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Use of opioids in the management of chronic non-cancer pain

Use of opioids in the management of chronic non-cancer pain
Author:
Richard Rosenquist, MD
Section Editors:
Mark D Aronson, MD
Scott Fishman, MD
Deputy Editor:
Marianna Crowley, MD
Literature review current through: Feb 2022. | This topic last updated: Jan 21, 2022.

INTRODUCTION — Chronic pain is among the most frequent reasons for seeking medical attention in the United States [1]. A Centers for Disease Control and Prevention analysis of the National Health Interview Survey for 2016 reported that approximately 50 million Americans were burdened with chronic pain, and approximately 19.6 million had high impact chronic pain [2].

This topic will discuss the use of opioids in the management of chronic non-cancer pain. Other treatments for chronic non-cancer pain and the use of opioids for cancer pain are discussed separately. (See "Cancer pain management with opioids: Optimizing analgesia" and "Approach to the management of chronic non-cancer pain in adults", section on 'General approach'.)

The use of opioids in the management of chronic pain from specific etiologies is discussed in the relevant topics. As examples:

Diabetic neuropathy (see "Management of diabetic neuropathy", section on 'Not recommended')

Low back pain (see "Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment", section on 'Pharmacologic therapy for persistent symptoms')

Chronic pancreatitis (see "Chronic pancreatitis: Management", section on 'Analgesics')

Fibromyalgia (see "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Analgesics')

OPIOID THERAPY IN THE CONTEXT OF THE OPIOID EPIDEMIC — Opioids are commonly prescribed for chronic pain; per capita opioid prescription increased by 7.3 percent from 2007 to 2012 [1,3-5]. However, progressive increases in opioid-related deaths have prompted a significant reappraisal of the role of opioids in treating chronic non-cancer pain. Opioid prescribing has decreased since 2012 [6], but unintended overdoses associated with both prescription and non-prescription opioids remain unacceptably high [7], and a number of initiatives have been designed to reduce opioid use and overdose [8]. The Centers for Disease Control and Prevention published its authoritative Guideline for Prescribing Opioids for Chronic Pain in 2017 [9]. This guideline offers recommendations to primary care clinicians who prescribe opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. Although these guidelines are not binding by state or federal law, they offer guidance for prescribers and are often utilized by policymakers including federal and local regulators, such as medical boards, in determining the standard of care and defining specific rules for the prescription of opioids for acute, sub-acute, and chronic pain. However, the CDC has warned against a misapplication of its guidelines [10]. Specifically, they caution against setting hard dose limits, discontinuing patients at higher dosages, abruptly tapering opioids, or erroneously applying these guidelines to opioid agonist therapy for opioid use disorder.

OPIOIDS

Mechanism of action — Opioids produce analgesia by acting on central and peripheral mu-, kappa-, and delta-opioid receptors (table 1) to inhibit the transmission of nociceptive input and the perception of pain. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Pharmacology'.)

Based upon their effects on the mu receptor, opioids are often divided into pure agonists and agonist-antagonists (table 2). Buprenorphine is a unique opioid with high affinity but low intrinsic activity at the mu opioid receptor and antagonism at the kappa opioid receptor. The use of buprenorphine for chronic pain is discussed below. (See 'Buprenorphine for chronic pain' below.)

Tramadol and tapentadol are centrally acting analgesics whose mode of action is based both on the mu opioid receptor binding and monoamine (serotonin and norepinephrine) reuptake blockade (mixed mechanism).

Opioid formulations — Opioids come in immediate-release/short-acting (IR/SA) and extended-release/long-acting (ER/LA) preparations (table 3 and table 4). Opioids can be administered through a wide variety of routes; when used for chronic non-cancer pain, the most common routes of administration are oral or transdermal.

Short-acting — There are many IR/SA opioids available that can be used in the management of chronic non-cancer pain (table 3). Meperidine should not be used for chronic pain because of central nervous system toxicity and the availability of less toxic and more effective alternative drugs [11]. Prescribing IR/SA opioids for chronic non-cancer pain is discussed below. (See 'Initiating a trial of opioid therapy' below and 'Chronic opioid therapy' below.)

Long-acting — ER/LA opioids (table 4) should be reserved for the management of cancer pain, use in palliative care, or conditions associated with persistent pain that is otherwise disabling and associated with significant functional impairment [9]. Most pain experts avoid use of ER/LA opioids in opioid-naïve patients. They are not indicated for "as-needed" analgesia. Prescribing ER/LA opioids for chronic non-cancer pain is discussed below. (See 'Choice of agent and dosing for chronic therapy' below.)

Abuse deterrent — Abuse-deterrent opioid formulations (ADFs) have been developed to decrease opioid misuse, using a variety of technologies [12]. (See "Abuse deterrent opioids".)

We do not routinely prescribe ADF opioids rather than non-ADF opioids, unless required by law. A number of studies have found reductions in misuse, overdose, and diversion of abuse deterrent OxyContin [13,14]. However, there is no evidence that patients cease opioid misuse because of the ADF. Rather, there is an associated increase in the use of and overdose with other opioids, most notably heroin [15-17]. In addition, ADFs do not prevent patients from taking multiple tablets and therefore higher doses than prescribed [9]. Abuse-deterrent drugs are generally more expensive than non-abuse-deterrent opioids and may not be covered by insurance.

INDICATIONS FOR OPIOID THERAPY — Opioid therapy for the treatment of chronic non-cancer pain is controversial due to insufficient evidence of long-term efficacy and the risk of serious harm [9,18-24]. In a 2018 meta-analysis of 96 randomized trials including approximately 26,200 patients with chronic non-cancer pain, 42 high quality trials compared opioids with placebo [25]. The use of opioids was associated with a small reduction in pain (-0.69 cm on a 10 cm scale), slightly improved physical functioning (weighted mean difference, 2.8 points on a 100 point scale), and an increase in the risk of vomiting (relative risk [RR] 3.44, 95% CI 2.89-4.10) compared with placebo. Opioid use was associated with a similar small benefit when compared with nonopioid medications, though the evidence was from low- to moderate-quality studies. For patients with chronic non-cancer pain, the decision to begin opioid therapy must be weighed carefully.

Opioids should only be initiated for the treatment of chronic non-cancer pain when [9,26,27]:

Alternative lower risk therapies have not provided sufficient pain relief or cannot be used (eg, contraindications to non-opioid analgesics) and

Pain is adversely affecting a patient's function and/or quality of life and

When the potential benefits of opioid therapy outweigh potential harms and

After discussion with the patient of all risks, benefits, and alternatives to opioid therapy

Opioids should only be continued when there is well-documented benefit after a trial of opioid therapy.

When possible, opioids should be combined with nonopioid pharmacotherapy and nonpharmacologic therapies as appropriate to achieve therapeutic goals with the lowest effective doses of all medications [9,26]. Limiting opioids may be especially difficult for patients with conditions that preclude the use of nonopioid analgesics (eg, nonsteroidal antiinflammatory drugs [NSAIDs], acetaminophen), such as kidney disease, high risk of bleeding, concomitant use of aspirin or anticoagulant medications, some gastrointestinal diseases, and hepatic dysfunction. (See "Approach to the management of chronic non-cancer pain in adults", section on 'General approach'.)

EVALUATION OF RISK PRIOR TO INITIATING THERAPY — Before initiating treatment with opioids for chronic non-cancer pain, clinicians should assess patients for risks of overdose and opioid use disorder (OUD) [26,28]. In addition, the goals of therapy as well as the potential risks and benefits should be discussed thoroughly with the patient. The Centers for Disease Control and Prevention checklist is a useful tool when prescribing opioids for chronic non-cancer pain (table 5).

Opioid therapy is rarely appropriate for patients who are at high risk for opioid misuse. For patients at lower risk, clinicians can employ a variety of risk management strategies for monitoring patients on opioids. However, the effectiveness of these strategies is not clear, and they must not be used as absolute evidence of safety. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Opioid analgesics' and 'Monitoring and risk management strategies during trial' below.)

Risk assessment — As part of the decision to initiate a trial of opioid therapy, we assess risk for overdose and misuse. For patients who are felt to be at high risk of opioid misuse or overdose, we avoid prescribing opioids if possible. In high-risk patients for whom opioid therapy is the only potentially effective option, we consult and comanage with an addiction medicine specialist to maximize benefit and reduce risk. We assess risk as follows, and use a risk screening tool:

Assess for personal or family history of substance misuse or psychiatric disorder We take a careful personal and family history for alcohol or drug use disorder and personal history of psychiatric disorders, as these are the most important risk factors for misuse. (See 'Risks of misuse and overdose' below and "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Risk assessment'.)

If there is a possible psychiatric comorbidity, prior to treatment with opioids, patients should be evaluated and treated when appropriate and/or referred to a mental health professional.(See "Evaluation of chronic non-cancer pain in adults", section on 'Psychiatric comorbidity'.) Patients with histories of substance misuse, or substance misuse disorder should be managed in collaboration with an addiction specialist.

Review history through a state prescription drug monitoring program (PDMP) We review a patient's history of using controlled substances through the state PDMP (available in most states) [9] while recognizing that PDMPs are unable to detect many patients with OUD [29],and that PDMPs of all 50 states are not interconnected. Review of the PDMP is required by some states prior to opioid prescribing and periodically thereafter [30]. Concerning information (eg, previously on opioids and found to use multiple providers or pharmacies and/or doses >50 morphine milligram equivalents [MME], concurrent use of benzodiazepines) on a PDMP should trigger an in-depth conversation with the patient to identify risk factors for potential drug overdose/misuse. If there is evidence of aberrant behaviors and concern for OUD, patients should be referred to an addiction medicine specialist for OUD treatment. Medication treatment for OUD with methadone in an opioid treatment program (OTP) or buprenorphine in an office-based setting or OTP should be considered for all patients with overlapping OUD and chronic pain. The final decision on whether to prescribe will be individualized. However, we do not prescribe opioids to patients who are already receiving opioids from another prescriber. (See 'Patients with aberrant behaviors' below and 'Monitoring and risk management strategies during trial' below.)

Information about state PDMPs can be found on the National Association of State Controlled Substances Authorities website. State-based PDMPs are designed to capture data on prescriptions for either scheduled II-IV or II-V drugs (table 6); a few states monitor only for schedule II drugs [31,32]. Reports will generally provide information on the drug dispensed; the date, dose, and quantity; prescriber name and Drug Enforcement Agency (DEA) number; and the pharmacy name and location. The accuracy of the PDMP is dependent upon the pharmacist uploading the information into the database. Some PDMPs operate proactively, routinely analyzing prescription data to identify individuals, clinicians, or pharmacies with unusual patterns of use. Most are passive, however, and are utilized only for specific requests or searches. Reporting requirements, including the time for fulfillment of requests, are variable.

Baseline urine drug screening – We obtain a baseline urine drug test for all patients to assess for any current use of opioids/illicit substances prior to providing any opioid prescriptions. Some centers use saliva testing as an alternative. (See "Urine drug testing for patients with chronic pain".)

Patients who test positive for unexpected opioids/illicit substances are at very high risk, and these patients are likely not appropriate for opioid therapy. (See 'Monitoring and risk management strategies during trial' below and "Testing for drugs of abuse (DOAs)".)

Patients who drink alcohol – There is no known safe level of alcohol use for patients who take opioids [33]. We advise our patients to avoid concurrent use of opioids and alcohol because of increased potential risk.

Patients who use cannabis – The use of cannabis and cannabinoids for chronic pain is controversial, as is the decision to prescribe opioids to patients who also use cannabis products, and practice varies widely. These issues are complicated by the mixed and varied legal status of these substances in various locations. The author practices in a state in which recreational cannabis is not legal, and at an institution that does not permit obtaining a state physician certificate to recommend marijuana or the recommendation of medical marijuana or cannabis products. His approach is as follows:

We avoid prescribing opioids to patients who are actively using cannabis either medically or recreationally.

We perform urine drug screens prior to prescribing and randomly during each year that we are prescribing. If we find THC or other drugs of abuse prior to prescribing we never start. If they are found during a random drug screen, we taper opioids off.

Risk assessment tools — Clinical instruments have been historically developed to identify patients who are at potential risk for misuse of prescribed opioids [34-36]. Most instruments were developed to predict aberrant behaviors, rather than misuse or addiction. Few high-quality studies have assessed the diagnostic accuracy of these instruments for predicting opioid misuse [37-40].

We use one of the following instruments prior to initiation of opioid therapy:

The Opioid Risk Tool (ORT) – The ORT (form 1) is a free and brief self-administered form that consists of ten yes or no items in five categories (family and personal history of substance use disorder, age, history of preadolescent sexual abuse and psychologic disease) [34]. Scores in the 0 to 3 range are associated with low risk, 4 to 7 with moderate risk, and ≥8 with high risk. Although the ORT is useful due to its brevity and ease of scoring, concerns have been raised about the potential for deception.

In a retrospective cohort study of approximately 1200 patients who received opioid therapy for chronic non-cancer pain, a simplified unweighted version of the ORT (the ORT-OUD) was derived to predict development of an opioid use disorder with high sensitivity and specificity [41]. However, this study included only White patients without a prior history of substance abuse disorder. Further validation is required before recommending the ORT-OUD for routine screening prior to or during opioid therapy.  

The Screener and Opioid Assessment for Patients with Pain (SOAPP) – SOAPP (table 7 and form 2) is a proprietary 14-item, self-administered form that captures the primary determinants of aberrant drug-related behavior [35]. A score of ≥7 identifies 91 percent of patients who are high-risk.

A revised version (SOAPP-R) containing 24 questions is also available (form 3 and table 8) [36]. We use the SOAPP tool, as the additional questions for the SOAPP-R may be a hindrance to patients completing the questionnaire.

We use the ORT or the ORT-OUD to monitor patients during chronic opioid therapy. (See 'Ongoing risk assessment and management' below.)

Risk stratification — Risk stratification remains a controversial means of assigning different levels of risk based on objective and subjective patient information. Patients are often stratified as follows for risks of overdose, misuse, and aberrant behaviors (see 'Risk assessment' above and 'Patients with aberrant behaviors' below and "Prevention of lethal opioid overdose in the community", section on 'Risk factors'):

Low risk — Patients without a personal or family history of alcohol or substance use disorder, without psychiatric disorders, and/or who are low-risk based on screening instruments are low-risk for opioid misuse. These patients may be managed by primary care clinicians with appropriate monitoring [42]. (See 'Monitoring and risk management strategies during trial' below.)

Moderate risk — Patients at moderate risk have some risk factors for opioid misuse (eg, family history of substance misuse). These patients may also have histories of psychiatric disorders [42]. Patients at moderate risk require more controls incorporated into the prescribing and monitoring approach. Some of these patients may benefit from consultation with appropriate specialist support.

High risk — We avoid opioid use in patients who are at the highest risk of opioid misuse, if possible. These include patients with a personal history of substance use disorder, overdose, or significant underlying psychiatric disorders. If opioid therapy is appropriate for these patients, they should be monitored carefully and managed in collaboration with an addiction medicine specialist. Opioids should not be prescribed for chronic non-cancer pain for patients with active untreated addiction. (See "Prevention of lethal opioid overdose in the community", section on 'Risk factors'.)

INITIATING A TRIAL OF OPIOID THERAPY — Opioid therapy should always be initiated as a trial, with the understanding that therapy will be discontinued if harms outweigh the benefits and/or the goals of therapy are not being met.

A coordinated multidisciplinary program with risk reduction strategies for patients who receive opioid therapy may reduce the percentage of patients who ultimately take high doses of opioids (ie, >100 morphine milligram equivalents per day) [43-46].

Setting patient responsibilities, expectations, and treatment goals — When initiating opioid therapy for appropriate patients with chronic non-cancer pain, clinicians should establish patient responsibilities for therapy, discuss the risks of opioid therapy, and establish treatment goals with patients [9,26]. The Centers for Disease Control and Prevention checklist is a useful tool when prescribing opioids in chronic non-cancer pain (table 5).

Patient responsibilities – Patient responsibilities include taking opioids only as prescribed, not taking a higher dose or more often than prescribed, and not obtaining opioids from other prescribers. If there are cognitive limitations that may interfere with opioid therapy, a caregiver may need to take responsibility for opioid therapy management. Patients should also be informed of any monitoring that will be used as precautions (eg, prescription drug monitoring program [PDMP] information and/or urine drug testing). (See 'Monitoring and risk management strategies during trial' below.)

Risks of therapy – When opioid therapy is initiated, providers should discuss the risks of therapy. These include both common (eg, constipation, nausea, vomiting, physiologic opioid dependence and tolerance) and serious adverse effects (eg, respiratory depression), risks of overdose and opioid use disorder (OUD), and risks to other household members if opioids are unintentionally ingested. (See 'Monitoring for adverse effects' below and "Prevention and management of side effects in patients receiving opioids for chronic pain" and 'Risks of misuse and overdose' below and 'Discontinuing therapy' below.)

Treatment goals and shared decision making – It is important to have a discussion and ensure there is a shared discussion with the patient at the start of therapy to determine treatment end points. One way to set goals is to use "SMART" goals: Specific, Measurable, Attainable, Relevant, and Time-limited [47]. As an example, a

Specific goal of increasing walking by 1000 steps per day can be

Measured with an activity monitor or cell phone step counter, is an

Attainable goal to improve function, is

Relevant to everyday life, and can be given as a

Time limited assignment to complete over a one or two month period.

Goals may include decreasing pain and improving functional capacity and/or quality of life. Patients should be realistic about the possible benefits of opioids and should also understand that the goals do not include being completely pain-free [9]. Patients should also understand that the need for opioid therapy will be continually reassessed. Opioids can be continued when they serve the goals of treatment for reduced pain and enhanced function and quality of life but discontinued when they are ineffective or harm the patient with adverse effects.

Opioid agreement/consent form — Once we have discussed patient responsibilities, risks of therapy, and treatment goals with patients, we have them complete an opioid pain agreement and/or consent form prior to initiating opioid therapy [26]. Opioid pain agreements/consent forms outline the responsibilities of the patient and provider. They may also specify the way prescriptions will be given and monitoring during treatment. (See 'Setting patient responsibilities, expectations, and treatment goals' above.)

There is little evidence regarding the efficacy of opioid agreements in decreasing opioid misuse. A systematic review of the literature found four poor- to fair-quality observational studies that compared patients who completed treatment agreements with matched or historical controls without treatment agreements [48]. Opioid misuse was decreased modestly (7 to 23 percent) with the use of a treatment agreement, with or without urine drug testing. Guidelines suggest that opioid agreements are helpful to set patient expectations when initiating opioid therapy [9,26].

Choice of agent and dose — When starting opioid-naïve patients with chronic non-cancer pain on opioid therapy, we start with immediate-release/short-acting (IR/SA) agents at the lowest effective dose (table 3) [9]. Opioid-naïve patients should not be started on extended-release/long-acting (ER/LA) opioids as initial therapy. Some providers avoid combination drugs (eg, opioids compounded with acetaminophen or NSAIDs), as titrating dosing can become difficult because of the risks of toxicity associated with the nonopioid component, particularly if concurrently used with other over-the-counter medications. (See 'Chronic opioid therapy' below.)

The clinical potency and effectiveness of opioids can vary unpredictably among patients, with some patients achieving excellent relief with one agent, while other patients require a different drug (table 3). It is not possible to predict the optimal dosing regimen for a given patient. For this reason, we titrate the dose by slowly increasing it, typically in no more than 25 to 50 percent increments as a percentage of the total daily dose. Increases should be made after a steady state has been achieved (ie, at least four to five drug half-lives) (table 3). In practice, we establish a maximum daily dose to be used, and adjust dose at the next monthly visit after assessing efficacy.

The risks of overdose increase with higher doses of opioids, and the risks and benefits of opioid therapy need to be reconsidered with any dose escalation. When the dose goes up, the evidence for benefit remains weak to inadequate, but the evidence for risks suggests higher risk with higher dosages, thus the risk/benefit ratio shifts accordingly [9]. If there is minimal benefit from opioid therapy at a given dose, we evaluate patients for alternative medications. Some experts avoid increasing dosing to ≥90 mg of morphine milligram equivalents (MME)/day, as there is little evidence to support improved function with these high doses. (See 'Risks of misuse and overdose' below.)

Tramadol and tapentadol, which are mixed mechanism opioids with additional norepinephrine and serotonin reuptake inhibition, are of uncertain benefit for patients with chronic pain. They may be considered as second or third line treatment for patients with fibromyalgia who have not responded to initial therapy with other medications, however these opioid medications have the same risks associated with all opioids and must be used judiciously and carefully (see "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Analgesics'). Efficacy of these drugs for other types of chronic pain is unclear. A systematic review found that tramadol improved functional outcomes and pain in patients with fibromyalgia [49], but was no more effective than nonsteroidal antiinflammatory drugs (NSAIDs) or nortriptyline for relief of other chronic pain. (See "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Analgesics'.)

A 2015 systematic review including four randomized trials found that compared with placebo or oxycodone, tapentadol was associated with a reduction in pain intensity in patients with chronic musculoskeletal pain from knee osteoarthritis and low back pain [50]. However, the review concluded that the clinical significance of these findings was unclear, as there was only a modest difference between interventions in efficacy outcomes, there were high withdrawal rates in the trials, and there was a lack of data for the primary outcome in some studies. In contrast with the results of this study, in a randomized trial including 240 patients with chronic back pain or hip or knee osteoarthritis pain, opioid therapy did not result in significantly better pain related function over 12 months [24].

In 2021 the Food and Drug Administration of the US (FDA) mandated that the tramadol label must include a warning regarding hyponatremia and hypoglycemia [51]. The warning was prompted by rarely reported cases of severe hyponatremia in patients taking tramadol, most of which occurred in females >65 years of age and within the first week of therapy. There are also reported cases of severe hypoglycemia with tramadol, most in patients with diabetes and in the first 30 days of therapy [52].

Monitoring for adverse effects — Adverse effects are common during opioid therapy. In particular, patients taking opioids should be monitored for constipation, nausea, vomiting, sedation, impaired psychomotor function, and urinary retention. Additionally, prescribers should remain vigilant for changes in health status that might increase risks with opioids, such as respiratory, renal, or hepatic insufficiency; sleep apnea; or mental illness, including substance use disorder.

The cognitive effects of opioids may impair a patient's ability to drive. Driving safety for patients on opioids is discussed separately. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Driving safety'.)

Sleep-disordered breathing is an increasingly recognized complication of chronic opioid use. This is discussed separately. (See "Sleep-disordered breathing in patients chronically using opioids".)

Patients on opioid therapy may develop opioid-induced hyperalgesia, a state of nociceptive sensitization caused by exposure to opioids in which patients treated with opioids become more sensitive to certain painful stimuli [53]. Paradoxically, opioid therapy potentially aggravates pre-existing pain under these conditions, and pain and function improve for some patients who successfully taper off of opioids [53-59]. (See 'Discontinuing therapy' below.)

Long-term opioid use can lead to hypogonadism, immunosuppression, and increased risk of myocardial infarction [60]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain".)

The side effect profile of tramadol is similar to that of other opioids, although the incidence of gastric upset may be higher. Seizures are an additional risk, particularly in patients who take antidepressants, neuroleptics, or other drugs that decrease the seizure threshold. Tramadol and tapentadol have additional safety concerns associated with their serotonin and norepinephrine reuptake inhibition, including the potential for serotonin syndrome (see "Serotonin syndrome (serotonin toxicity)"). Tramadol has also been associated with increased risk for suicide [61]. Tapentadol is associated with a lower risk of gastrointestinal side effects.

Strategies to minimize opioid side effects include the use of preventive measures (eg, constipation prophylaxis), slow titration of doses; verifying that the symptoms are attributable to the opioid, changing the dosing regimen or route of administration, using a nonopioid or adjuvant analgesic for an opioid-sparing effect, and sometimes adding a drug to counteract the side effect. If side effects become problematic during dose titration, it is reasonable to change drugs (table 3) or decrease the dose to determine if side effects diminish.

Risks of misuse and overdose — Opioid therapy always carries the risk of misuse and overdose. Even short-term treatment with opioids for acute pain is associated with increased likelihood of long-term opioid use [62,63], which is in turn associated with opioid use disorder and overdose. Risk factors for misuse of opioids among patients who are prescribed opioids include a personal or family history of substance use disorder, younger age (<40 to 45 years of age), more severe pain, and co-occurring mental health disorders. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Risk factors' and 'Evaluation of risk prior to initiating therapy' above.)

The epidemiology and risk factors for opioid overdose are discussed separately. The factors that must be considered when prescribing opioids for chronic pain are discussed here. (See "Prevention of lethal opioid overdose in the community", section on 'Epidemiology'.)

Higher average daily dose – Among patients on chronic opioid therapy, the risk of an overdose increases with the average daily dose [64-69]. For example, one study found that compared with doses <20 MME/day, those taking higher doses were at increased risk for overdose (adjusted hazard ratio [HR] 1.44 for 20 to 49 MME/day, 3.73 for 50 to 99 MME/day, and 8.87 for ≥100 MME/day) [9]. It is not clear if the correlation between overdose and prescription dosing reflects patient differences or the impact of higher opioid doses.

Multiple prescribers/prescriptions – The risk of overdose also increases with multiple prescribers, the use of multiple pharmacies, and overlapping opioid prescriptions [64-66,70]. If any of these situations are encountered, the prescriber should either stop prescribing opioids or contact other prescribers to arrange for a single source for opioid prescription.  

Prolonged use – The risk of overdose increases with longer duration of use [71].

Use of ER/LA opioids – There may be a higher risk of overdose with the use of ER/LA opioids, particularly if therapy is initiated with ER/LA opioids [72].

Genetics – Polymorphisms of cytochrome P450 (CYP) genes that affect drug metabolism are increasingly being identified. Polymorphisms may contribute to either diminished or absent metabolic enzymes, or excessive metabolism of a compound, either of which can change the clinical effect of a given dose of opioid. (See "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug metabolism'.)

Drug interactions — We try to avoid concurrent use of benzodiazepines and opioids because additive respiratory depression increases the risk of overdose and all-cause mortality [9,73-78]. Increased sedation may also occur with simultaneous use of opioids and alcohol, butyrophenones, phenothiazines, sedative-hypnotics, tricyclic antidepressants, and anticonvulsants (ie, gabapentin or pregabalin). Concomitant administration of opioids with gabapentin or pregabalin is associated with an increase in opioid-related mortality [79,80]. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Gabapentin and pregabalin'.) Gabapentinoids are also increasingly misused among individuals who use opioids [81].

Opioids may interact with drugs that are either inhibitors or inducers of the CYP enzymes (ie, CYP3A4 and CYP2D6) (table 9 and table 10 and table 11).  

Specific interactions may be determined using the drug interactions tool (Lexicomp drug interactions) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.

Co-prescription of naloxone — Providers should discuss availability of naloxone with all patients who receive opioid prescriptions, and should particularly consider prescribing intranasal naloxone (Narcan) rescue kits to patients at increased risk of overdose (eg patients on >50 MME or who are also taking benzodiazepines). Some states have mandated that naloxone be offered to patients who receive chronic opioids at any dose [82,83]. In 2020 the US Food and Drug Administration (FDA) required that labels for all opioids include the recommendation that care providers discuss availability of naloxone with all patients who are prescribed opioids, and specifically consider co-prescribing naloxone for patients who take benzodiazepines or other central nervous system depressants, who have a history of prior opioid overdose, or who have household members at risk for accidental ingestion [84].

The patient and members of the patient’s household should be educated on the signs of overdose and use of naloxone. (See "Prevention of lethal opioid overdose in the community", section on 'Community-based intervention'.)

Follow-up during trial — During a trial of opioid therapy, safe and effective management requires a patient-centered treatment plan and ongoing assessment of outcomes [9]. The benefits and harms of opioid therapy should be assessed within one month of starting therapy [9]. A shorter interval for follow-up is appropriate for patients who are at higher risk for misuse. (See 'Risk assessment' above and 'Risk stratification' above.)

Patients who do not have relief with opioid therapy at one month are not likely to have relief at six months [9]. It is essential that an assessment is made and therapy modified and possibly discontinued if goals are not being met. To continue opioid therapy, patients should have satisfactory relief of pain with tolerable or manageable adverse effects (where the benefits outweigh the burdens of any adverse effects), improved function (in either physical or psychosocial domains), and lack of aberrant drug-related behaviors [85,86]. (See 'Discontinuing therapy' below and 'Setting patient responsibilities, expectations, and treatment goals' above.)

Monitoring and risk management strategies during trial — All patients on chronic opioid therapy require ongoing vigilance and risk management. Risk stratification may be helpful but remains controversial. Regardless of whether patients are believed to be at low or high risk for adverse opioid effects, prescribers should remain vigilant throughout opioid therapy for changes in health status that might raise concerns for increased risks with opioids, such as respiratory, renal, or hepatic insufficiency; sleep apnea; or mental illness, including substance use disorder. Various risk management strategies have been advocated for management of patients on opioids (table 12). These strategies should be individualized based on the likelihood of problematic drug-related behavior [87], according to risk stratification, as follows (see 'Risk stratification' above):

Low risk Monitoring for low-risk patients should include regular follow-up appointments with ongoing assessment of the need for opioid treatment, regular urine drug screening, and regularly checking the PDMP. (See 'Low risk' above.)

Routine follow-up – All patients on opioid therapy should be followed regularly, seen at least every 8 to 12 weeks [9]. At each visit, we continue to discuss the goals of opioid therapy, and document analgesic benefit, functional benefit, side effects, and continued counseling on the use of opioid therapy and the potential risks.

Periodic drug screens – Bio-fluid (typically urine) measurement of drug concentrations can provide objective evidence to help identify and assess patients who are receiving opioid drugs. However, interpretation of urine tests for drugs of abuse is not always straightforward [88,89]. (See "Testing for drugs of abuse (DOAs)", section on 'Interpreting results'.)

If urine drug testing results are inconsistent with therapy (eg, a prescribed drug is missing or a non-prescribed or illicit drug is present), we discontinue opioid therapy, and if appropriate, refer the patient to an addiction medicine specialist. A systematic review of 11 studies that evaluated the effect of opioid agreements or urine drug testing on drug misuse found the studies to be of generally poor to fair quality, with inconsistent evidence that these interventions are effective [48]. (See "Testing for drugs of abuse (DOAs)", section on 'Interpreting results' and "Testing for drugs of abuse (DOAs)", section on 'Opioids'.)

Use of data from PDMPs – Providers should review the state's PDMP regularly while prescribing opioids for patients. These tools provide up to date information on controlled substances being prescribed and dispensed within the state and when there are agreements with other states, over a much larger geographic region. They often provide insight into other prescriptions that might increase individual risk such as co-prescribing benzodiazepines or other sedatives or prescriptions being obtained from multiple providers. This information helps to optimize appropriate and safe prescribing of opioids in the setting of chronic non-cancer pain [90,91]. (See 'Risk assessment' above.)

Moderate risk Patients at moderate risk of misuse require more intensive monitoring (table 12). In addition to the monitoring for low-risk patients, this may include more frequent follow-up and mandatory clinic visits for refills. Some of these patients may benefit from consultation with appropriate specialist support. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Risk management'.)

High risk In the rare case in which opioid therapy is appropriate for high-risk patients, they should be monitored carefully and co-managed with an addiction specialist (generally addiction medicine and/or pain medicine).

Specific strategies that can be employed for these patients include pill counts (asking the patient to bring in all unused opioids at each visit), co-prescribing with naloxone, and consultation with family members. Pill counts may not be reliable, however, as it is possible to rent pills to fill in missing medication for a clinic visit. (See "Prevention of lethal opioid overdose in the community", section on 'Community-based naloxone' and 'Opioid formulations' above.)

CHRONIC OPIOID THERAPY — Opioid therapy should only be continued long term in patients who have demonstrated that the benefits outweigh harms during an initial trial of therapy. A 2014 systematic review of 39 studies in patients with chronic non-cancer pain treated with opioids found no evidence of long-term benefit, but found increased risk of serious harm (eg, increased risk of overdose) that was dose-dependent [92,93]. (See 'Risks of misuse and overdose' above and 'Initiating a trial of opioid therapy' above.)

The adverse events that may occur during a trial of opioid therapy are also common with chronic opioid therapy. A 2017 overview of 16 systematic reviews of adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain reported a 78 percent risk of adverse events of any type (eg, constipation, dizziness, nausea with opioids), and a 7.5 percent risk of serious adverse events, based on very low- to moderate-quality data [94]. The included reviews did not report the incidence of addiction, depression, or sleep disturbances associated with chronic opioid therapy. Prevention and management of side effects of opioid therapy are discussed separately. (See "Prevention and management of side effects in patients receiving opioids for chronic pain".)

Choice of agent and dosing for chronic therapy — Patients in whom the benefits of opioid therapy outweigh the harms can be continued on the immediate-release/short-acting (IR/SA) opioid (table 3) used during the initial trial of opioid therapy. The decision to convert from an IR/SA opioid to an extended-release/long-acting (ER/LA) opioid (table 4) should be individualized. ER/LA opioids should be reserved for severe continuous pain and should only be started in patients who have been taking opioids for at least one week [9]. There is no evidence that ER/LA opioids in general are more effective than IR/SA opioids, and the risks of overdose and misuse are greater with ER/LA opioids. (See 'Opioids' above and 'Risks of misuse and overdose' above.)

Converting from IR/SA to ER/LA — Immediate-release/short-acting (IR/SA) opioids (table 3) can be converted to extended release/long-acting (ER/LA) opioids (table 4) as follows:

Converting different formulation (IR/SA to ER/LA) but same medication – When converting from an IR/SA to an ER/LA formulation for the same medication (eg, morphine IR to morphine ER), medications can be converted in a 1:1 ratio with the ER/LA doses divided into two or three times daily. For example, if a patient uses 30 mg total of morphine IR, they can be converted to 15 mg of morphine ER twice daily. However, even with the same medication, patients may respond differently to ER/LA formulations, and it may be prudent to decrease the dose.

Converting different formulation and medication In patients who are already taking an opioid, a change in the opioid can begin with a starting dose by cautiously applying the information in the equianalgesic dose table (table 13) [95,96] (related Pathway(s): Morphine milligram equivalent calculator for adults with chronic non-cancer pain). The data in equianalgesic tables and calculators serve only as a broad guide, however, and cannot be used without adjustments; nor do they guarantee safety. Equianalgesic doses of buprenorphine have not been established, and may vary widely depending on the preparation used and patient factors [97]. Milligram morphine equivalent doses for methadone are also notoriously inaccurate; conversion from other opioids to methadone is challenging and should only be managed by clinicians familiar with the use of methadone. (See 'Methadone and fentanyl' below.)

When converting from an IR/SA to an ER/LA agent for both different formulation and medications, we employ the principles of opioid rotation (table 14) and decrease the equianalgesic dose initially. Patients should be monitored for efficacy and adverse reactions, and the dose adjusted accordingly. (Related Pathway(s): Morphine milligram equivalent calculator for adults with chronic non-cancer pain.) (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Equianalgesic opioid dose conversion'.)

Buprenorphine for chronic pain — Buprenorphine is an opioid that is often used for maintenance pharmacotherapy for opioid use disorder (OUD), but it may also be prescribed for chronic pain.

Formulations for chronic pain – The US Food and Drug administration (FDA) has approved two buprenorphine preparations (buccal and transdermal) for pain severe enough to require daily round the clock opioid therapy for which alternative treatment options are inadequate [98,99]. Buprenorphine preparations prescribed for OUD are typically combination preparations that include naloxone, whereas the formulations prescribed for chronic pain typically do not contain naloxone. Doses administered for severe pain are typically lower than doses used for maintenance pharmacotherapy for OUD. The recommended starting dose of the buccal film for chronic pain is 75 mcg buccal, compared with a range of 8 to 16 mg on the first day initiating buprenorphine for OUD therapy. In the United States, prescription of buprenorphine for maintenance pharmacotherapy for OUD requires a special license and training from the Drug Enforcement Agency (DEA), whereas prescription for chronic pain does not.

Advantages – Buprenorphine is a mu-opioid receptor agonist with high affinity for the receptor but low intrinsic activity, and is an antagonist at the kappa-opioid receptor. It produces little physical dependence [100-102], is associated with less opioid-induced hyperalgesia than other opioids, and importantly, produces less respiratory depression than other long acting opioids. Buprenorphine has a ceiling effect for respiratory depression, but not for analgesia, at clinically meaningful doses [103,104]. Thus, some clinicians, including some contributors to this topic, feel that it is a safer option than other long-acting opioids for patients who require round the clock opioid for chronic pain. Other contributors disagree and do not routinely prescribe buprenorphine over other opioids.

Adverse effects – Despite advantages, buprenorphine is associated with the same safety concerns as all other opioids. When choosing an opioid based on risk profile, it is important to recognize that buprenorphine's beneficial effects with respect to respiratory depression are lost when it is administered along with other respiratory depressants. Thus, significant respiratory depression can occur if buprenorphine is used along with benzodiazepines, alcohol, or other respiratory depressants. In addition, buprenorphine is an abusable drug [105] and risk assessment, monitoring, and risk management strategies should be the same for buprenorphine as they are for other opioids. Most overdoses of buprenorphine have occurred with inappropriate use of high-dose buprenorphine prescribed for treatment of OUD in combination with other central nervous system depressants. If overdose does occur, high doses of naloxone may be required, as well as either repeated dosing or an infusion. (See "Acute opioid intoxication in adults", section on 'Buprenorphine and naloxone'.)  

There are a number of reports of dental problems associated with the use of buprenorphine formulations dissolved in the mouth, including the buccal formulation and sublingual tablets [106,107]. Reported problems include dental caries, abscesses, and damaged teeth, many of which have required tooth removal. Patients who use oral dissolving buprenorphine should swish water around the teeth and gums and swallow the water once the film has completely dissolved, should see a dentist soon after starting buprenorphine, and should notify the dentist that they are taking the drug. The FDA has issued a safety advisory for this issue and will be mandating a related label change for buprenorphine. The advisory cites >300 reported cases of dental damage with use of buprenorphine; the incidence of these problems is unknown.

Dosing and administration – Buprenorphine has poor oral bioavailability (approximately 10 percent); thus it is primarily used by intravenous, sublingual, buccal film, or transdermal routes of administration. The recommended starting doses of the approved formulations for opioid naïve patients for chronic pain are 75 mcg buccal buprenorphine once daily or every 12 hours (FDA label) or 5 mcg/hour transdermal patch (FDA label). Similar to other opioids, further doses should be titrated slowly and incrementally, while evaluating side effects and analgesic benefit (see 'Choice of agent and dose' above). Opioid-naïve patients in one study required 150 to 450 mcg buccal twice daily for analgesia for low back pain [108]. Maximal doses of these buprenorphine preparations are 900 mcg buccal and 20 mcg/hour transdermal. Buprenorphine does not accumulate in patients with renal failure and is not removed by dialysis [109].

Because of its high affinity for the mu opioid receptor, buprenorphine displaces other mu opioids and can precipitate withdrawal in patients who are taking opioids long term and who have not been completely tapered off of their medication prior to initiating pharmacotherapy for opioid use disorder with buprenorphine (see "Medication for opioid use disorder", section on 'Buprenorphine: Opioid agonist'). For chronic pain patients who will continue opioid therapy, tapering totally off of opioids prior to initiating buprenorphine is not advised, and small studies suggest that a taper off other opioids may not be necessary to prevent withdrawal with buprenorphine [110,111]. However, all other around the clock opioids should be discontinued once buprenorphine is started.

The optimal regimen for managing the transition to buprenorphine is not clear, and practice varies. The author usually uses the buccal formulation of buprenorphine for chronic pain patients, and largely follows the manufacturer’s directions for initiation of therapy, as follows:

Taper the patient's current opioid to ≤30 milligram morphine equivalents (MME) per day

Base the initial buprenorphine dose on the prior MME dose

-For patients who were receiving <30 MME per day, initial buprenorphine dose 75 mcg buccal once daily or every 12 hours

-For patients who were receiving 30 to 89 MME per day, initial buprenorphine dose 150 mcg every 12 hours

-For patients who were receiving ≥90 MME per day, initial buprenorphine dose 300 mcg every 12 hours

Titrate further doses upwards in increments of 150 mcg every 12 hours, no more frequently than every four days, to the lowest dose that provides adequate analgesia and minimizes side effects (maximum dose 900 mcg buccal every 12 hours). For patients who require escalation to higher doses, reconsider whether or not the patient's pain is actually opioid sensitive.

Regimens for rotating from other opioids to transdermal buprenorphine are emerging. Similar to the buccal preparation, the manufacturers recommend tapering other opioids to ≤30 MME per day, and basing initial dosing on prior daily MME. However, this is an evolving area of knowledge and clinical experience [112].

Management of buprenorphine during episodes of acute pain, including perioperative pain, is discussed in detail separately. (See "Management of acute pain in adults with opioid use disorder", section on 'Patients taking buprenorphine'.)

Methadone and fentanyl — Methadone and fentanyl should only be prescribed by providers familiar with these medications. Methadone should not be the first choice for an ER/LA agent in the treatment of chronic non-cancer pain and should only be prescribed with close monitoring [9]. (See "Medication for opioid use disorder", section on 'Adverse effects'.)

In the United States, Risk Evaluation and Mitigation Strategies (REMS) were created by the FDA for clinicians who prescribe ER/LA opioids. Participation is not mandatory except for transmucosal immediate-release fentanyl (TIRF) preparations through the TIRF REMS access program. To prescribe TIRF preparations, REMS requires registration of outpatient prescribers, pharmacies, distributors, and patients. Prescribers may not prescribe TIRF for outpatient use until they have completed enrollment in the TIRF REMS program and a knowledge assessment. The REMS for TIRF includes mandatory statements signed by the patient and prescriber, which outline patient and clinician responsibilities for safe opioid use.

Follow-up and monitoring during chronic opioid therapy — The benefits and harms for patients on chronic opioid therapy should be assessed at least every three months for patients on stable doses of opioids [9]. Patients should be seen more frequently after dosing changes, particularly if initiating or increasing ER/LA opioids [9]. The risks for overdose increase in the first week after a dosing change. Patients who are transitioned to or have dosing increases of methadone should be seen within three days, or within one week for other ER/LA opioids.

Patients should continue to be monitored similarly to when they were initiated on opioids. Changes in health status should be continually addressed, as they may raise concerns for increased risks with opioids. These include respiratory, renal, or hepatic insufficiency; sleep apnea; or mental illness, including substance use disorder. Patients at higher risk for opioid misuse/aberrant behaviors may need more frequent monitoring. (See 'Monitoring and risk management strategies during trial' above.)

At each visit, patients should be assessed for pain intensity, functional status, progress toward therapy goals, adverse effects, and adherence with prescribed pharmacologic and ancillary treatment [26]. To continue opioid therapy, patients should have satisfactory relief of pain with tolerable or manageable adverse effects (where the benefits outweigh the burdens of any adverse effects), stable or improved function (in either physical or psychosocial domains), and lack of aberrant drug-related behaviors [85,86]. If the benefits of opioid therapy do not outweigh the harms, therapy should be modified or discontinued. (See 'Monitoring and risk management strategies during trial' above and 'Discontinuing therapy' below and "Prevention and management of side effects in patients receiving opioids for chronic pain".)

Ongoing risk assessment and management — Several standardized tools are available to assess and monitor patients who are high risk or exhibiting aberrant behaviors. However, these tools were initially developed to evaluate patients prior to the initiation of opioid therapy, and there are few studies that have evaluated their efficacy [38,39,113]. We assess patients with the Opioid Risk Tool (ORT) or the Opioid Risk Tool-Opioid Use Disorder (ORT-OUD) to monitor patients during opioid therapy. Patients who are found to be at high risk of developing an opioid use disorder during therapy or who screen positive for aberrant behaviors should be referred for further evaluation and treatment.  

The Current Opioid Misuse Measure (COMM) (form 4 and table 15) may assist in identifying whether a patient currently on long-term opioid therapy may be exhibiting aberrant behaviors associated with misuse of opioid medications over the course of treatment [114].

The Diagnosis, Intractability, Risk, Efficacy (DIRE) score (table 16) was designed to predict analgesia and adherence during long-term opioid treatment, but it may also be useful during ongoing treatment [115]. Each category (diagnosis, intractability, efficacy, and risk [psychological, chemical health, reliability, and social support]) is rated from one to three, with higher scores indicating a greater possibility of successful opioid therapy. The tool requires a good history and a good relationship with the patient and takes less than two minutes to complete.

The Addiction Behavior Checklist (ABC) (table 17) may also be useful in evaluating adverse behaviors and inappropriate opioid use in some patients with chronic pain [116].

The ORT is discussed above. (See 'Risk assessment tools' above.)

Other issues — Patients on chronic opioids may require modification of therapy because of breakthrough pain, acute pain, or opioid tolerance.

Breakthrough pain – Breakthrough pain is common in populations with cancer pain [117,118]. The coadministration of an IR/SA "rescue" dose is often used when treating pain from cancer with ER/LA opioids. However, patients with chronic non-cancer pain may request opioids for breakthrough pain as a means of increasing the opioid dose. We generally avoid opioid medications for breakthrough pain and try to find effective nonopioid or nonpharmacologic options.

Acute pain The management of acute pain in patients on chronic opioid therapy is discussed elsewhere. (See "Management of acute pain in the patient chronically using opioids for non-cancer pain".)

Opioid tolerance Tolerance is a predictable neuro-adaptive process that results in the loss of effect over time (and the requirement of larger doses for the same analgesic effect). Tolerance is beneficial when it occurs to side effects such as nausea, but it can be a problem if it occurs to analgesia. Of note, patients generally do not develop tolerance to opioid-induced constipation.

When tolerance to the analgesic effect develops, the analgesic response to opioids can sometimes be reestablished by the practice of opioid rotation. We rotate opioids in patients who had previously responded to opioid therapy but note a decrease in pain control over time and require increased doses of opioids, particularly when doses are ≥50 morphine milligram equivalents (MME). When switching between opioids as part of a rotation regimen, the equianalgesic dose of the new opioid should be calculated, and the initial dose of the new opioid should be reduced by 25 to 50 percent (75 to 90 percent for methadone), to adjust for lack of complete cross tolerance. (Related Pathway(s): Morphine milligram equivalent calculator for adults with chronic non-cancer pain.) It is important to routinely assess for effectiveness and the development of side effects while rotating to a new opioid. (table 18). Opioid rotation is discussed separately. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'How to perform opioid rotation'.)

PATIENTS WITH ABERRANT BEHAVIORS — Aberrant behaviors occur on a continuum and must be carefully assessed. Aberrant behaviors associated with opioid use include misuse, opioid use disorder (OUD), and diversion:

Misuse Misuse refers to use of any medication outside the manner and intent for which it was prescribed. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Prescription drug misuse'.)

Opioid use disorder – OUD is defined as a problematic pattern of opioid use that leads to serious impairment or distress. The diagnosis of OUD is discussed in detail separately. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Diagnosis'.)

Diversion Diversion refers to the redistribution of a drug to an unintended recipient or into the illicit marketplace. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Diversion'.)

Serious aberrant behaviors that usually warrant discontinuation of therapy include unsanctioned dose escalations, repeated visits to the office or emergency department requesting pain medication, losing prescriptions or seeking early refills, deterioration in function, acquiring drugs from nonmedical sources, using illicit drugs, selling medications, and repeated violation of an opioid agreement. Other behaviors, such as resisting changes in therapy, complaining about the need for more drugs, or using the drug to treat another symptom, may be less serious but need to be evaluated.

The emergence of a single aberrant behavior does not necessarily confirm the presence of a substance use disorder or illicit behavior, but should be carefully considered, and treatment decisions should be individualized [26,85,86,119-122]. Referral for further evaluation and treatment may be appropriate, including referral to a pain specialist and/or evaluation for substance use disorder for potentially starting medication-assisted treatment (MAT). (See "Clinical assessment of substance use disorders".)

DISCONTINUING THERAPY — Therapy may be discontinued for ineffectiveness, development of intolerable side effects, opioid-induced hyperalgesia, development of opioid use disorder (OUD), or diversion. Patients who are withdrawn from opioid therapy should continue to be offered the opportunity to be treated with nonopioid or nonpharmacologic therapies for their chronic pain. Patients who develop OUD should be referred to an addiction specialist and offered medication for OUD, such as methadone or buprenorphine. (See 'Monitoring for adverse effects' above and "Approach to the management of chronic non-cancer pain in adults", section on 'General approach'.)

Prior to discontinuing opioids, unless opioids are discontinued because of diversion, it is important to develop an appropriate discontinuation schedule with the patient, and to taper the opioid appropriately. Even short-term exposure to an opioid can cause physical dependence, which manifests as the appearance of withdrawal symptoms upon reduction or discontinuation of therapy.

Opioid tapering to a lower dose or discontinuation is discussed in detail separately. (See "Opioid tapering for patients with chronic pain".)

REFRACTORY PAIN — For patients who require particularly large doses of opioids, the effects of systemic administration may become intolerable. Such patients may be candidates for an implantable spinal delivery system that permits intrathecal administration of opioid. Intrathecal analgesic therapy should be reserved for intractable severe pain with significant impact on quality of life that is refractory to all other appropriate treatments.

The choice of agent, side effects, and complications of neuraxial infusions of opioids and other agents for chronic pain are discussed separately. (See "Cancer pain management: Interventional therapies", section on 'Choice of agent' and "Cancer pain management: Interventional therapies", section on 'Outcomes' and "Cancer pain management: Interventional therapies", section on 'Complications'.)

SPECIAL POPULATIONS — Some populations have increased risks with the use of opioids.

Older patients — Opioids should be used cautiously in older adults, as they are at higher risk of adverse effects. The use of opioids in the treatment of chronic pain in older adults is discussed separately. (See "Treatment of chronic non-cancer pain in older adults", section on 'Opioids'.)

Kidney disease — Patients with chronic kidney disease are at higher risk for toxic side effects of opioids compared with patients with normal renal function, due to accumulation of toxic or active metabolites, altered drug binding, increased sensitivity to central nervous system effects, increased permeability of the blood brain barrier, and altered drug distribution. The use of opioids in the management of chronic pain in patients with kidney disease is discussed separately. (See "Management of chronic pain in advanced chronic kidney disease", section on 'Opioids'.)

Liver failure — Opioids should be used with caution in patients with liver failure or cirrhosis. Cirrhosis may result in delayed gastric emptying, compromised gastric mucosal absorption due to gastritis, and alterations in volume of distribution due to ascites or alterations in protein binding. This is discussed elsewhere. (See "Management of pain in patients with advanced chronic liver disease or cirrhosis", section on 'Opioids'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic pain management".)

SUMMARY AND RECOMMENDATIONS

Opioid therapy for the treatment of chronic non-cancer pain is controversial, due to insufficient evidence of long-term efficacy and the risk of serious harm in the context of the ongoing opioid addiction and overdose epidemic in the United States. Opioid therapy should not be used as a first line option for chronic non-cancer pain. (See 'Indications for opioid therapy' above.)

For patients with chronic non-cancer pain, opioids should only be used when other potentially effective and safer therapies have not provided sufficient pain relief and pain is adversely affecting a patient's function and/or quality of life and when the potential benefits of opioid therapy outweigh potential harms. Opioids should be combined with nonopioid pharmacotherapy and nonpharmacologic therapies as appropriate. (See 'Indications for opioid therapy' above and "Approach to the management of chronic non-cancer pain in adults", section on 'General approach'.)

Before initiating treatment with opioids for chronic non-cancer pain, clinicians should assess patients for risks of overdose and opioid use disorder (OUD). Opioid therapy may not be appropriate for patients who are at risk for opioid misuse. (See 'Evaluation of risk prior to initiating therapy' above.)

Opioid therapy should always be initiated as a trial, with the understanding that therapy will be discontinued if harms outweigh benefits and/or the goals of therapy are not being met. The Centers for Disease Control and Prevention checklist is a useful tool when prescribing opioids in chronic non-cancer pain (table 5). We practice shared decision making and have all patients complete an opioid pain agreement and/or consent form prior to initiating opioid therapy. (See 'Setting patient responsibilities, expectations, and treatment goals' above and 'Opioid agreement/consent form' above.)

When starting opioid-naïve patients on a trial of opioid therapy, we start with low doses of immediate-release/short-acting (IR/SA) agents (table 3). Opioid-naïve patients should not be started on extended-release/long-acting (ER/LA) opioids as initial therapy. (See 'Opioids' above.)

Adverse effects are common during opioid therapy. In particular, patients on opioids should be monitored for constipation, nausea, vomiting, sedation, impaired psychomotor function, and urinary retention. (See 'Monitoring for adverse effects' above.)

Opioids have the potential to interact with a variety of medications, primarily other central nervous system depressants. Avoid concurrent use of benzodiazepines, sedative medications, anticonvulsants (ie, gabapentin or pregabalin), and additional opioids, as concurrent use increases the risk of overdose. Alcohol and any other respiratory depressants should be avoided. (See 'Risks of misuse and overdose' above.)

During a trial of opioid therapy, the benefits and harms of opioid therapy should be assessed within one month of starting therapy. A shorter interval for follow-up is appropriate for patients who are at higher risk for misuse. (See 'Follow-up during trial' above.)

Various risk management strategies may be used to manage patients on opioids (table 12). None of these strategies have been proven to be effective and each should be individualized based on the likelihood of problematic drug-related behavior. (See 'Monitoring and risk management strategies during trial' above.)

Opioid therapy should only be continued after a trial and only in patients who have demonstrated that benefits outweigh harms during an initial trial of therapy. (See 'Chronic opioid therapy' above.)

The benefits and harms for patients on chronic opioid therapy should be assessed at least every three months for patients on stable doses of opioids. Patients should be seen more frequently after dosing changes, particularly if initiating or increasing long-acting opioids. (See 'Follow-up and monitoring during chronic opioid therapy' above.)

Aberrant behaviors occur on a continuum and must be carefully assessed. Aberrant behaviors associated with opioid use include misuse, OUD, and diversion. (See 'Patients with aberrant behaviors' above.)

Therapy may be discontinued for ineffectiveness, development of intolerable side effects or opioid-induced hyperalgesia, development of opioid use disorder (OUD), diversion, or a variety of reasons. Patients should be gradually tapered off of opioids and should continue to be treated with nonopioid therapies for their chronic pain. (See 'Discontinuing therapy' above.)

Some populations have increased risks with the use of opioids (eg, older patients, those with kidney disease, liver disease, sleep apnea, or mental health disorders). (See "Treatment of chronic non-cancer pain in older adults", section on 'Opioids' and "Management of chronic pain in advanced chronic kidney disease", section on 'Opioids' and "Management of pain in patients with advanced chronic liver disease or cirrhosis", section on 'Opioids'.)

REFERENCES

  1. Watkins EA, Wollan PC, Melton LJ 3rd, Yawn BP. A population in pain: report from the Olmsted County health study. Pain Med 2008; 9:166.
  2. CDC MMWR Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults - United States, 2016, September 14, 2018 / 67(36);1001–1006.
  3. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies Press, Washington 2011. http://www.nap.edu/read/13172/chapter/1 (Accessed on March 14, 2016).
  4. Levy B, Paulozzi L, Mack KA, Jones CM. Trends in Opioid Analgesic-Prescribing Rates by Specialty, U.S., 2007-2012. Am J Prev Med 2015; 49:409.
  5. The American Pain Society in conjunction with the American Academy of Pain Medicine. Guideline for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain: Evidence Review. http://americanpainsociety.org/uploads/education/guidelines/chronic-opioid-therapy-cncp.pdf (Accessed on April 06, 2016).
  6. Zhu W, Chernew ME, Sherry TB, Maestas N. Initial Opioid Prescriptions among U.S. Commercially Insured Patients, 2012-2017. N Engl J Med 2019; 380:1043.
  7. Scholl L, Seth P, Kariisa M, et al. Drug and Opioid-Involved Overdose Deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018; 67:1419.
  8. https://www.cdc.gov/drugoverdose/maps/rxrate-maps.html.
  9. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep 2016; 65:1.
  10. https://www.cdc.gov/media/releases/2019/s0424-advises-misapplication-guideline-prescribing-opioids.html.
  11. Drugs for pain. Treat Guidel Med Lett 2010; 8:25.
  12. Pappagallo M, Sokolowska M. The implications of tamper-resistant formulations for opioid rotation. Postgrad Med 2012; 124:101.
  13. Severtson SG, Bartelson BB, Davis JM, et al. Reduced abuse, therapeutic errors, and diversion following reformulation of extended-release oxycodone in 2010. J Pain 2013; 14:1122.
  14. Butler SF, Cassidy TA, Chilcoat H, et al. Abuse rates and routes of administration of reformulated extended-release oxycodone: initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatment. J Pain 2013; 14:351.
  15. Coplan PM, Kale H, Sandstrom L, et al. Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics. Pharmacoepidemiol Drug Saf 2013; 22:1274.
  16. Cicero TJ, Ellis MS, Surratt HL. Effect of abuse-deterrent formulation of OxyContin. N Engl J Med 2012; 367:187.
  17. Cassidy TA, DasMahapatra P, Black RA, et al. Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation. Pain Med 2014; 15:440.
  18. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003; 349:1943.
  19. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage 1996; 11:203.
  20. Von Korff M, Kolodny A, Deyo RA, Chou R. Long-term opioid therapy reconsidered. Ann Intern Med 2011; 155:325.
  21. Franklin GM, American Academy of Neurology. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology 2014; 83:1277.
  22. Chaparro LE, Furlan AD, Deshpande A, et al. Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review. Spine (Phila Pa 1976) 2014; 39:556.
  23. Reinecke H, Weber C, Lange K, et al. Analgesic efficacy of opioids in chronic pain: recent meta-analyses. Br J Pharmacol 2015; 172:324.
  24. Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA 2018; 319:872.
  25. Busse JW, Wang L, Kamaleldin M, et al. Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis. JAMA 2018; 320:2448.
  26. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009; 10:113.
  27. Frieden TR, Houry D. Reducing the Risks of Relief--The CDC Opioid-Prescribing Guideline. N Engl J Med 2016; 374:1501.
  28. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016. JAMA 2016; 315:1624.
  29. Hawk K, D'Onofrio G, Fiellin DA, et al. Past-year Prescription Drug Monitoring Program Opioid Prescriptions and Self-reported Opioid Use in an Emergency Department Population With Opioid Use Disorder. Acad Emerg Med 2018; 25:508.
  30. Haffajee RL, Jena AB, Weiner SG. Mandatory use of prescription drug monitoring programs. JAMA 2015; 313:891.
  31. Alliance of States with Prescription Monitoring Programs. http://www.pmpalliance.org/ (Accessed on August 26, 2012).
  32. Brandeis University. Schneider Institutes for Health Policy. Prescription Monitoring Program Center of Excellence Briefing on PMP Effectiveness. http://www.pmpexcellence.org/sites/all/pdfs/pmp_effectiveness_brief_revised_3_29_12.pdf.
  33. Chou R. Five Things to Know When a Psychiatric Patient Is Prescribed Opioids for Pain. JAMA Psychiatry 2021; 78:220.
  34. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med 2005; 6:432.
  35. Butler SF, Budman SH, Fernandez K, Jamison RN. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain 2004; 112:65.
  36. Butler SF, Fernandez K, Benoit C, et al. Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J Pain 2008; 9:360.
  37. https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm#T1_down.
  38. Chou R, Fanciullo GJ, Fine PG, et al. Opioids for chronic noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline. J Pain 2009; 10:131.
  39. Lawrence R, Mogford D, Colvin L. Systematic review to determine which validated measurement tools can be used to assess risk of problematic analgesic use in patients with chronic pain. Br J Anaesth 2017; 119:1092.
  40. Klimas J, Gorfinkel L, Fairbairn N, et al. Strategies to Identify Patient Risks of Prescription Opioid Addiction When Initiating Opioids for Pain: A Systematic Review. JAMA Netw Open 2019; 2:e193365.
  41. Cheatle MD, Compton PA, Dhingra L, et al. Development of the Revised Opioid Risk Tool to Predict Opioid Use Disorder in Patients with Chronic Nonmalignant Pain. J Pain 2019; 20:842.
  42. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med 2005; 6:107.
  43. Parchman ML, Penfold RB, Ike B, et al. Team-Based Clinic Redesign of Opioid Medication Management in Primary Care: Effect on Opioid Prescribing. Ann Fam Med 2019; 17:319.
  44. Dublin S, Walker RL, Shortreed SM, et al. Impact of initiatives to reduce prescription opioid risks on medically attended injuries in people using chronic opioid therapy. Pharmacoepidemiol Drug Saf 2019; 28:90.
  45. Von Korff M, Dublin S, Walker RL, et al. The Impact of Opioid Risk Reduction Initiatives on High-Dose Opioid Prescribing for Patients on Chronic Opioid Therapy. J Pain 2016; 17:101.
  46. Saunders KW, Shortreed S, Thielke S, et al. Evaluation of Health Plan Interventions to Influence Chronic Opioid Therapy Prescribing. Clin J Pain 2015; 31:820.
  47. Passik SD, Squire P. Current risk assessment and management paradigms: snapshots in the life of the pain specialist. Pain Med 2009; 10 Suppl 2:S101.
  48. Starrels JL, Becker WC, Alford DP, et al. Systematic review: treatment agreements and urine drug testing to reduce opioid misuse in patients with chronic pain. Ann Intern Med 2010; 152:712.
  49. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ 2006; 174:1589.
  50. Santos J, Alarcão J, Fareleira F, et al. Tapentadol for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 2015; :CD009923.
  51. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020281s049lbl.pdf.
  52. Fournier JP, Azoulay L, Yin H, et al. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med 2015; 175:186.
  53. Lee M, Silverman SM, Hansen H, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011; 14:145.
  54. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006; 104:570.
  55. Baron MJ, McDonald PW. Significant pain reduction in chronic pain patients after detoxification from high-dose opioids. J Opioid Manag 2006; 2:277.
  56. Hooten WM, Townsend CO, Sletten CD, et al. Treatment outcomes after multidisciplinary pain rehabilitation with analgesic medication withdrawal for patients with fibromyalgia. Pain Med 2007; 8:8.
  57. Townsend CO, Kerkvliet JL, Bruce BK, et al. A longitudinal study of the efficacy of a comprehensive pain rehabilitation program with opioid withdrawal: comparison of treatment outcomes based on opioid use status at admission. Pain 2008; 140:177.
  58. Kidner CL, Mayer TG, Gatchel RJ. Higher opioid doses predict poorer functional outcome in patients with chronic disabling occupational musculoskeletal disorders. J Bone Joint Surg Am 2009; 91:919.
  59. Krumova EK, Bennemann P, Kindler D, et al. Low pain intensity after opioid withdrawal as a first step of a comprehensive pain rehabilitation program predicts long-term nonuse of opioids in chronic noncancer pain. Clin J Pain 2013; 29:760.
  60. Chou R, Deyo R, Devine B, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. http://www.effectivehealthcare.ahrq.gov/ehc/products/557/1971/chronic-pain-opioid-treatment-report-140929.pdf (Accessed on March 14, 2016).
  61. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlerfsfor HumanMedicalProducts/ucm213264 (Accessed on July 16, 2008).
  62. 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.
  63. Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use - United States, 2006-2015. MMWR Morb Mortal Wkly Rep 2017; 66:265.
  64. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011; 305:1315.
  65. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med 2010; 152:85.
  66. Braden JB, Russo J, Fan MY, et al. Emergency department visits among recipients of chronic opioid therapy. Arch Intern Med 2010; 170:1425.
  67. Gomes T, Mamdani MM, Dhalla IA, et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011; 171:686.
  68. Liang Y, Turner BJ. Assessing risk for drug overdose in a national cohort: role for both daily and total opioid dose? J Pain 2015; 16:318.
  69. Dilokthornsakul P, Moore G, Campbell JD, et al. Risk Factors of Prescription Opioid Overdose Among Colorado Medicaid Beneficiaries. J Pain 2016; 17:436.
  70. Yang Z, Wilsey B, Bohm M, et al. Defining risk of prescription opioid overdose: pharmacy shopping and overlapping prescriptions among long-term opioid users in medicaid. J Pain 2015; 16:445.
  71. Kuo YF, Raji MA, Chen NW, et al. Trends in Opioid Prescriptions Among Part D Medicare Recipients From 2007 to 2012. Am J Med 2016; 129:221.e21.
  72. Miller M, Barber CW, Leatherman S, et al. Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy. JAMA Intern Med 2015; 175:608.
  73. Gaither JR, Goulet JL, Becker WC, et al. The Association Between Receipt of Guideline-Concordant Long-Term Opioid Therapy and All-Cause Mortality. J Gen Intern Med 2016; 31:492.
  74. Dasgupta N, Funk MJ, Proescholdbell S, et al. Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality. Pain Med 2016; 17:85.
  75. Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J Prev Med 2015; 49:493.
  76. Park TW, Saitz R, Ganoczy D, et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ 2015; 350:h2698.
  77. Sun EC, Dixit A, Humphreys K, et al. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ 2017; 356:j760.
  78. Xu KY, Hartz SM, Borodovsky JT, et al. Association Between Benzodiazepine Use With or Without Opioid Use and All-Cause Mortality in the United States, 1999-2015. JAMA Netw Open 2020; 3:e2028557.
  79. Gomes T, Juurlink DN, Antoniou T, et al. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med 2017; 14:e1002396.
  80. Gomes T, Greaves S, van den Brink W, et al. Pregabalin and the Risk for Opioid-Related Death: A Nested Case-Control Study. Ann Intern Med 2018; 169:732.
  81. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction 2016; 111:1160.
  82. http://www.healthvermont.gov/sites/default/files/documents/pdf/REG_opioids-prescribing-for-pain.pdf.
  83. Virginia Department of Health Professions. Board of Medicine. Board of Medicine Regulations on opioid prescribing and buprenorphine. Published 2017. https://www.dhp.virginia.gov/medicine/newsletters/OpioidPrescribingBuprenorphine03142017.pdf.
  84. FDA safety communication on discussing naloxone with all patients prescribed opioid pain relievers available online at https://www.fda.gov/media/140360/download (Accessed on July 30, 2020).
  85. Passik SD, Kirsh KL, Donaghy KB, Portenoy RK. Pain and aberrant drug-related behaviors in medically ill patients with and without histories of substance abuse. Clin J Pain 2006; 22:173.
  86. Passik SD, Kirsh KL. Assessing aberrant drug-taking behaviors in the patient with chronic pain. Curr Pain Headache Rep 2004; 8:289.
  87. Volkow ND, McLellan AT. Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies. N Engl J Med 2016; 374:1253.
  88. Haymond, S; Nagpal, G; Heiman, H . Urine drug screens to monitor opioid use for chronic pain. JAMA 2017; 11:1061.
  89. Mahajan G. Role of Urine Drug Testing in the Current Opioid Epidemic. Anesth Analg 2017; 125:2094.
  90. Bachhuber MA, Tuazon E, Nolan ML, et al. Impact of a prescription drug monitoring program use mandate on potentially problematic patterns of opioid analgesic prescriptions in New York City. Pharmacoepidemiol Drug Saf 2019; 28:734.
  91. Strickler GK, Zhang K, Halpin JF, et al. Effects of mandatory prescription drug monitoring program (PDMP) use laws on prescriber registration and use and on risky prescribing. Drug Alcohol Depend 2019; 199:1.
  92. Chou R, Deyo R, Devine B, Hansen R, Sullivan S, Jarvik JG, Blazina I, Dana T, Bougatsos C, Turner J. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evidence Report/Technology Assessment No. 218. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality; September 2014. www.effectivehealthcare.ahrq.gov/reports/final.cfm.
  93. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015; 162:276.
  94. Els C, Jackson TD, Kunyk D, et al. Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: an overview of Cochrane Reviews. Cochrane Database Syst Rev 2017; 10:CD012509.
  95. Fine PG, Portenoy RK, Ad Hoc Expert Panel on Evidence Review and Guidelines for Opioid Rotation. Establishing "best practices" for opioid rotation: conclusions of an expert panel. J Pain Symptom Manage 2009; 38:418.
  96. Knotkova H, Fine PG, Portenoy RK. Opioid rotation: the science and the limitations of the equianalgesic dose table. J Pain Symptom Manage 2009; 38:426.
  97. Cote J, Montgomery L. Sublingual buprenorphine as an analgesic in chronic pain: a systematic review. Pain Med 2014; 15:1171.
  98. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021306s015s019lbl.pdf.
  99. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207932s000lbl.pdf.
  100. Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 1978; 35:501.
  101. Fudala PJ, Jaffe JH, Dax EM, Johnson RE. Use of buprenorphine in the treatment of opioid addiction. II. Physiologic and behavioral effects of daily and alternate-day administration and abrupt withdrawal. Clin Pharmacol Ther 1990; 47:525.
  102. Tompkins DA, Smith MT, Mintzer MZ, et al. A double blind, within subject comparison of spontaneous opioid withdrawal from buprenorphine versus morphine. J Pharmacol Exp Ther 2014; 348:217.
  103. Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth 2006; 96:627.
  104. Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 2005; 94:825.
  105. https://www.samhsa.gov/data/sites/default/files/DAWN106/DAWN106/sr106-buprenorphine.htm.
  106. Suzuki J, Mittal L, Woo SB. Sublingual buprenorphine and dental problems: a case series. Prim Care Companion CNS Disord 2013; 15.
  107. https://www.fda.gov/media/155352/download.
  108. Rauck RL, Potts J, Xiang Q, et al. Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain. Postgrad Med 2016; 128:1.
  109. Filitz J, Griessinger N, Sittl R, et al. Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine. Eur J Pain 2006; 10:743.
  110. Freye E, Anderson-Hillemacher A, Ritzdorf I, Levy JV. Opioid rotation from high-dose morphine to transdermal buprenorphine (Transtec) in chronic pain patients. Pain Pract 2007; 7:123.
  111. Webster L, Gruener D, Kirby T, et al. Evaluation of the Tolerability of Switching Patients on Chronic Full μ-Opioid Agonist Therapy to Buccal Buprenorphine. Pain Med 2016; 17:899.
  112. Kornfeld H, Reetz H. Transdermal buprenorphine, opioid rotation to sublingual buprenorphine, and the avoidance of precipitated withdrawal: a review of the literature and demonstration in three chronic pain patients treated with butrans. Am J Ther 2015; 22:199.
  113. Clark MR, Hurley RW, Adams MCB. Re-assessing the Validity of the Opioid Risk Tool in a Tertiary Academic Pain Management Center Population. Pain Med 2018; 19:1382.
  114. Butler SF, Budman SH, Fernandez KC, et al. Development and validation of the Current Opioid Misuse Measure. Pain 2007; 130:144.
  115. Belgrade MJ, Schamber CD, Lindgren BR. The DIRE score: predicting outcomes of opioid prescribing for chronic pain. J Pain 2006; 7:671.
  116. Wu SM, Compton P, Bolus R, et al. The addiction behaviors checklist: validation of a new clinician-based measure of inappropriate opioid use in chronic pain. J Pain Symptom Manage 2006; 32:342.
  117. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990; 41:273.
  118. Portenoy RK, Bennett DS, Rauck R, et al. Prevalence and characteristics of breakthrough pain in opioid-treated patients with chronic noncancer pain. J Pain 2006; 7:583.
  119. Wiedemer NL, Harden PS, Arndt IO, Gallagher RM. The opioid renewal clinic: a primary care, managed approach to opioid therapy in chronic pain patients at risk for substance abuse. Pain Med 2007; 8:573.
  120. Argoff CE, Kahan M, Sellers EM. Preventing and managing aberrant drug-related behavior in primary care: systematic review of outcomes evidence. J Opioid Manag 2014; 10:119.
  121. Sehgal N, Manchikanti L, Smith HS. Prescription opioid abuse in chronic pain: a review of opioid abuse predictors and strategies to curb opioid abuse. Pain Physician 2012; 15:ES67.
  122. Meltzer EC, Rybin D, Meshesha LZ, et al. Aberrant drug-related behaviors: unsystematic documentation does not identify prescription drug use disorder. Pain Med 2012; 13:1436.
Topic 93598 Version 37.0

References

1 : A population in pain: report from the Olmsted County health study.

2 : A population in pain: report from the Olmsted County health study.

3 : A population in pain: report from the Olmsted County health study.

4 : Trends in Opioid Analgesic-Prescribing Rates by Specialty, U.S., 2007-2012.

5 : Trends in Opioid Analgesic-Prescribing Rates by Specialty, U.S., 2007-2012.

6 : Initial Opioid Prescriptions among U.S. Commercially Insured Patients, 2012-2017.

7 : Drug and Opioid-Involved Overdose Deaths - United States, 2013-2017.

8 : Drug and Opioid-Involved Overdose Deaths - United States, 2013-2017.

9 : CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016.

10 : CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016.

11 : Drugs for pain.

12 : The implications of tamper-resistant formulations for opioid rotation.

13 : Reduced abuse, therapeutic errors, and diversion following reformulation of extended-release oxycodone in 2010.

14 : Abuse rates and routes of administration of reformulated extended-release oxycodone: initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatment.

15 : Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics.

16 : Effect of abuse-deterrent formulation of OxyContin.

17 : Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation.

18 : Opioid therapy for chronic pain.

19 : Opioid therapy for chronic nonmalignant pain: a review of the critical issues.

20 : Long-term opioid therapy reconsidered.

21 : Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology.

22 : Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review.

23 : Analgesic efficacy of opioids in chronic pain: recent meta-analyses.

24 : Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial.

25 : Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis.

26 : Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.

27 : Reducing the Risks of Relief--The CDC Opioid-Prescribing Guideline.

28 : CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016.

29 : Past-year Prescription Drug Monitoring Program Opioid Prescriptions and Self-reported Opioid Use in an Emergency Department Population With Opioid Use Disorder.

30 : Mandatory use of prescription drug monitoring programs.

31 : Mandatory use of prescription drug monitoring programs.

32 : Mandatory use of prescription drug monitoring programs.

33 : Five Things to Know When a Psychiatric Patient Is Prescribed Opioids for Pain.

34 : Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool.

35 : Validation of a screener and opioid assessment measure for patients with chronic pain.

36 : Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R).

37 : Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R).

38 : Opioids for chronic noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline.

39 : Systematic review to determine which validated measurement tools can be used to assess risk of problematic analgesic use in patients with chronic pain.

40 : Strategies to Identify Patient Risks of Prescription Opioid Addiction When Initiating Opioids for Pain: A Systematic Review.

41 : Development of the Revised Opioid Risk Tool to Predict Opioid Use Disorder in Patients with Chronic Nonmalignant Pain.

42 : Universal precautions in pain medicine: a rational approach to the treatment of chronic pain.

43 : Team-Based Clinic Redesign of Opioid Medication Management in Primary Care: Effect on Opioid Prescribing.

44 : Impact of initiatives to reduce prescription opioid risks on medically attended injuries in people using chronic opioid therapy.

45 : The Impact of Opioid Risk Reduction Initiatives on High-Dose Opioid Prescribing for Patients on Chronic Opioid Therapy.

46 : Evaluation of Health Plan Interventions to Influence Chronic Opioid Therapy Prescribing.

47 : Current risk assessment and management paradigms: snapshots in the life of the pain specialist.

48 : Systematic review: treatment agreements and urine drug testing to reduce opioid misuse in patients with chronic pain.

49 : Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects.

50 : Tapentadol for chronic musculoskeletal pain in adults.

51 : Tapentadol for chronic musculoskeletal pain in adults.

52 : Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain.

53 : A comprehensive review of opioid-induced hyperalgesia.

54 : Opioid-induced hyperalgesia: a qualitative systematic review.

55 : Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

56 : Treatment outcomes after multidisciplinary pain rehabilitation with analgesic medication withdrawal for patients with fibromyalgia.

57 : A longitudinal study of the efficacy of a comprehensive pain rehabilitation program with opioid withdrawal: comparison of treatment outcomes based on opioid use status at admission.

58 : Higher opioid doses predict poorer functional outcome in patients with chronic disabling occupational musculoskeletal disorders.

59 : Low pain intensity after opioid withdrawal as a first step of a comprehensive pain rehabilitation program predicts long-term nonuse of opioids in chronic noncancer pain.

60 : Low pain intensity after opioid withdrawal as a first step of a comprehensive pain rehabilitation program predicts long-term nonuse of opioids in chronic noncancer pain.

61 : Low pain intensity after opioid withdrawal as a first step of a comprehensive pain rehabilitation program predicts long-term nonuse of opioids in chronic noncancer pain.

62 : New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults.

63 : Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use - United States, 2006-2015.

64 : Association between opioid prescribing patterns and opioid overdose-related deaths.

65 : Opioid prescriptions for chronic pain and overdose: a cohort study.

66 : Emergency department visits among recipients of chronic opioid therapy.

67 : Opioid dose and drug-related mortality in patients with nonmalignant pain.

68 : Assessing risk for drug overdose in a national cohort: role for both daily and total opioid dose?

69 : Risk Factors of Prescription Opioid Overdose Among Colorado Medicaid Beneficiaries.

70 : Defining risk of prescription opioid overdose: pharmacy shopping and overlapping prescriptions among long-term opioid users in medicaid.

71 : Trends in Opioid Prescriptions Among Part D Medicare Recipients From 2007 to 2012.

72 : Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy.

73 : The Association Between Receipt of Guideline-Concordant Long-Term Opioid Therapy and All-Cause Mortality.

74 : Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality.

75 : Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines.

76 : Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study.

77 : Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis.

78 : Association Between Benzodiazepine Use With or Without Opioid Use and All-Cause Mortality in the United States, 1999-2015.

79 : Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study.

80 : Pregabalin and the Risk for Opioid-Related Death: A Nested Case-Control Study.

81 : Gabapentin misuse, abuse and diversion: a systematic review.

82 : Gabapentin misuse, abuse and diversion: a systematic review.

83 : Gabapentin misuse, abuse and diversion: a systematic review.

84 : Gabapentin misuse, abuse and diversion: a systematic review.

85 : Pain and aberrant drug-related behaviors in medically ill patients with and without histories of substance abuse.

86 : Assessing aberrant drug-taking behaviors in the patient with chronic pain.

87 : Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies.

88 : Urine drug screens to monitor opioid use for chronic pain

89 : Role of Urine Drug Testing in the Current Opioid Epidemic.

90 : Impact of a prescription drug monitoring program use mandate on potentially problematic patterns of opioid analgesic prescriptions in New York City.

91 : Effects of mandatory prescription drug monitoring program (PDMP) use laws on prescriber registration and use and on risky prescribing.

92 : Effects of mandatory prescription drug monitoring program (PDMP) use laws on prescriber registration and use and on risky prescribing.

93 : The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop.

94 : Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: an overview of Cochrane Reviews.

95 : Establishing "best practices" for opioid rotation: conclusions of an expert panel.

96 : Opioid rotation: the science and the limitations of the equianalgesic dose table.

97 : Sublingual buprenorphine as an analgesic in chronic pain: a systematic review.

98 : Sublingual buprenorphine as an analgesic in chronic pain: a systematic review.

99 : Sublingual buprenorphine as an analgesic in chronic pain: a systematic review.

100 : Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction.

101 : Use of buprenorphine in the treatment of opioid addiction. II. Physiologic and behavioral effects of daily and alternate-day administration and abrupt withdrawal.

102 : A double blind, within subject comparison of spontaneous opioid withdrawal from buprenorphine versus morphine.

103 : Buprenorphine induces ceiling in respiratory depression but not in analgesia.

104 : Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.

105 : Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.

106 : Sublingual buprenorphine and dental problems: a case series.

107 : Sublingual buprenorphine and dental problems: a case series.

108 : Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain.

109 : Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine.

110 : Opioid rotation from high-dose morphine to transdermal buprenorphine (Transtec) in chronic pain patients.

111 : Evaluation of the Tolerability of Switching Patients on Chronic Fullμ-Opioid Agonist Therapy to Buccal Buprenorphine.

112 : Transdermal buprenorphine, opioid rotation to sublingual buprenorphine, and the avoidance of precipitated withdrawal: a review of the literature and demonstration in three chronic pain patients treated with butrans.

113 : Re-assessing the Validity of the Opioid Risk Tool in a Tertiary Academic Pain Management Center Population.

114 : Development and validation of the Current Opioid Misuse Measure.

115 : The DIRE score: predicting outcomes of opioid prescribing for chronic pain.

116 : The addiction behaviors checklist: validation of a new clinician-based measure of inappropriate opioid use in chronic pain.

117 : Breakthrough pain: definition, prevalence and characteristics.

118 : Prevalence and characteristics of breakthrough pain in opioid-treated patients with chronic noncancer pain.

119 : The opioid renewal clinic: a primary care, managed approach to opioid therapy in chronic pain patients at risk for substance abuse.

120 : Preventing and managing aberrant drug-related behavior in primary care: systematic review of outcomes evidence.

121 : Prescription opioid abuse in chronic pain: a review of opioid abuse predictors and strategies to curb opioid abuse.

122 : Aberrant drug-related behaviors: unsystematic documentation does not identify prescription drug use disorder.