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algorithms. Figure 1 is an example of one of the algo- rithms and provides recommendations on determination of appropriateness for opioid therapy, with the initial rec- ommendation that nonpharmacologic and nonopioid pharmacologic therapies be initiated over opioid therapy for chronic pain. Table 1 summarizes all 18 recommen- dations. Of all the recommendations, this paper high- lights a few of the more unique areas of clinical importance.

Initiation of Opioid Therapy

Recommendation 1

a. We recommend against initiation of long-term opioid therapy for chronic pain. (Strong against)

b. We recommend alternatives to opioid therapy such as self-management strategies and other nonphar- macological treatments. (Strong for)

c. When pharmacologic therapies are used, we recom- mend nonopioids over opioids. (Strong for)

There is a rapidly growing understanding of the signifi- cant harms of LOT even at low doses (see the Dose, Follow-up, and Taper of Opioids section), including overdose and opioid use disorder (OUD). At the same time, there is a lack of high-quality evidence that LOT improves pain, function, and/or quality of life. When considering the benefits of LOT, it is important to con- sider whether LOT will result in clinically meaningful improvements in function such as readiness to return to work/duty and/or measurable improvement in other areas of function. The literature review identified no high-quality studies evaluating the efficacy of LOT for outcomes lasting longer than 16 weeks. Given the lack of evidence showing sustained functional benefit of LOT and moderate evidence outlining harms, nonopioid treatments are preferred for chronic pain.

Psychological therapies (e.g., cognitive behavioral inter- ventions such as cognitive behavioral therapy [CBT] and biofeedback), exercise, and multidisciplinary biopsycho- social rehabilitation have been found to be effective for pain reduction in multiple pain conditions [9–11]. These interventions are safe and have not been shown to in- crease morbidity or mortality. While exercise and psy- chological therapies have not been compared directly with LOT, there is clear evidence that LOT has signifi- cant evidence for harm, even at low doses, that esca- lates with increasing dose. There is insufficient evidence to recommend psychological over physical therapies or vice versa; the choice of CBT, exercise, and/or biopsy- chosocial rehabilitation should be individualized based on patient assessment and a shared decision-making process [12].

In addition, nonopioid pharmacologic agents should be tried and optimized before consideration of opioid medications. Unless contraindicated, nonsteroidal anti- inflammatory drugs (NSAIDs) and serotonin- norepinephrine reuptake inhibitors (SNRIs) have been

shown to be beneficial for chronic pain [10]. Other non- opioid medications should also be considered before opioids given the significant morbidity and mortality as- sociated with opioid analgesics at even relatively low doses. As this is a LOT guideline and not a pain guide- line, the potential harms of nonopioid therapy were not quantified and compared with LOT.

This recommendation was given a STRONG grade be- cause of the moderate evidence showing definite harms in the way of deaths, overdoses, and development of OUD. Based on the evidence, it was considered that opioid therapy should no longer be given when all non- opioid approaches fail due to the substantial risk of harms.

The CDC guideline states, “Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patients.” Our guideline takes a stronger stance against opioid therapy, largely driven by the risk for development of opioid use disorder. Both guidelines find little evidence of benefit for long-term opioid use.

Duration of Opioid Therapy

Recommendation 2

If prescribing opioid therapy for patients with chronic pain, we recommend a short duration. (Strong for)

Note: Consideration of opioid therapy beyond 90 days requires re-evaluation and discussion with patient of risks and benefits.

The pillars for this recommendation are a paucity of re- search showing benefit for LOT, the strength of the evi- dence demonstrating the potential for life-threatening harm, and the substantial heightened risk for developing OUD in patients who receive OT beyond 90 days.

Two studies of chronic noncancer pain (CNCP) patients support the strong advisement being made in this rec- ommendation. Edlund et al. (2014) [13] examined the claims data from a health insurance database between 2000 and 2005 to examine factors predictive of devel- oping OUD. They found that, even greater than opioid dose, duration of OT was the strongest predictor of de- veloping OUD. The odds ratio (OR) of developing OUD ranged from 14.92 for low-dose chronic prescriptions to 122.45 for high-dose chronic opioid administration. A second study by Boscarino et al. (2011) [14] examined medical records from a large health care system. Through interviews with a random sample of patients on LOT, they examined factors associated with and the prevalence of OUD (using the Diagnostic and Statistical Manual of Mental Disorders [DSM] 4 and 5 criteria). These results showed that the prevalence of lifetime

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Pa�ent with chronic pain

Obtain biopsychosocial assessment (see Sidebar A)

Is referral/consulta�on for evalua�on and treatment indicated (e.g., mental health, SUD,

more intensive interdisciplinary care)?

Refer/consult with appropriate interdisciplinary treatments

Educate pa�ent and family about treatment op�ons, including educa�on on: • Known risks and unknown long-term benefits of OT • Risks of SUD and overdose • Need for risk mi�ga�on strategies • Naloxone rescue

Discuss and complete wri�en informed consent with pa�ent and family

Determine and document treatment plan

Sidebar A: Components of Biopsychosocial Assessment • Pain assessment including history, physical exam,

comorbidi�es, previous treatment and medica�ons, dura�on of symptoms, onset and triggers, loca�on/radia�on, previous episodes, intensity and impact, pa�ent percep�on of symptoms

• Pa�ent func�onal goals • Impact of pain on family, work, life • Review of previous diagnos�c studies • Addi�onal consulta�ons and referrals • Coexis�ng illness and treatments and effect on pain • Significant psychological, social, or behavioral factors

that may affect treatment • Family history of chronic pain • Collateral of family involvement • Pa�ent beliefs/knowledge of:

• The cause of their pain • Their treatment preferences • The perceived efficacy of various treatment op�ons

For pa�ents already on OT, include assessment of psychological factors (e.g., beliefs, expecta�ons, fears) related to con�nuing vs. tapering OT

Proceed to Module B

Yes

Educate/re-educate on: • Nonopioid management • Self-management to improve func�on and quality of life • Realis�c expecta�ons and limita�ons of medical treatment

Sidebar B: Examples of Absolute Contraindica�ons to Ini�a�ng Opioid Therapy for Chronic Pain • True life-threatening allergy to opioids • Ac�ve SUD • Elevated suicide risk (see VA/DoD

Suicide CPG) • Concomitant use of benzodiazepines

Implement and op�mize nonopioid treatments for chronic pain (e.g., physical, psychological, and complementary and

integra�ve treatments)

• Complete opioid risk assessment • Do pa�ent risks outweigh benefits? Consider

strength and number of risk factors and pa�ent preference (see Sidebar B)

Is adding OT to comprehensive pain therapy indicated at this �me? (see Sidebar C)

Is the pa�ent willing to engage in a comprehensive pain care plan? Sidebar C: Considera�on Checklist for

LOT for Chronic Pain • Risks do not outweigh poten�al

modest benefits • Pa�ent is experiencing severe chronic

pain that interferes with func�on and has failed to adequately respond to indicated nonopioid and nondrug therapeu�c interven�ons

• Pa�ent is willing to con�nue to engage in comprehensive treatment plan including nonopioid treatments and implementa�on of learned ac�ve strategies that meets his or her needs to be successful with plan of care

• Clear and measurable treatment goals are established

• Pa�ent is able to access adequate follow-up for OT (see Recommenda�ons 7-9)

• PDMP and UDT are concordant with expecta�ons

• Review of recent medical records is concordant with diagnosis and risk assessment

• Pa�ent is fully informed and consents to the therapy

Are these treatments effec�ve in managing pain and op�mizing func�on?

Is pa�ent prepared to accept responsibili�es of and is provider prepared

to implement risk mi�ga�on strategies?

Yes

Has the pa�ent been on daily OT for pain for more than 3 months?

Exit algorithm; manage with nonopioid modali�es

Yes

Proceed to Module D

Yes

17 18

Figure 1 Determination of appropriateness for opioid therapy. Note: Nonpharmacologic and nonopioid pharmacologic therapies are preferred for chronic pain. OT ¼ opioid therapy; PDMP ¼ prescription drug monitoring program; SUD ¼ substance abuse disorder; UDT ¼ urine drug test; VA/DoD Suicide CPG ¼ US Department of Veterans Affairs/US Department of Defense “Clinical Practice Guideline for the Assessment and Management of Patients at Risk for Suicide.”

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OUD for patients on LOT was 34.9% (based on DSM-5 criteria) and 35.5% (based on DSM-4 criteria).

The CDC guideline does not specifically address this issue.

Initiation or Continuation of Opioid Therapy in Patients Younger than Age 30 Years

Recommendation 6

a. We recommend against long-term opioid therapy for patients younger than age 30 years secondary to higher risk of opioid use disorder and overdose. (Strong against)

b. For patients younger than age 30 years currently on long-term opioid therapy, we recommend close mon- itoring and consideration for tapering when risks ex- ceed benefits. (Strong for)

All patients who chronically take opioids for pain are at risk for OUD, especially those who are younger than age 30 years. This is of particular concern in the DoD and VA patient populations due to the increased fre- quency of chronic pain secondary to injury relative to the general population. Six studies were identified that examined age as a predictor of OUD, respiratory/central nervous system depression, and/or overdose; four of the six studies were rated as moderate-quality evidence [13,15–17]. Two were rated as low-quality evidence [18,19]. Five studies demonstrated that age was in- versely associated with the risk of OUD and overdose [13,15–17,19]. One study showed that older subjects had a higher hazard ratio (HR) of overdose, but this study was of low quality [18]. Therefore, the Work Group’s overall confidence in the quality of the evidence was judged as moderate.

Similar to other risk factors, age younger than 30 years should be weighed heavily in the risk-benefit calculus for initiating LOT. Age younger than 30 years is not an absolute contraindication to LOT as there may be some situations where the benefits of LOT clearly outweigh the risks of OUD and overdose. Hospitalized patients re- covering from battlefield injuries, for example, are known to have less chronic pain, depression, and post- traumatic stress disorder (PTSD) when their pain is ag- gressively managed starting soon after injury [20]. In those cases, LOT may be appropriate only if risk mitiga- tion strategies are employed and patients are titrated off LOT as soon as it is appropriate.

The added risk younger patients using opioids face for OUD and overdose (in comparison with older patients) is significant. Edlund et al. (2014) [13] found that sub- jects age 18 to 30 years carried 11 times the odds of OUD and overdose in comparison with those older than age 65. Furthermore, Bohnert et al. (2011) [15] found that subjects older than age 70 years had a substantially lower chance of developing OUD or overdose (HR ¼

0.06) in comparison with subjects in the 18–29 years age category.

Younger patients are also at a higher risk of opioid mis- use (as suggested by a UDT indicating high-risk medi- cation-related behavior). Turner et al. (2014) [21] showed patients in the 45–64 years age group were sig- nificantly less likely to have an aberrant UDT (detection of a nonprescribed opioid, nonprescribed benzodiaze- pine, illicit drug, or tetrahydrocannabinol [THC]) in com- parison with patients in the 20–44 years age group. Patients in the 45–64 years and 65 years and older age groups were significantly less likely than the 20–44 years age group to have nondetection of a prescribed opioid as well (indicating possible diversion) [21]. Further sup- porting this recommendation is evidence in other areas that shows that developing brains (age < 30 years) are at increased risk of addiction when exposed to addictive substances early in life [22–25].

The CDC guideline states, “Factors associated with in- creased risk for misuse included history of substance use disorder, younger age, major depression, and use of psychotropic medications” but does not particularly identify a restrictive age in the consideration of opioid therapy.

Concurrent Sedatives

Recommendation 5

We recommend against the concurrent use of benzo- diazepines and opioids. (Strong against)

Note: For patients currently on long-term opioid therapy and benzodiazepines, consider tapering one or both when risks exceed benefits and obtaining specialty con- sultation as appropriate.

Harms outweigh benefits for the concurrent use of ben- zodiazepines and LOT. There is moderate-quality evi- dence that concurrent use of benzodiazepines with prescription opioids increases the risk of overdose and overdose death [26,27]. In a retrospective cohort study, the adjusted odds ratio (AOR) for drug overdose was highest for individuals on LOT for chronic pain who also received concurrent long-term benzodiazepine therapy [26]. Furthermore, there is a lack of evidence in favor of long-term therapy with benzodiazepines and opioids for chronic pain [28].

Once initiated in combat veterans, benzodiazepines can be very difficult to discontinue due to withdrawal, which is often compounded by ensuing exacerbations of PTSD symptoms. Moreover, abrupt discontinuation of benzo- diazepines should be avoided as it can lead to serious ad- verse effects including seizures and death. Tapering benzodiazepines should be performed with caution and within a team environment when possible [29].

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In addition to benzodiazepines, the addition of other psychoactive medications to LOT must be made with caution. We suggest not prescribing “Z-drugs” (e.g., zol- pidem, eszopiclone) to patients who are on LOT as moderate-quality evidence demonstrates that the com- bination of zolpidem and opioids increases the AOR of overdose [26]. The evidence reviewed also identifies po- tential adverse outcomes (e.g., risk of overdose) with the combined use of antidepressants and opioids in patients who do not have depression [26]. This particu- lar study did not differentiate between classes of antide- pressants, limiting the ability of the Work Group to recommend for or against prescribing opioids and a specific class of antidepressants. As such, there is no specific recommendation with respect to using specific classes of antidepressants and LOT.

The CDC guideline states, “Clinicians should avoid pre- scribing opioid pain medication and benzodiazepines concurrently whenever possible.” This statements is similar, however, to the CDC Guideline, which states, “The clinical evidence review did not address risks of benzodiazepine co-prescription among patients pre- scribed opioids. However, the contextual evidence re- view found evidence in epidemiologic series of concurrent benzodiazepine use in large proportions of opioid-related overdose deaths.” This guideline did re- view the evidence in making our recommendation.

Risk Mitigation

Recommendation 7

We recommend implementing risk mitigation strategies upon initiation of long-term opioid therapy, starting with an informed consent conversation covering the risks and benefits of opioid therapy as well as alterna- tive therapies. The strategies and their frequency should be commensurate with risk factors and include:

• ongoing, random urine drug testing (including ap- propriate confirmatory testing);

• checking state prescription drug monitoring programs;

• monitoring for overdose potential and suicidality; • providing overdose education; • prescribing of naloxone rescue and accompanying

education. (Strong for)

A paradigm shift occurred in the approach to ensuring and documenting patient and provider understanding and expectations regarding the risks and benefits of LOT. While the prior paradigm allowed for opioid ther- apy agreements (also known as opioid contracts), the realized increased risk and ethical concerns have replaced agreements with an informed consent process. Refusal of this process by the patient may lead to changes in whether to proceed with LOT.

The confidence in the quality of the evidence was mod- erate for UDT and frequent follow-up and was low for opioid treatment agreements/informed consent. The fre- quency of follow-up and monitoring should be based on patient level of risk as determined by an individual risk assessment.

Implementing more extensive risk mitigation strategies entails an investment of resources. Primary care pro- viders may require more time with patients to shared decision-making and treatment planning. More frequent follow-up of patients on LOT can affect access to care for all empaneled patients.

The CDC guideline has risk mitigation split into several sections. It states, “When prescribing opioids for chronic pain, clinicians should use urine drug testing before start- ing opioid therapy and consider urine drug testing at least annually.” It also states, “Clinicians should review the patient’s history of controlled substance prescriptions us- ing state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and pe- riodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months.” These are in agreement with our guideline. The CDC guideline also states, “Although the clinical evidence review did not find studies evaluating the effectiveness of written agreements or treatment plans (KQ4), clinicians and patients who set a plan in advance will clarify expectations regarding how opioids will be prescribed and monitored, as well as situa- tions in which opioids will be discontinued or doses tapered.” Our guideline specifies informed consent as re- quired with any medical procedure/medication with a higher level of risk.

Our guideline recommends the coprescription of nalox- one rescue and accompanying education as a risk miti- gation strategy based on 22 observational studies but recognizes that clinical efficacy has not been estab- lished for the use of methadone or exceptionally potent opioids. It also notes that multiple doses maybe re- quired for some overdoses.

In regards to naloxone rescue, the CDC guideline did not research naloxone’s efficacy but states, “Most experts agreed that clinicians should consider offering naloxone when prescribing opioids to patients at in- creased risk for overdose, including patients with a his- tory of overdose, patients with a history of substance use disorder, patients taking benzodiazepines with opioids, patients at risk for returning to a high dose to which they are no longer tolerant, and patients taking higher dosages of opioids (�50 MME/d). Practices should provide education on overdose prevention and naloxone use to patients receiving naloxone prescrip- tions and to members of their households.”

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Risk Mitigation—Suicidality

Recommendation 8

We recommend assessing suicide risk when consider- ing initiating or continuing long-term opioid therapy and intervening when necessary. (Strong for)

Every suicide is a tragic outcome. According to the VA- DoD 2013 “Assessment and Management for Patients at Risk for Suicide,” 22% of all suicides occur in veter- ans [30]. They further state that rates of suicide in the population of veterans using the VA health care system are higher than those of the general population and es- pecially higher in those with a mental health diagnosis. The Va-DoD 2013 suicide guideline stresses removing lethal means from the suicidal patient’s environment for those in the moderate or severe risk categories. Opioid prescriptions are one of those possible means. This suggestion is supported by a large retrospective obser- vational study in veterans that found increased levels of risk with increased dose. Compared with patients re- ceiving 20 or fewer milligrams per day (mg/d), hazard ratios were 2.15 for 100þmg/d [31]. This evidence was not causal as the patients on higher doses could have more poorly treated pain. The issue is complicated by pain being an independent suicide risk factor [32,33].

Based on this information, the Work Group recom- mended that suicide be assessed or reassessed at each step of opioid therapy. It was given a grade of strong for, with moderate evidence supporting increased monitoring as being protective for suicide attempts.

The CDC guideline mentions suicide attempts or risks as a factor in using opioid therapy, but it does not spe- cifically advocate monitoring.

Dose, Follow-up, and Taper of Opioids

Recommendation 10

If prescribing opioids, we recommend prescribing the lowest dose of opioids as indicated by patient-specific risks and benefits. (Strong for)

Note: There is no absolutely safe dose of opioids.

Recommendation 11

As opioid dosage and risk increase, we recommend more frequent monitoring for adverse events, including opioid use disorder and overdose. (Strong for)

Note: Risks for opioid use disorder start at any dose and increase in a dose-dependent manner. Risks for overdose and death significantly increase at a range of 20–50 mg morphine equivalent daily dose.

Recommendation 12

We recommend against opioid doses over 90 mg mor- phine equivalent daily dose for treating chronic pain. (Strong against)

Note: For patients who are currently prescribed doses over 90 mg morphine equivalent daily dose, evaluate for tapering to reduced dose or to discontinuation.

There is moderate-quality evidence from retrospective cohort and retrospective case-control studies indicating that risk of prescription opioid overdose and overdose death exists even at low opioid dosage levels and that it increases with increasing doses. Significant risk (approx- imately 1.5 times) exists at a daily dosage range of 20 to less than 50 mg morphine equivalent daily dose (MEDD) and further increases (approximately 2.6 times) at a range of 50 to less than 100 mg MEDD compared with the risk at less than 20 mg MEDD. Risk continues to increase at higher dosage ranges (�100 mg MEDD) [15,18,26,34]. In a prospective cohort study (not in- cluded in the evidence review as it did not include infor- mation on acute vs chronic pain in the patient population), Dasgupta et al. (2015) [35] compared resi- dents of North Carolina who had received an opioid prescription in the last year to residents who had not. The study examined the outcome of population-based rates of opioid overdose mortality by opioid dose, with- out use of a presupposed threshold. There was no safe dose of opioid. Among the more than nine million indi- viduals followed for one year, 629 died from opioid over- dose. Of these 629 individuals, 151 had no record of having been dispensed an opioid. Of the 478 patients who died from an opioid overdose who were prescribed opioids, 235 (49%) had been prescribed less than 80 mg MEDD. Overdose incidence rate ratios (IRRs) doubled each time the MEDD ranges increased from 60.0–79.9 mg to 80.0–99.9 mg (IRR ¼ 2.9 to 6.2), then to 120–139.9 mg (IRR ¼ 14.1), 160–179.9 mg (IRR ¼ 29.5), and 350–399.9 mg (IRR ¼ 63.2).

The CDC guideline recommendations are very similar, with 50 and 90 MEDD dose limits.

Opioid Tapering

Recommendation 14

We recommend tapering to reduced dose or discontinuation of long-term opioid therapy when risks of long-term opioid therapy outweigh benefits. (Strong for)

Note: Abrupt discontinuation should be avoided unless required for immediate safety concerns.

LOT use should be regularly reassessed by clinicians, with consideration of tapering or discontinuation when

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the risks exceed the benefits of therapy. Observational studies suggest that when opioids are tapered or dis- continued within the context of a multimodal pain reha- bilitation care plan, patients can experience an improvement in their pain, function, and mood [36,37]. Nonpharmacologic therapies and nonopioid pharmaco- logic therapies are preferred and should be optimized. Several factors should be taken into consideration when determining the balance of risks and benefits of OT, recognizing that multiple risk factors increase cumulative risk [38,39]. These factors include concerns about OUD or substance use disorder (SUD), medical or mental health conditions that increase risk, concomitant medi- cations that increase overdose risk, unmanageable side effects, and lack of clinically meaningful improvement in function. Abrupt discontinuation of opioids may be justi- fied in certain high-risk circumstances. When there is evidence for diversion, the clinician may need to discon- tinue OT and frequently assess for withdrawal symp- toms. The tapering treatment plan should be individualized and should address the pace of tapering, setting of care, and frequency of follow-up. Low fre- quency of follow-up in primary care and limited access to comprehensive interdisciplinary specialty pain, reha- bilitation, mental health, and addiction services may be barriers to tapering LOT. Tapering may unmask underly- ing OUD. Therefore, frequent assessment for OUD is recommended.

The rate of taper takes into account several factors, in- cluding initial dose, formulations available, and risk fac- tors that increase harm. A gradual taper over months, or even years, with 5% to 20% dose reduction every four weeks is indicated for higher opioid doses and/or longer duration of OT. In some patients, a faster taper, such as a 5% to 20% reduction per week, may be needed when risks are too high to consider a gradual taper. Specialty consultation should be obtained if the risks warrant a more rapid taper. Such risks include nonadherence to the treatment plan and escalating high-risk medication-related behaviors. These patients will need frequent follow-up and reevaluation of SUD, mental health, and/or co-occurring medical conditions with every dose change. It should be recognized that el- evated dose alone poses increased risk of overdose, overdose death, adverse effects, and the development of OUD.

A biopsychosocial assessment including evaluation of medical, psychiatric, and co-occurring substance use conditions, as well as the patient’s social support sys- tem, should be completed prior to the initiation of an opioid taper. The risks and benefits of the current opioid regimen should be weighed with the risks and benefits associated with a reduction in opioid dose. Follow-up should occur within a range of one week to one month after any opioid dosage change and should include ed- ucation about self-management strategies and the risks associated with OT.

Clinicians should consider using an interdisciplinary, team-based approach that may include primary care, mental health, pain specialty/rehabilitation, physical ther- apy, and/or SUD services during the opioid tapering process. Additional research is needed to identify the opioid tapering processes that are associated with the best patient outcomes among a broad range of domains including general functioning, psychosocial functioning, mood, pain-related disability, and adverse outcomes assessed in the short, medium, and long term.

The CDC guideline has a similar section on tapering en- titled “Considerations for tapering opioids” and a similar finding of nonsuperiority of one method over another.

Recommendation 17

We recommend offering medication-assisted treatment for opioid use disorder to patients with chronic pain and opioid use disorder. (Strong for)

Note: See the VA/DoD “Clinical Practice Guideline for the Management of Substance Use Disorders.”

OUD is associated with premature death from opioid overdose and other medical complications such as ac- quired immunodeficiency syndrome (AIDS), hepatitis C, and sepsis. On average, OUD carries a 40% to 60% 20-year mortality rate [40]. Persons with OUD are at high risk for premature death, not only from opioid over- dose but also from other consequences. Thus, provid- ing firstline treatment is important to save lives as well as to improve the quality of life.

Strong evidence supports the use of opioid agonist ther- apy (e.g., methadone, buprenorphine/naloxone) as first- line treatment for moderate to severe OUD. One multicenter RCT tested patient responses to tapering of buprenorphine/naloxone to discontinuation over four to 12 weeks, plus two regimens of outpatient counseling [40]. The results of the study suggest that medication- assisted treatment (MAT) with buprenorphine/naloxone and brief structured counseling by the prescribing physi- cian can be successful for about half of selected patients with prescription OUD, whereas withdrawal management alone, even with close weekly follow-up and counseling, is successful for less than 10% of patients. Furthermore, the presence of chronic pain does not seem to interfere with the success of MAT, based on the conclusions of an RCT by Weiss et al. (2011) [41] and a meta-analysis by Dennis et al. (2015) [42].

Given the high mortality associated with OUD and the safety and efficacy of MAT for OUD in multiple clinical trials and meta-analyses, we recommend MAT for those who meet DSM-5 criteria for OUD. Those who do not respond to minimal counseling may benefit from a com- prehensive assessment and more intensive treatment of

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OUD and any co-occurring conditions in SUD specialty care settings.

On this subject, the CDC guideline states, “Clinicians should offer or arrange evidence-based treatment (usu- ally medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder.” There is agree- ment between the two guidelines.

Recommendation 18

a. We recommend alternatives to opioids for mild to moderate acute pain. (Strong for)

b. We suggest use of multimodal pain care including nonopioid medications as indicated when opioids are used for acute pain. (Weak for)

c. If take-home opioids are prescribed, we recommend that immediate-release opioids are used at the low- est effective dose, with opioid therapy reassessment no later than three to five days later to determine if adjustment or continuing opioid therapy is indicated. (Strong for)

Note: Patient education about opioid risks and alterna- tives to opioid therapy should be offered.

The VA-DoD guideline targets the contribution of opioids given for acute pain therapy leading to prolonged use of opioids and the risks accompanying their use. They did not evaluate the benefits compared with risks of acute opioid therapy nor the efficacy of alternative treatments for mild to moderate pain, even though they are recom- mended. They cite Halbert et al. [43] and Deyo et al. [44], who looked at opioid prescribing in a medical pop- ulation. Deyo et al.’s study of 536,767 patients found that 5% of those who received six or more refills be- came chronic users, with rural location, prescription of long-acting medications, and increased age being other risks. Halbert et al. focused on the contribution of mood disorders and a more than twofold increase in numbers of patients transitioning to chronic use in those with mood disorders. The above medical studies and three surgical studies [45–47], one using postoperative hip, postoperative knee, and general postoperative popula- tions, were cited as identifying duration of use as risk factors leading from acute use to LOT. Overdose risks as described by Bohnert et al. [15] and Zedler et al. [18] were also cited as reasons to reassess acute opioid use in three to five days.

The reasoning for using a reassessment in three to five days was not detailed in the discussion section of this recommendation.

The CDC guideline states, “When opioids are used for acute pain, clinicians should prescribe the lowest effec- tive dose of immediate-release opioids and should pre- scribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven

days will rarely be needed.” These guidelines are in con- cordance in regards to acute use leading to LOT and the risks thereof and to not using long-acting medica- tions for acute pain. There is a difference in acute use risk mitigation, with the CDC favoring limitation of pre- scription to three days with a seven-day provision for outliers, compared with a three- to five-day reassess- ment. This softer recommendation may have been due to a lack of data on the efficacy of the acute use of opioids, making it harder to balance risk and benefits.

Discussion

While there is a significant amount of concordance be- tween this guideline and the CDC guideline [3], they dif- fer in a few critical aspects. The CDC guideline uses expert determination and focuses on the overdose and death prevention end points in making their recommen- dations while this guideline is evidence determined and additionally gives consideration to recent data relating to the development of substance use disorder as a major end point. Further major differences perhaps more rele- vant in the unique VA-DoD population are the specific avoidance of LOT for patients younger than age 30 years due to the risk of abuse or overdose, a stron- ger avoidance of concurrent benzodiazepine use recom- mendation, a focus on suicide prevention, a short-term reassessment strategy for acute pain, and a specific three-month time frame to prevent transition from less than three months to long-term therapy.

This guideline also requires the use of informed consent as part of the prescribing risk mitigation process, whereas the CDC passed on the use of either informed consent or agreements. The comprehensive risk mitiga- tion strategy also includes ongoing random urine drug testing, providing overdose education, suicide preven- tion, and prescribing naloxone rescue medications. Interdisciplinary management should be instituted for all chronic pain patients to address the problem through multiple modalities, with the overall goal of reducing opi- oid requirement and using nonpharmacologic and non- opioid pharmacologic methods as the preferred method for treatment of chronic pain. This approach may require increased resources that could impact all enrolled patients, but the level of risk suggests strong measures as required.

This guideline’s creation was unique compared with other nonopioid guidelines. After the key questions were developed and researched, the US Congress passed the CARA Act, requiring us to consider the CDC guide- line in writing our guideline. The CDC guideline develop- ment was helpful in identifying areas of concern and taking the backlash from patients, industry, and practi- tioners invested in opioid therapy.

Second, as this was a guideline renewal, we had only a limited number of questions that we could ask, despite the large amount of new studies. Careful construction of the key questions mitigated these concerns.

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Table 1 VA/DoD OT CPG recommendations

# Recommendation Strength* Category †

Initiation and Continuation of Opioids

1. a. We recommend against initiation of long-term opioid therapy for

chronic pain.

b. We recommend alternatives to opioid therapy such as self-

management strategies and other nonpharmacological treatments.

c. When pharmacologic therapies are used, we recommend nonop-

ioids over opioids.

a. Strong

against

b. Strong for

c. Strong for

Reviewed,

new-replaced

2. If prescribing opioid therapy for patients with chronic pain, we recom-

mend a short duration.

Note: Consideration of opioid therapy beyond 90 days requires

re-evaluation and discussion with patient of risks and benefits.

Strong for Reviewed,

new-added

3. For patients currently on long-term opioid therapy, we recommend

ongoing risk mitigation strategies (see Recommendations 7–9),

assessment for opioid use disorder, and consideration for tapering

when risks exceed benefits (see Recommendation 14).

Strong for Reviewed,

new-replaced

4. a. We recommend against long-term opioid therapy for pain in

patients with untreated substance use disorder.

b. For patients currently on long-term opioid therapy with evidence of

untreated substance use disorder, we recommend close monitor-

ing, including engagement in substance use disorder treatment,

and discontinuation of opioid therapy for pain with appropriate

tapering (see Recommendations 14 and 17).

a. Strong

against

b. Strong for

Reviewed,

amended

5. a. We recommend against the concurrent use of benzodiazepines

and opioids.

Note: For patients currently on long-term opioid therapy and benzo-

diazepines, consider tapering one or both when risks exceed

benefits and obtaining specialty consultation as appropriate (see

Recommendation 14 and VA/DoD substance use disorders CPG).

Strong against Reviewed,

new-added

6. a. We recommend against long-term opioid therapy for patients

younger than age 30 years secondary to higher risk of opioid use

disorder and overdose.

b. For patients younger than age 30 years currently on long-term opi-

oid therapy, we recommend close monitoring and consideration for

tapering when risks exceed benefits (see Recommendations 14

and 17).

a. Strong

against

b. Strong for

Reviewed,

new-replaced

Risk Mitigation

7. We recommend implementing risk mitigation strategies upon initiation

of long-term opioid therapy, starting with an informed consent con-

versation covering the risks and benefits of opioid therapy as well

as alternative therapies. The strategies and their frequency should

be commensurate with risk factors and include: • ongoing, random urine drug testing (including appropriate

confirmatory testing); • checking state prescription drug monitoring programs; • monitoring for overdose potential and suicidality; • providing overdose education; • prescribing of naloxone rescue and accompanying education.

Strong for Reviewed,

new-replaced

8. We recommend assessing suicide risk when considering initiating or

continuing long-term opioid therapy and intervening when

necessary.

Strong for Reviewed,

amended

(continued)

VA-DoD Guideline for Opioid Therapy

937

Table 1 Continued

# Recommendation Strength* Category†

9. We recommend evaluating the benefits of continued opioid therapy

and the risk for opioid-related adverse events at least every three

months.

Strong for Reviewed, new-

replaced

Type, Dose, Follow-up, and Taper of Opioids

10. If prescribing opioids, we recommend prescribing the lowest dose of

opioids as indicated by patient-specific risks and benefits.

Note: There is no absolutely safe dose of opioids.

Strong for Reviewed, new-

replaced

11. As opioid dosage and risk increase, we recommend more frequent

monitoring for adverse events including opioid use disorder and

overdose.

Note: • Risks for opioid use disorder start at any dose and increase in a

dose-dependent manner. • Risks for overdose and death significantly increase at a range of

20–50 mg morphine equivalent daily dose.

Strong for Reviewed, new-

replaced

12. We recommend against opioid doses over 90 mg morphine equivalent

daily dose for treating chronic pain.

Note: For patients who are currently prescribed doses over 90 mg

morphine equivalent daily dose, evaluate for tapering to reduced

dose or to discontinuation (see Recommendations 15 and 16).

Strong against Reviewed, new-

replaced

13. We recommend against prescribing long-acting opioids for acute

pain, as an as-needed medication, or on initiation of long-term

opioid therapy.

Strong against Reviewed, new-

replaced

14. We recommend tapering to reduced dose or to discontinuation of

long-term opioid therapy when risks of long-term opioid therapy

outweigh benefits.

Note: Abrupt discontinuation should be avoided unless required for

immediate safety concerns.

Strong for Reviewed, new-

added

15. We recommend individualizing opioid tapering based on risk assess-

ment and patient needs and characteristics.

Note: There is insufficient evidence to recommend for or against

specific tapering strategies and schedules.

Strong for Reviewed, new-

added

16. We recommend interdisciplinary care that addresses pain, substance

use disorders, and/or mental health problems for patients present-

ing with high risk and/or aberrant behavior.

Strong for Reviewed, new-

replaced

17. We recommend offering medication-assisted treatment for opioid use

disorder to patients with chronic pain and opioid use disorder.

Note: See the VA/DoD “Clinical Practice Guideline for the

Management of Substance Use Disorders.”

Strong for Reviewed, new-

replaced

Opioid Therapy for Acute Pain

18. a. We recommend alternatives to opioids for mild-to-moderate acute

pain.

b. We suggest use of multimodal pain care including nonopioid medi-

cations as indicated when opioids are used for acute pain.

c. If take-home opioids are prescribed, we recommend that

immediate-release opioids are used at the lowest effective dose,

with opioid therapy reassessment no later than three to five days

afterward to determine if adjustment or continuing opioid therapy

is indicated.

Note: Patient education about opioid risks and alternatives to opioid

therapy should be offered.

a. Strong for

b. Weak for

c. Strong for

Reviewed, new-

added

*For additional information, please refer to the section on Grading Recommendations. † For additional information, please refer to the section on Recommendation Categorization and Appendix H.

Rosenberg et al.

938

Additionally, the CARA Act required us to add two sec- tions, naloxone rescue and acute pain prescriptions leading to LOT, which had been initially overlooked. So, it is not surprising that this guideline is comparable with the CDC guideline, with largely corresponding areas of concern.

The guideline renewal rules complicated the process in that there are different evidentiary rules regarding prior recommendations as opposed to new recommenda- tions. However, there were no 2010 recommendations that made it into the 2017 guideline unchanged or unre- searched. Finally, the regulations regarding opioid ther- apy vary on a state-to-state basis, and while the VA and DoD practice within a federal framework, the practi- tioners’ licenses are granted on a state basis, guiding their practice. The use of outside practitioners through contracts or fee for service complicates matters further.

Some may consider the strength of recommendation for some of these recommendations to be too high. It bears repeating that the weight of the evidence for harms was consistently much greater than the evidence of benefit. The paradigm shift is profound from the 2003 VA-DoD opioid therapy guideline, in which opioid therapy was advocated, to the 2010 opioid therapy guideline, in which we advocate for careful use when nothing else works, to this current guideline, in which chronic opioid therapy is to be avoided, even when other treatments don’t work. Most of us have patients whom we have successfully managed for years with moderate doses of opioids. It is difficult to accept science that conflicts with our clinical experience and may prompt patients who have been accustomed to more liberal opioid prescrib- ing to object to risk mitigation or thoughtful tapering and even leave the clinic. Panel members too felt this angst, and every effort was made to minimize these potential disturbances, cautioning against abrupt discontinuation and patient abandonment and advocating for suicide assessment and alternative treatment availability. We were concerned that readers would concentrate too tightly on the recommendations and not read the dis- cussion, so notes of caution were inserted into the rec- ommendations. We added patient education via a patient summary guide, explaining how the science of opioid therapy is changing and the new understanding of opioid risks. While pain management strategies should be individualized based on the unique challenges and preferences for each patient, these guidelines high- light the importance of the conservative use of LOT for non-end-of-life chronic pain due to the lack of evidence for benefit combined with the risk of side effects and OUD. We also recognized that these guidelines could be used to standardize care. The benefits of standardi- zation should be administered lightly, allowing for opti- mal pain care, respectful of patient preferences when possible.

Finally, medical guidelines are only as good as the evi- dence and the providers. State and national laws are also rapidly changing. This guideline may need to be

changed as new studies are reported. We can look for- ward to new studies examining LOT, the effects of miti- gation strategies, and the development of novel medications and therapies. These examples of future science will shape pain medicine and our guidelines.

Acknowledgments

The authors wish to thank Work Group members: From the DoD, Elizabeth Rees Atayde, RN, MSN, FNP, CCM, CPHM; MAJ Robert Brutcher, PharmD, PhD; Corinne Devlin, MSN, RN, FNP-BC; LTC William Grief, MD; James Hardin, LCSW-C, MAC; Connie Kurihara, RN; CDR Marisol Martinez, PharmD; Capt Erick C. Messler, PhD; LTC Jason Silvernail, DPT, DSc, FAAOMPT; CAPT Necia Williams, MD. From the VA, Michael O. Chaffman, PharmD, BCPS; Karen Drexler, MD; Franz Macedo, DO; Aram Mardian, MD; Anthony J. Mariano, PhD; Ilene Robeck, MD; Friedhelm Sandbrink, MD; Maria Silveira, MD, MA, MPH; Nancy Wiedemer, MSN, RN, ANP-BC. From the Lewin Group, Clifford Goodman, PhD; Christine Jones, MS, MPH, PMP; Erika Beam, MS; Anjali Jain, MD. From the ERCI Institute, Kristen E. D’Anci, PhD; Nancy M. Sullivan, BA; James Reston, PhD, MPH; Mrin Joshi, MS; Erin Payne, MS; Raj Stewart, PhD; Stacey Uhl, MS; Allison Gross, MLS. From the Veterans Health Administration Office of Quality, Safety and Value, Eric Rodgers, PhD, FNP, BC; Rene Sutton, BS, HCA; James Sall, PhD, FNP- BC. From Sigma Health Consulting, LLC, Frances Murphy, MD, MPH.

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3 Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States,2016. MMWR Recomm Rep 2016;65(1):1–49.

4 Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases in drug and opioid overdose deaths— United States, 2000-2014. MMWR Morb Mortal Wkly Rep 2016;64(50–51):1378–82.

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