In contrast to prior efforts to limit opioid use since the early 1900s,1 2 3 , 4 5 6 7–9 10–13 14
In 2009, there were 201.9 million Schedule II through IV (including strong and weak) opioid prescriptions paid in the United States. It is estimated that 4.9% of US adults used opioids in the prior week and 2.0% used them regularly.15 , 16 17
Opioid use and deaths associated with opioids have also risen closely together.18–27 28 29 , 30 19 , 27 , 31–34
There have been an increasingly large number of policies and guidelines that have been developed to address opioids.35–63 64 , 65 66
GUIDELINE FOCUS
The American College of Occupational and Environmental Medicine (ACOEM) Opioids Guideline is designed to provide health care providers who are the primary target users of this guideline with evidence-based guidance on the use of opioids for treatment in the specific settings of acute (up to 1 month' duration), subacute (1 to 3 months' duration), chronic (>3 months' duration), and postoperative pain. This report summarizes findings from the 220-page ACOEM Opioids Guideline (960 references) and addresses the following questions developed by the Evidence-based Practice Opioids Panel:
What evidence supports the need for a history and physical examination before prescribing opioids?
Are opioids superior to other medications or other treatments for pain relief and functional improvement?
Is screening for risk factors effective for reducing adverse effects of treatment from opioids?
What is the dose–response relationship between morphine-equivalent dose and overdoses, fatalities, and other adverse effects?
What evidence addresses the balance of risk and benefits of opioid use for acute, subacute, chronic, and postoperative pain?
Are opioids efficacious for treatment of acute, subacute, chronic, and postoperative nonmalignant pain?
Are opioid treatment agreements (opioid contract, doctor/patient agreement, or informed consent) effective?
What is the prevalence of aberrant urine drug screening results among patients using opioids for treatment of chronic pain?
What evidence supports the use of intrathecal drug delivery systems for treatment of chronic, nonmalignant pain?
What tapering regimens are effective for weaning off opioids?
TARGET POPULATION
The primary target population is working-age adults, although the literature searches included articles addressing all adults. Thus, it is recognized that the principles may apply more broadly.
GUIDELINE DEVELOPMENT PROCESS
A detailed methodology document specifies evidence selection, scoring, incorporation of cost considerations,67 68–70
Guidance was drafted using tables of evidence that abstracted the epidemiological evidence. Draft text and tables were forwarded to the multidisciplinary Evidence-based Practice Opioids Panel (Michael S. Weiss, Kirk Bowden, Fernando Branco, Kimberly DuBrueler, Charl Els, Steven Mandel, David W. McKinney, Rafael Miguel, Kathryn L. Mueller, Robert J. Nadig, Michael I. Schaffer, Larry Studt, James B. Talmage, Russell L. Travis, and Thomas Winters). The Panel reviewed the evidence and finalized the text and recommendations. This guideline achieved 100% Panel agreement for all developed guidance.
EVIDENCE REVIEW AND GRADING
All evidence related to opioids in prior ACOEM Practice Guidelines 39 , 71–78 http://www.acoem.org/PubMedSearchDetails.aspx 68–70 68–70
The search strategies identified a total of 264,617 article titles, which were screened, with all potentially appropriate study abstracts reviewed and evaluated against specified inclusion and exclusion criteria. A total of 263 studies were included in these analyses. Articles reporting the studies were critically appraised and scored, and a total of 157 were of high and moderate quality addressing pain treatment.
COMMENTS AND MODIFICATION
Guidance was developed with sufficient detail to facilitate assessment of compliance (Institute of Medicine [IOM]) and auditing/monitoring (Appraisal of Guidelines for Research and Evaluation [AGREE]).66 , 67 39 , 71–78
The only AGREE67 66
The Evidence-based Practice Opioids Panel and the Research Team have complete editorial independence from ACOEM and Reed Group, which have not influenced the guideline. The literature is routinely monitored and formally searched at least annually for evidence that would materially affect this guidance. This guideline is planned to be updated at least every 3 years or more frequently should evidence require it.
A separate report on this guideline's findings concerning the use of opioids for safety sensitive work is available elsewhere.79
CLINICAL RECOMMENDATIONS
Comprehensive History and Physical Examination
No quality studies assess the utility of a history and physical examination. Nevertheless, the Panel's consensus recommendation is that a careful history and physical examination are highly important for appropriate pain management and consideration of opioid prescriptions regardless of pain acuity (Table 1 ). The Panel recommended to evaluate current and prior pharmacological and nonpharmacological methods for safe and effective control of pain, associated symptoms, and function.63 , 80–82 62 , 63 , 80 , 81 , 83 , 84 63 , 80 , 83
TABLE 1-a: Summary of Panel Recommendations for Use of Opioids (Evidence-Rating; Confidence Level Rating).
TABLE 1-b: Summary of Panel Recommendations for Use of Opioids (Evidence-Rating; Confidence Level Rating).
Acute Pain
There were four quality trials of acute pain patients treated with opioids compared with placebo, with a small overall magnitude of benefit, whereas the adverse effects profile was high. Among trials for treatment of acute pain, ibuprofen was reportedly superior to codeine or acetaminophen for acute injuries including fractures.85 86 * 87 88 89 90 91 92 † 93 94–105 106–108
Routine use of opioids for treatment of acute pain is strongly not recommended and the recommendation for select use of opioids based purely on the evidence is downgraded from “A” to “C” (Table 1 ). Although there are a few trials of patients with acute pain treated with opioids compared with placebo, the overall magnitude of benefit is small while the adverse effects profile is sufficiently high that this resulted in the recommendation being downgraded. When needed, the lowest effective dose of a short-acting opioid is recommended for those with acute, severe pain uncontrolled by other agents such as nonsteroidal anti-inflammatory drugs (NSAIDs).109 90 , 91 110 Fig. 1 ). Exceeding that dose should be based on documented need, and incremental functional gain increased surveillance for adverse effects and frequent reconsideration of benefit versus risk. Lower doses are also indicated in the elderly, women,111 Table 2 ).17 , 29 , 30 , 32 , 112–133 134 , 135 136 Table 2 ).
FIGURE 1: Death rate (hazard ratio) vs morphine equivalent dosage (mg/d). Statistical significance present for acute and chronic pain at and above 50 mg/day of oral morphine equivalent dose. Adapted from Dunn
201 and Bohnert.
110 TABLE 2: Risk Factors for Adverse Effects and Death from Opioids
29 , 30 , 32 , 41 , 54 , 62 , 112–116 , 118–133 , 136–239 Postoperative Pain
Findings and recommendations for postoperative pain management with opioids are mostly comparable with those treating acute pain (Table 1 ). Nevertheless, studies also include at least one trial showing modestly improved long-term knee range of motion and less opioid use with pregabalin for 14 days plus epidural and opioid management after total knee arthroplasty.240 241 242 243 , 244 245–250 Fig. 1 ). Nevertheless, the evidence that early ambulation is critical to functional recovery is strong. Therefore, oversedation that interferes with function is a concern. For patients on chronic opioids preoperatively, especially moderate to high doses, consultation with a physician experienced in managing these complex cases may be necessary. Thus, thoughtful use of short-acting opioids for postoperative pain management is recommended for limited use as adjunctive therapy to more effective treatments with recommendations summarized in Table 1 . Prescription drug monitoring programs should be checked. Psychiatric and/or mental health consultation should be considered for those who do not improve as expected and require high doses or ongoing opioid use. For those requiring opioid use beyond 1 month, the subacute/chronic opioid use recommendations given later apply.
Chronic Noncancer Pain
There are 67 high- or moderate-quality placebo-controlled clinical trials addressing opioid use for patients with chronic pain. Of these, 52% lasted up to 1 month, 12% were 1 to 2 months, and 34% were 3 months in duration. Only one trial was longer than 3 months at 16 weeks.251 252
For treatment of subacute and chronic pain, there is quality evidence that other medications and treatments are at least equivalent if not superior for subacute or chronic pain (eg, NSAIDs,253–256 257 258 252 259 257 260 253 254 256 255 261 reduced pain thresholds.262 263
Tramadol is a synthetic opioid and is a controlled substance in some US states. Tramadol is associated with potential abuse264 79
For subacute and chronic pain, an opioid trial, preceded by full informed consent and a trial agreement, is recommended if other evidence-based approaches for functional restorative pain therapy have been implemented, with documented adherence, and with inadequate improvement in function63 , 81 Tables 1 and 3 ). Pain or pain scales alone are recommended as insufficient reasons.82 , 113 , 265–276 Table 3 ).
TABLE 3: Opioids for Treatment of Chronic Pain With Factors to Consider an Opioid Trial, Trial Parameters, and Opioid Maintenance Continuation
Treatment Agreements and Informed Consent
Although there are no quality studies to document efficacy of opioid consent forms and/or opioid treatment agreement contracts, they are commonly used to monitor patients on opioids.39 , 41 , 62 , 63 , 277 , 278 62 , 63 , 279–282 www.mdguidelines.com/documents/stateguidelines/apg3_opioid_06_treatment_agreement.pdf
Urine Drug Screening
Most evidence documents aberrant drug screen prevalence rates of 32% to 45%.277 , 280 , 281 , 283–286 280 , 281 63 Fig. 1 ). It is recommended to be performed in a federally certified laboratory with a two-step process including confirmatory gas chromatography–mass spectroscopy. In certain situations, other screenings (eg, hair particularly for information regarding remote use287–292 279 , 293 , 294 40 , 81
Opioid Rotation
Conversion of opioids to an MED is helpful to transfer from one opioid to another. This is most commonly performed to attempt to achieve a better functional outcome and/or to reduce adverse effects. Quality evidence to support this practice has not been published. Several resources are available295 , 296 297 298 299–302
Tapering Opioids
Many studies have described widely varying rates of tapering opioids, mostly ranging from 10% per week to 50% per day.40 , 56 , 303 , 304
“Breakthrough Pain”
Non–cancer-related breakthrough pain (BTP) has been treated with opioids.305–308 309
Intrathecal Opioids
No quality studies document efficacy of intrathecal opioid delivery systems for treatment of chronic nonmalignant pain. Intrathecal opioid delivery systems are invasive and costly, with possible significant adverse effects, including potential long-term sequelae from both implantation/retention of the devices, including granuloma formation, and those associated with the concurrent use of intrathecal opioids.137 , 138 , 310–313
Adverse Effects
Opioids have been associated with numerous adverse effects, which differ somewhat on the basis of the specific drug and route of administration. In aggregate, these effects include (see also Table 2 ) opioid-induced hyperalgesia,139 , 140 54 , 141–178 62 , 138 , 179–192 136 , 193–196 197 132 197 , 198 199
There is no quality literature to identify which patients can be safely prescribed opioids without escalation of dose or other adverse risks. This caused a downgrading of the level of evidence from “C” to “I” especially when combined with evidence of adverse effects (see Table 2 ) in addition to concerns regarding the inability to control escalating doses.309 259 , 314–318 319–321
Although the clinical interview remains an important method to identify risk for aberrant drug-related behaviors,322 , 323 41 , 322–342 200 , 262 , 271 , 273 , 322 , 323 , 325–328 , 331 , 340 , 341 , 343–354 355 , 356
Opioid deaths have been associated with CYP2D6 and OPRMI gene variations,357–361 362 363–366 367 364–366 , 368 , 369–387
Opioids are moderate to high cost, depending on the duration of treatment. Provider and organizational barriers to implement recommendations to prescribe nonopioid medications and therapies are low, consisting primarily of altering practice habits. Barriers regarding dose limit recommendations are similarly low, consisting primarily of altering practice habits. Barriers to dose reduction are greater for established patients, especially on higher doses. Tools are identified to assess functional progress, assessing opioid risk, and guidance to assist with tapering. Urine drug testing guidance has been developed.
RESEARCH RECOMMENDATIONS
None of 28 comparative effectiveness trials reviewed reported that opioids are superior to other medications or treatments for acute, subacute, chronic, or postoperative pain. Several trials suggested that opioids are inferior to other medications, generally NSAIDs. Reported magnitudes of benefit of opioids compared with placebo are modest. As there currently is none, high-quality evidence regarding objective gains in function from treatment with opioids for chronic pain is a particularly important need.
For chronic pain, there are no placebo-controlled trials lasting more than 4 months. Thus, long-term efficacy of opioids for chronic pain is unknown. There also is no quality literature to identify which patients can safely be prescribed opioids without escalation of dose or other adverse risks. This caused a downgrading of the level of evidence from “C” to “I” especially when combined with evidence of major adverse effects reviewed elsewhere in addition to concerns regarding the inability to control escalating doses.309
Many of the studies have low sample sizes and the designs of the trials vary, especially for treatment of chronic pain. In those studies that include all patients in a randomized controlled trial, overall dropout rates (including washout phases, run-in phases, conversion phases, titration phases, trial “enrichment” phases, as well as those who drop out during the trial) and adverse effect profiles each frequently exceed 50% and several are more than 75%.261 , 308 , 314 , 319 , 388–393 394 308 , 314 , 319 , 388 , 390–393
The vast majority of the trials of opioids either are industry-sponsored or have significant conflicts of interest. By contrast, epidemiological studies of motor vehicle crash risk associated with opioids show no significant conflicts of interest.79 395–398 395
The number of comparative trials with nonopioid treatment arms compared to an opioid is fairly limited and focused on a few medications. Altogether, there are 9 acute pain, 7 peri/postoperative, and 12 chronic pain comparative trials that scored high or moderate quality. Industry sponsorship of these is similarly 73.9%. Thus, the large majority of evidence regarding efficacy of opioids is at least partially industry-sponsored or with conflicts of interest. These analyses provide additional direction for needed nonconflicted research.
APPLICABILITY AND IMPLEMENTATION ISSUES
Strengths of this guideline include its systematic synthesis of many quality studies. The evidence is largely consistent for many of the guideline questions, including both strong and weak opioids. Findings include a lack of studies showing superiority of opioids for pain treatment. The dose–response relationship between morphine equivalent dose and risk of fatality has been reproduced, and duplicated between acute and chronic pain patients. Therefore, the overall evidence base is strongly supportive of most of this guideline's recommendations. This guideline has also identified additional interventions that, if implemented, would likely reduce the adverse effects and mortality.
Weaknesses of this guideline include the relatively few comparative trials and heavy industry sponsorship of trials and conflicts of interest in the vast majority of studies. Implementation of this guideline could potentially result in pain, which could be undertreated when it may be successfully treated with opioids, although the guideline includes provisions to avoid that.
SUMMARY
The ACOEM Evidence-based Practice Opioids Panel concludes that quality evidence currently fails to demonstrate superiority of opioids to other medications and treatments for treatment of pain. It recommends comprehensive history and physical examinations. Selective use of the lowest effective, short-acting opioid dose is recommended as adjunctive treatment for patients with acute and postoperative pain that is inadequately treated with NSAIDs or other treatments. The strongest risk factors for overdose and deaths include concomitant use of benzodiazepines, illicit substances, unemployment status, psychiatric disorders, and a substance(s) abuse history. Opioid consent and treatment agreements are recommended for treatment of subacute and chronic pain with opioids. Carefully conducted trials on highly select patients with subacute and chronic pain are recommended, as well as opioid maintenance only with documented functional gain(s). A strong and reproducible dose–response relationship identifies a recommended MED limit of 50 mg/day for acute or chronic pain. Higher doses are recommended to require documented commensurately greater functional benefit(s).
ACKNOWLEDGMENTS
The Evidence-based Practice Opioids Panel recognizes the considerable work of the managing editors: Marianne Dreger, MA (Production), and Julie A. Ording, MPH (Research). The Opioids Panel also much appreciates the research for this guideline that was conducted by the research team: Ulrike Ott, MSPH; Atim C. Effiong, MPH; Deborah G. Passey, MS; William G. Caughey, MS; Holly Uphold, PhD; Alzina Koric, MPP; Zac Carter, BS; Zachary C. Arnold, BS; Katherine Schwei, BS; Kylee Tokita, BS; Leslie M. Cepeda-Echeverria; Ninoska De Jesus; and Jeremiah L. Dortch, BS. Drs Hegmann and Thiese also conducted research for this guideline. Dr Harris served as the Opioids Panel methodologist.
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* Valdecoxib is currently withdrawn from the market. Cited Here
† Flupirtine also has evidence of efficacy, although not currently approved in the United States. Cited Here
