joint Surg Am. 2017;99:1–9.
44. Mason MJ, Golladay G, Jiranek W, et al. Depression moderates the relationship between pain and the nonmedical use of opioid medication among adult outpatients. J Addict Med. 2016;10:408–413.
45. Harris K, Curtis J, Larsen B, et al. Opioid pain medication use after dermatologic surgery: a prospective observational study of 212 dermatologic surgery patients. JAMA Dermatol. 2013;149:317–321.
46. Bartels K, Mayes LM, Dingmann C, Bullard KJ, Hopfer CJ, Binswanger IA. Opioid use and storage patterns by patients after hospital discharge following surgery. PLoS One. 2016;11:e0147972.
47. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol. 2011;185:551–555.
48. Volkow ND, McLellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N Engl J Med. 2016;374:1253–1263.
49. Menendez ME, Ring D, Bateman BT. Preoperative opioid misuse is associated with increased morbidity and mortality after elective orthopaedic surgery. Clin Orthop Relat Res. 2015;473:2402–2412.
50. Hah JM, Sharifzadeh Y, Wang BM, et al. Factors associated with opioid use in a cohort of patients presenting for surgery. Pain Res Treat. 2015;2015:829696.
51. Rodgers J, Cunningham K, Fitzgerald K, Finnerty E. Opioid consumption following outpatient upper extremity surgery. J Hand Surg Am. 2012;37:645–650.
52. Alam A, Gomes T, Zheng H, Mamdani MM, Juurlink DN, Bell CM. Long-term analgesic use after low-risk surgery: a retrospective cohort study. Arch Intern Med. 2012;172:425–430.
53. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA. 2016;315:1624–1645.
54. Bateman BT, Franklin JM, Bykov K, et al. Persistent opioid use following cesarean delivery: patterns and predictors among opioid-naive women. Am J Obstet Gynecol. 2016;215:353.e351–353.e318.
55. Martin BC, Fan MY, Edlund MJ, Devries A, Braden JB, Sullivan MD. Long-term chronic opioid therapy discontinuation rates from the TROUP study. J Gen Intern Med. 2011;26:1450–1457.
56. Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of and risk factors for chronic opioid use among opioid-naive patients in the postoperative period. JAMA Intern Med. 2016;176:1286–1293.
57. Brummett CM, Waljee JF, Goesling J, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152:e170504.
58. Jiang X, Orton M, Feng R, et al. Chronic opioid usage in surgical patients in a large academic center. Ann Surg. 2017;265:722–727.
59. Johnson SP, Chung KC, Zhong L, et al. Risk of prolonged opioid use among opioid-naive patients following common hand surgery procedures. J Hand Surg Am. 2016;41:947–957.e3.
60. Waljee JF, Zhong L, Hou H, et al. The use of opioid analgesics following common upper extremity surgical procedures: a national, population-based study. Plast Reconstr Surg. 2016;137:355e–364e.
61. Raebel MA, Newcomer SR, Bayliss EA, et al. Chronic opioid use emerging after bariatric surgery. Pharmacoepidemiol Drug Saf. 2014;23:1247–1257.
62. Raebel MA, Newcomer SR, Reifler LM, et al. Chronic use of opioid medications before and after bariatric surgery. JAMA. 2013;310:1369–1376.
63. Zarling BJ, Yokhana SS, Herzog DT, Markel DC. Preoperative and postoperative opiate use by the arthroplasty patient. J Arthroplasty. 2016;31:2081–2084.
64. Anderson JT, Haas AR, Percy R, et al. Chronic opioid therapy after lumbar fusion surgery for degenerative disc disease in a workers’ compensation setting. Spine (Phila Pa 1976). 2015;40:1775–1784.
65. Kulshrestha S, Barrantes F, Samaniego M, Luan FL. Chronic opioid analgesic usage post-kidney transplantation and clinical outcomes. Clin Transplant. 2014;28:1041–1046.
66. Carroll I, Barelka P, Wang CK, et al. A pilot cohort study of the determinants of longitudinal opioid use after surgery. Anesth Analg. 2012;115:694–702.
67. Goesling J, Moser SE, Zaidi B, et al. Trends and predictors of opioid use after total knee and total hip arthroplasty. Pain. 2016;157:1259–1265.
68. Inacio MC, Hansen C, Pratt NL, Graves SE, Roughead EE. Risk factors for persistent and new chronic opioid use in patients undergoing total hip arthroplasty: a retrospective cohort study. BMJ Open. 2016;6:e010664.
69. Braden JB, Sullivan MD, Ray GT, et al. Trends in long-term opioid therapy for noncancer pain among persons with a history of depression. Gen Hosp Psychiatry. 2009;31:564–570.
70. Hah JM, Mackey S, Barelka PL, et al. Self-loathing aspects of depression reduce postoperative opioid cessation rate. Pain Med. 2014;15:954–964.
71. Hall BJ, Hood MM, Nackers LM, Azarbad L, Ivan I, Corsica J. Confirmatory factor analysis of the Beck Depression Inventory-II in bariatric surgery candidates. Psychol Assess. 2013;25:294–299.
72. Tully PJ, Winefield HR, Baker RA, Turnbull DA, de Jonge P. Confirmatory factor analysis of the Beck Depression Inventory-II and the association with cardiac morbidity and mortality after coronary revascularization. J Health Psychol. 2011;16:584–595.
73. Dahl JB, Møiniche S. Pre-emptive analgesia. Br Med Bull. 2004;71:13–27.
74. Liu SS, Buvanendran A, Rathmell JP, et al. A cross-sectional survey on prevalence and risk factors for persistent postsurgical pain 1 year after total hip and knee replacement. Reg Anesth Pain Med. 2012;37:415–422.
75. Vadivelu N, Mitra S, Schermer E, Kodumudi V, Kaye AD, Urman RD. Preventive analgesia for postoperative pain control: a broader concept. Local Reg Anesth. 2014;7:17–22.
76. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006;367:1618–1625.
77. Chan EY, Fransen M, Parker DA, et al. Femoral nerve blocks for acute postoperative pain after knee replacement surgery. Cochrane Database Syst Rev. 2014;5:CD009941.
78. Richman JM, Liu SS, Courpas G, et al. Does continuous peripheral nerve block provide superior pain control to opioids? A meta-analysis. Anesth Analg. 2006;102:248–257.
79. Memtsoudis SG, Poeran J, Cozowicz C, Zubizarreta N, Ozbek U, Mazumdar M. The impact of peripheral nerve blocks on perioperative outcome in hip and knee arthroplasty-a population-based study. Pain. 2016;157:2341–2349.
80. Andreae MH, Andreae DA. Regional anaesthesia to prevent chronic pain after surgery: a Cochrane systematic review and meta-analysis. Br J Anaesth. 2013;111:711–720.
81. Ladha KS, Patorno E, Liu J, Bateman BT. Impact of perioperative epidural placement on postdischarge opioid use in patients undergoing abdominal surgery. Anesthesiology. 2016;124:396–403.
82. Sun EC, Bateman BT, Memtsoudis SG, Neuman MD, Mariano ER, Baker LC. Lack of association between the use of nerve blockade and the risk of postoperative chronic opioid use among patients undergoing total knee arthroplasty: evidence from the Market scan database. Anesth Analg. 2017;125:999–1007.
83. Mueller KG, Memtsoudis SG, Mariano ER, Baker LC, Mackey S, Sun EC. Lack of association between the use of nerve blockade and the risk of persistent opioid use among patients undergoing shoulder arthroplasty: evidence from the Marketscan® database. Anesth Analg. 2017;125:1014–1020.
84. Dunn LK, Durieux ME. Perioperative use of intravenous lidocaine. Anesthesiology. 2017;126:729–737.
85. Leliefeld PH, Wessels CM, Leenen LP, Koenderman L, Pillay J. The role of neutrophils in immune dysfunction during severe inflammation. Crit Care. 2016;20:73.
86. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology. 2000;93:858–875.
87. Grigoras A, Lee P, Sattar F, Shorten G. Perioperative intravenous lidocaine decreases the incidence of persistent pain after breast surgery. Clin J Pain. 2012;28:567–572.
88. Terkawi AS, Sharma S, Durieux ME, Thammishetti S, Brenin D, Tiouririne M. Perioperative lidocaine infusion reduces the incidence of post-mastectomy chronic pain: a double-blind, placebo-controlled randomized trial. Pain Physician. 2015;18:E139–E146.
89. Farag E, Ghobrial M, Sessler DI, et al. Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery. Anesthesiology. 2013;119:932–940.
90. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113:639–646.
91. Suzuki M. Role of N-methyl-D-aspartate receptor antagonists in postoperative pain management. Curr Opin Anaesthesiol. 2009;22:618–622.
92. Radvansky BM, Shah K, Parikh A, Sifonios AN, Le V, Eloy JD. Role of ketamine in acute postoperative pain management: a narrative review. Biomed Res Int. 2015;2015:749837.
93. McNicol ED, Tzortzopoulou A, Cepeda MS, et al. Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis. Br J Anaesth. 2011;106:764–775.
94. Macario A, Royal MA. A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain. Pain Pract. 2011;11:290–296.
95. Fassoulaki A, Melemeni A, Stamatakis E, Petropoulos G, Sarantopoulos C. A combination of gabapentin and local anaesthetics attenuates acute and late pain after abdominal hysterectomy. Eur J Anaesthesiol. 2007;24:521–528.
96. Sen H, Sizlan A, Yanarateş O, et al. The effects of gabapentin on acute and chronic pain after inguinal herniorrhaphy. Eur J Anaesthesiol. 2009;26:772–776.
97. Yan PZ, Butler PM, Kurowski D, Perloff MD. Beyond neuropathic pain: gabapentin use in cancer pain and perioperative pain. Clin J Pain. 2014;30:613–629.
98. Alayed N, Alghanaim N, Tan X, Tulandi T. Preemptive use of gabapentin in abdominal hysterectomy: a systematic review and meta-analysis. Obstet Gynecol. 2014;123:1221–1229.
99. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17:131–157.
100. Zhang S, Paul J, Nantha-Aree M, et al. Reanalysis of morphine consumption from two randomized controlled trials of gabapentin using longitudinal statistical methods. J Pain Res. 2015;8:79–85.
101. Paul JE, Nantha-Aree M, Buckley N, et al. Randomized controlled trial of gabapentin as an adjunct to perioperative analgesia in total hip arthroplasty patients. Can J Anaesth. 2015;62:476–484.
102. Clarke HA, Katz J, McCartney CJ, et al. Perioperative gabapentin reduces 24 h opioid consumption and improves in-hospital rehabilitation but not post-discharge outcomes after total knee arthroplasty with peripheral nerve block. Br J Anaesth. 2014;113:855–864.
103. Grosen K, Drewes AM, Højsgaard A, Pfeiffer-Jensen M, Hjortdal VE, Pilegaard HK. Perioperative gabapentin for the prevention of persistent pain after thoracotomy: a randomized controlled trial. Eur J Cardiothorac Surg. 2014;46:76–85.
104. Ladha KS, Patorno E, Huybrechts KF, Liu J, Rathmell JP, Bateman BT. Variations in the use of perioperative multimodal analgesic therapy. Anesthesiology. 2016;124:837–845.
105. Arumugam S, Lau CS, Chamberlain RS. Use of preoperative gabapentin significantly reduces postoperative opioid consumption: a meta-analysis. J Pain Res. 2016;9:631–640.
106. Fabritius ML, Geisler A, Petersen PL, et al. Gabapentin for post-operative pain management— a systematic review with meta-analyses and trial sequential analyses. Acta Anaesthesiol Scand. 2016;60:1188–1208.
107. Center for Substance Abuse Treatment. Enhancing Motivation for Change in Substance Abuse Treatment. Treatment Improvement Protocol (TIP) Series, No. 35. HHS Publication No. (SMA) 12-4212. 1999.Rockville, MD: Substance Abuse and Mental Health Services Administration.
108. Elia N, Lysakowski C, Tramèr MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient- controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005;103:1296–1304.
109. Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. Br J Anaesth. 2011;106:292–297.
110. McCarberg B. Washington state opioid prescribing guidelines. Pain Med. 2015;16:1455–1456.
111. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2015;90:828–842.
112. Oliva EM, Christopher ML, Wells D, et al.; Veterans Health Administration Opioid Overdose Education and Naloxone Distribution National Support and Development Workgroup. Opioid overdose education and naloxone distribution: development of the Veterans Health Administration’s national program. J Am Pharm Assoc (2003). 2017;57:S168–S179.e164.