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Exploring the Use of Chronic Opioid Therapy for Chronic Pain: When, How, and for Whom?

Medical Clinics of North America, Volume 100, Issue 1, January 2016, Pages 81 - 102

This article provides a broad overview regarding intent to initiate and consider ongoing chronic opioid therapy (COT) for treatment of chronic noncancer pain (CNCP). COT should be an individualized decision based on a comprehensive evaluation, assessment, and monitoring. It is imperative that providers discuss various risks and benefits of COT initially and at follow-up visits, and continue appropriate monitoring and follow-up at regular intervals. The decision to initiate or continue opioid therapy is based on clinical judgment; however, it is understood that opioid and other medication therapy represent one piece of the complete treatment plan for patients with CNCP.

Keywords: Chronic opioid therapy, Chronic noncancer pain, Pain management, Opioid risk management, Opioid induced respiratory depression.

Key points

  • Chronic opioid therapy (COT) for the treatment of chronic noncancer pain (CNCP) should be individualized based on a comprehensive evaluation and assessment.
  • COT should be initiated on a trial basis; phases of the trial include initiation, titration, and maintenance.
  • Prescribers of COT must ensure that appropriate monitoring (eg, urine drug tests, prescription drug monitoring programs) and follow-up is done at regular intervals.
  • COT, if deemed appropriate, is just one piece of a complete treatment plan for patients with CNCP.


Prescribed chronic opioid therapy (COT) has dramatically increased over the past decade with resultant startling increased mortality.1 No doubt, a large portion of associated morbidity and mortality arise from inadequate education, lack of specialty providers, and ineffective support systems for excellent opioid pharmacotherapeutic management. Nevertheless, at the expense of legitimate patient access, media sensationalism has run amok collaterally with various political agendas2 and 3 irrespective of potential harm to patients requiring opioids.4 and 5

A 2014 Agency for Healthcare Research and Quality report identified 16,917 fatal prescription opioid overdoses occurred in 2011.6 Risks increase with higher daily opioid doses, concomitant benzodiazepine or sedative hypnotics, and in patients with mental health comorbidities. Patients receiving 100 or more morphine equivalents per day (MED) are at a 9-fold higher risk for opioid overdose. Moreover, the combination of prescription opioids and benzodiazepines is the most common cause of polysubstance overdose deaths nationwide.7, 8, 9, and 10 Nevertheless, correlation of MED to opioid risk should be interpreted carefully because there are no universally accepted morphine equivalents.11 Long-term efficacy data related to functional improvement on COT has come under great scrutiny with multiple review articles and position statements published in the last 12 months.12

Initial evaluation and assessment

Appropriate treatment considerations for chronic noncancer pain (CNCP) start with a comprehensive physical examination and assessment to determine which treatment modalities are most suitable.13 Before starting any medication, it is important to obtain the patient’s medical and psychiatric history and a family history, including various risk factors for substance abuse disorder, and to perform a psychosocial assessment. All of these elements are components of risk stratification that become critical in determining whether or not COT is appropriate.

Components of a comprehensive assessment are similar to those identified as the “universal precautions” in pain management related to diagnosis and treatment selection: (1) make a diagnosis with appropriate differential, (2) psychological assessment including risk of addictive disorders, and (3) periodically review pain diagnosis and comorbid conditions, including addictive disorders.14 It is suggested to triage patients based on results and findings in the initial assessment into one of several treatment level categories: primary care patients (those with the lowest risk; no past/current history of substance abuse and absence of major mental health comorbidity), primary care patients with specialist support (moderate risk patients; may have past or remote history of substance use or significant family history but are not actively addicted), and specialty pain management (those with the highest risk; active substance abuse or addiction and/or presence of major mental health comorbidities).14 Validated risk tools as outlined in Tables 1 and 2 are available for assessing opioid abuse and misuse; at least one from each category should be used before initiating COT.

Table 1 Comparison of risk stratification tools source: Adapted from Fudin J. Opioid risk stratification tools summarized. Available at: Accessed May 5, 2015, with permission; and Data from Compton P, Darakjian J, Miotto K. Screening for addiction in patients with chronic pain and “problematic” substance use: evaluation of a pilot assessment tool. J Pain Symptom Manage 1998;16(6):355–63.

Risk Tool Indication Question Format Scoring Advantages Disadvantages
DIRE Risk of opioid abuse and suitability of candidate for long-term opioid therapy 7 via patient interview Numeric, simple to interpret 2 min to complete
Correlates well with patient’s compliance and efficacy of long-term opioids therapy
Prospective validation needed
ORT Categorizes patients as low, medium, high risk 5 Numeric, simple to interpret <1 min to complete
Simple scoring
High sensitivity and specificity for stratifying patients
1 question based on patient’s knowledge of family history of substance abuse
PDUQ Assess for presence of addiction in chronic pain patients 42 items via patient interview Numeric, simple to interpret 3 items correctly predicted addiction or no addiction in 92% of patients 20 min to administer
SOAPP-R Primary care 24 Numeric, simple to interpret 5 min to complete
Easy to interpret results

Abbreviations: DIRE, Diagnosis; Intractability, Risk; Efficacy Score; ORT, opioid risk tool; PDUQ, prescription drug use questionnaire; SOAPP-R, Screener and Opioid Assessment for Patients with Pain-Revised.

Table 2 Comparison of opioid misuse assessment tools source: Adapted from Fudin J. Opioid risk stratification tools summarized. Available at: Accessed May 5, 2015; with permission.

Tool Indication Question Format Scoring Advantages Disadvantages
ABC Ongoing assessment of patients on COT 20 ≥3 indicates possible inappropriate opioid Concise
Easy to score
Studied at VA
Need validation outside VA
COMM Assess aberrant medications related behaviors in chronic pain 17 Numeric 10 min to complete
Useful for adherence assessment
Unknown reliability long term
PADT Streamline assessment of chronic pain outcomes using the 4 As N/A N/A 5 min to complete
Documents progress
Not intended to predict drug-seeking behavior or positive/negative outcomes

Abbreviations: ABC, Addiction Behaviors Checklist; COMM, Current Opioid Misuses Measure; PADT, Pain Assessment and Documentation Tool.

Pharmacologic Strategies: Opioid Trial

Before considering COT, appropriate nonopioid medications should be trialed after initial and ongoing attempts of lifestyle changes, diet and exercise, stretching, physical therapy, behavior modification, yoga, and/or other nonmedical modalities, particularly where there is supportive evidence.15

Opioids may be considered when a patient has moderate to severe pain that is affecting their function or quality of life, documented failure of alternative therapies, and when the benefits of therapy are expected to outweigh the potential risks. Implementing opioids should be considered a therapeutic trial of short-term duration to determine suitability for continued use based on assessment of risks versus benefits. When discussing an opioid trial with the patient and significant others, it is important to establish realistic therapeutic goals with the patient that will help to determine whether the trial was successful. These goals should be individualized to the patient and include components of reduction in pain, improvements in functioning and/or quality of life, and minimization of side effects or risk. Opioids should be just one piece of a patient’s pain management plan.16, 17, and 18

Before COT is initiated, it is essential to obtain informed consent, which is intended to ensure that the patient has all the necessary information to make a knowledgeable and informed decision commensurate with personal goals and preferences. Acknowledgment of benefits, risks, and alternatives to opioid therapy are essential components. Common and serious risks should be reviewed carefully with the patient and caregiver.16 and 18 Throughout therapy, there should be ongoing reevaluation of patient risks and benefits of therapy to ensure COT remains appropriate.16 and 18 Patients should understand the differences between addiction, tolerance, and physical dependence (Table 3).19

Table 3 Definitions of addiction, tolerance, and physical dependence source: Data from American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th edition. Washington, DC: Author; 2013; and VA/DoD. Clinical practice guidelines for management of opioid therapy for chronic pain. Available at: Accessed December 17, 2014.

Term Addiction
Addiction (Association 2013) “A problematic pattern of opioid use leading to clinically significant impairment or distress.”
Tolerance (VA/DoD 2010) “A form of neuroadaptation to the effects of chronically administered opioids, which is manifested by the need for increasing or more frequent doses of the medication to achieve the initial effects of the drug.”
Physical dependence (VA/DoD 2010) “A physiologic state in which abrupt cessation of the opioid, rapid tapering, or administration of an opioid antagonist, results in a withdrawal syndrome.”

Multiple guidelines advocate for the use of opioid treatment agreements in patients on COT. These may be implemented before initiating opioids and continually revisited throughout therapy.16, 17, and 18 Generally, opioid treatment agreements (Box 1) are used to foster the exchange of information, improve adherence, and develop treatment goals.20 Opioid treatment agreements outline the responsibilities of both the patient and provider and the conditions for continuation or discontinuation of COT.20 See other important practice considerations outlined in Box 1.

Box 1 Characteristics of an opioid treatment agreement source: Data from Refs.16, 18, and 20

  • Goals of therapy
  • Discussion of risks and benefits
  • Expectations about prescribing and taking opioids
    • Considered a trial
    • Use of one prescriber and one pharmacy
    • Avoiding abruptly stopping opioids
    • No early refills
    • No replacement of lost, stolen, or destroyed medication
    • Patients must inform providers of all medications being taken
  • Avoidance of alcohol and illicit substances while on opioids
  • Prohibition of sharing, selling, or providing others access to opioids
  • Follow-up and monitoring parameters
    • Office visits
    • Urine drug screeninga
    • Prescription drug monitoring programs
    • Pill countsb
  • Reasons for continuing or discontinuing opioids
  • Secure storage of medications

a Discussed in further detail elsewhere in this article.

b Pill counts are flawed because patients can borrow or rent medications from others.

Adverse effects and risks associated with opioids

Common adverse opioid effects include constipation, nausea/vomiting, dizziness, sedation, respiratory depression, and pruritus. Tolerance often develops to these side effects in time with the exception of constipation. To mitigate opioid-induced constipation, patients are often started on prophylactic bowel regimens including a stool softener and stimulant laxative(s). More recently we have seen an introduction of peripherally acting mu receptor opioid antagonists as an alternative to traditional therapies for opioid-induced constipation. Slow dose titration, opioid dose reduction, opioid rotation, extended release formulations, and symptom treatment are ways to prevent and manage opioid adverse effects.17 To date, there are no established consensus guidelines for the treatment of opioid-induced constipation.

Despite the use of opioids with the intent to reduce pain, high-dose opioids may lead to increased pain by what some believe to be opioid-induced hyperalgesia. Recently, Eisenberg and colleagues21 provided a comprehensive overview of opioid-induced hyperalgesia, which demonstrates limited evidence supporting opioid-induced hyperalgesia.

A major concern with opioid therapy is diminished respiration. Opioids contribute to sleep-disordered breathing. Opioid-induced respiratory depression may contribute to overdose and death. Opioid-induced respiratory depression is dose related and increased when combined with central nervous system depressants like alcohol, benzodiazepines, and/or other sedative–hypnotics such as carisoprodol.12, 16, 17, 18, and 22 Opioid overdose risk increases 4-fold at 50 to 100 mg (MED).12 and 22

Endocrine and immune system effects can occur with COT. By interacting with the hypothalamic–pituitary axis, opioids have been shown to decrease testosterone levels, leading to hypogonadism, sexual dysfunction, infertility, and a host of other medical anomalies associated with hypotestosteronemia.12, 16, 17, 18, 22, and 23 Other associated morbidities include falls and fractures, neonatal abstinence syndrome, cardiovascular effects including increased risk for myocardial infarction and QT prolongation (methadone), depression, and increased motor vehicle accidents.12 and 22

Contraindications to opioids

Absolute contraindications to opioid therapy are listed in Box 2. Opioid allergies are often incorrectly assigned and are specifically owing to histamine release, which is the most common cause of opioid-induced pruritus, but not a true allergy. Even anaphylaxis to one opioid does not preclude use of opioids from other structural classes. Table 4 outlines the chemistries of these various agents with relative cross-sensitivities.

Box 2 Contraindications to opioids source: Data from Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2–guidance. Pain Physician 2012;15(Suppl 3):S67–116; and VA/DoD. Clinical Practice Guidelines for Management of Opioid Therapy for Chronic Pain. Available at: Accessed August 25, 2015.

  • Respiratory instability
  • Acute psychiatric instability
  • Uncontrolled suicide risk
  • Active, untreated alcohol or substance use disorder
  • True opioid allergy
  • Concomitant medications with potential to cause life-limiting drug interactions
  • Prolonged QTc (≥500 ms) with methadone
  • Active diversion

Table 4 Chemical classes of opioids source: Adapted from Fudin J. Chemical classes of opioids. Available at: Accessed May 5, 2015; with permission.

Phenanthrenes Benzomorphans Phenylpiperidines Diphenylheptanes Phenylpropyl Amines
fx1 fx2 fx3 fx4 fx5
Morphine Pentazocine Meperidine Methadone Tramadol
Heroin (diacetyl-morphine)
Cross-sensitivity risk
Probable Possible Low risk Low risk Low risk

a Agents lacking the 6-OH group of morphine, possibly decreases cross-sensitivity within the phenanthrene group.

Codeine is contraindicated for use in pediatric patients undergoing tonsillectomy or adenoidectomy. A Black Box Warning has been issued for this indication owing to potential mortality among pediatric patients, including nursing infants. Several deaths occurred in children who were found to be ultrarapid metabolizers of the CYP2D6 enzyme, which is the enzyme that converts codeine into morphine.24

Treatment initiation, titration, and maintenance


An opioid trial consists of initiation, titration, and maintenance phases.17 The initial selection of an opioid medication and dose is patient individualized. For opioid-naïve patients, low doses should be initiated to ensure safety and tolerability. Patient preference, health status, dosing schedule, route of administration, patient’s prior experience, and tolerance level (Box 3) should be considered.25 and 26 Most guidelines prefer long-acting opioids in chronic pain for more consistent pain relief and uninterrupted sleep, adherence, and a possible lesser risk of addiction or abuse; however, this is not evidence based.18

Box 3 Criteria for opioid tolerance source: From FDA. FDA blueprint for prescriber education for extended release and long-acting opioid analgesics. Available at: Accessed August 24, 2015.

Patients receiving opioids on a daily basis for at least 1 week of

  • 60 mg oral morphine/d
  • 25 μg transdermal fentanyl/h
  • 30 mg oral oxycodone/d
  • 8 mg oral hydromorphone/d
  • 25 mg oral oxymorphone/d
  • Or an equianalgesic dose of any other opioid combination


The titration phase involves gradual dose increases to achieve the lowest effective dose that meets patient goals. Caution must be exercised to slowly titrate doses, because rapid escalation may lead to unintentional overdose. Opioid doses should not be adjusted until steady state has been reached, which is typically 5 half-lives (Table 5). During this phase, patients should be monitored closely with follow-up every 2 to 4 weeks until stable.17

Table 5 Comparison of extended-release (ER) opioid analgesics (or immediate release with *T1/2>12 h) source: Data from Refs.57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72

Opioid Brand Extended-Release Technology FDA-Approved Abuse Deterrent Technology Initial Dose Opioid Tolerant Only Doses/Dosage Forms Half-life (h)
Buprenorphinea Butrans Matrix No 5 μg/h patch Q7days ≥5 μg/h patch 26
Fentanyl Duragesic Matrix No 12 μg/h patch Q72H ≥25 μg/h patch 20–27 after removal
Hydrocodone Hysingla ER Film-coated Yes 20 mg PO Q24H Single dose ≥80 mg daily dose 7–9
Zohydro ER Beadtek Yes (not yet available) 10 mg PO Q12H Single dose ≥40 mg or ≥80 mg daily dose 8
Hydromorphone Exalgo OROS Yes 8 mg PO Q24H All tablets 10–11
Levorphanol* 2 mg PO Q8H 11–16
Methadone* Dolophine 5 mg PO Q8H 8–60
Morphine Avinza SODAS No 30 mg PO Q24H 90, 120 mg capsules 24
Embeda Pellets Yes 30 mg PO Q24H 100/4 mg capsules 29
Kadian Polymer-coated pellets No 10 mg PO Q24H 100, 130, 150, 200 mg capsules 11–13
MS Contin Film coated No 15 mg PO Q12H 100, 200 mg tablets Not listed
Oxycodone Oxycontin Film coated Yes 10 mg PO Q12H Single dose ≥40 mg or ≥80 mg daily dose 4.5
Targiniq ER Film coated No 10 mg/5 mg PO Q12H Single dose ≥40/20 mg or ≥80/40 mg daily dose 3.9–5.3
Xartemis XR PolyOx No (2) 7.5–325 mg PO Q12H None 4.5
Oxymorphone Opana ER INTAC No 5 mg PO Q12H None 9.4–11.3
Tapentadolb Nucynta ER Film-coated No 50 mg PO Q12H None 5

a Buprenorphine is a partial mu opioid agonist, kappa-opioid antagonist, delta-opioid receptor agonist, and a partial ORL-1 (nociceptin) agonist.

b Tapentadol is a centrally-acting synthetic analgesic with mu-opioid receptor agonist and norepinephrine reuptake inhibitor activity.

Abbreviation: FDA, US Food and Drug Administration.

Breakthrough Pain

Breakthrough pain is defined as a period of increased pain in patients with cancer-related pain with otherwise stable well-controlled pain; however, many have expanded the concept to include non–cancer-related pain. Different types of breakthrough pain include spontaneous, incidental, and end-of-dose failure.27 Ultimately, the use of breakthrough pain medications should be minimized in chronic pain patients through titration of the baseline opioid dose or use of adjunctive agents.17 A reasonable dose for breakthrough pain medication is 10% to 15% of the total daily opioid dose.27

Opioid Rotation

When patients fail to achieve analgesic and functional benefits with escalating doses of opioids, the potential cause for this must be evaluated, for example, adherence, drug–drug interactions, polymorphism, or worsening of the condition. If there is no identifiable reason, rotation to another opioid may be considered.16, 17, and 18 Opioid rotation can be defined as a therapeutic strategy that involves switching from 1 opioid to another in an effort to improve patient outcomes. Opioid rotations may be within the same opioid chemical class or between opioid chemical classes. Opioid alternatives could be considered in the cases of poor tolerability owing to side effects. Other considerations for opioid rotation include changes in patient status (consider buprenorphine transdermal once weekly), as well as availability, cost, and patient preference. Conversion tables are available but are not standardized. These tables list the doses of different opioids that presumably result in similar analgesic benefits. Table 6 provides one example.27

Table 6 Equianalgesic opioid dosing source: Data from McPherson ML. Demystifiying opioid conversion calculations: a guide for effective dosing. Bethesda (MD): American Society of Health-System Pharmacists; 2010.

Opioid Parenteral (mg) Oral (mg)
Buprenorphine 0.3 0.4 (SL)
Codeine 100 200
Fentanyl 0.1 N/A
Hydrocodone N/A 30
Hydromorphone 1.5 7.5
Methadone Multiple strategies N/A
Morphine 10 30
Oxycodone 10 20
Oxymorphone 1 10

Methadone dosing is highly variable and conversion to/from other opioids is NOT linear.

Abbreviation: N/A, not applicable.

Frequently, a 25% to 50% decrease in dose is used in opioid rotations to account for incomplete cross-tolerance.16, 17, and 18 Conversions may be completed via 2 strategies: stepwise or single step. In single-step rotations, the previous opioid is discontinued and the new opioid is initiated. When switching between large doses of opioids, the authors recommend a stepwise conversion be used. This involves reducing the initial opioid MED by 25% to 50% and converting that to an equianalgesic dose of an alternate opioid.17

Equianalgesic charts are subject to several flaws. Limited equianalgesic dosing data are available from the chronic pain population. Conversion tables are notoriously flawed and none consider patient specific factors like age, weight, body surface area, pharmacogenetics, drug interactions, organ dysfunction, or comorbid conditions. When using equianalgesic dosing tables or online calculators, it is often assumed the data are bidirectional when they may only be unidirectional and conservative only in one direction.27 Given all of these concerns, equianalgesic dosing tables are only guides and patient-specific factors should be incorporated into the ultimate dose with a monitoring plan to ensure safety and efficacy.28

Reassessment and follow-up

When pain regimens are reviewed for appropriateness, the popularized 4 As—analgesia, adverse effects, activities, and adherence—should be evaluated.16, 17, and 29 It is prudent to follow-up with patients within 2 to 4 weeks depending on stratified risk level, concomitant therapy, and comorbid conditions. High-risk patients should be seen more frequently and include patients with a history of substance use disorder, older patients, patients with comorbid physical or psychological conditions, and those with an unstable or dysfunctional social milieu.17 and 18 For patients with an increased risk of substance abuse or misuse, if they can be safely and reasonably maintained on opioids with strict compliance monitoring and have limited other therapeutic options, abuse deterrent formulations may be considered. Long-acting opioids with US Food and Drug Administration (FDA)–approved indications are listed in Table 5. And finally, stable lower risk patients may be seen in clinic every 3 to 6 months.18

Monitoring parameters

Appropriate and timely COT monitoring is vital in the management of chronic pain. Urine drug tests (UDT) generally by immunoassay (IA), prescription drug monitoring programs, behavioral assessments, and “pill counts” have been used in the monitoring of COT.16 In the authors’ experience, the latter is a futile exercise serving only to promulgate inconvenience and hardship for legitimate patients, because it is quite easy for substance abusers to borrow medications from others. Patients on methadone should have baseline electrocardiograms and be monitored closely for electrolyte abnormalities (eg, hypokalemia and hypomagnesemia) and liver function impairment.30 Guidelines for methadone electrocardiogram monitoring are summarized in Table 7.30

Table 7 Guidelines for methadone electrocardiogram (ECG) monitoring source: Data from Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain 2014;15(4):321–37.

Frequency Recommendations Considerations


  • Before initiation of methadone:
    • Risk factors for QTc interval prolongationa
    • Any record of previous ECG with QTc >450 ms
    • Past medical history of ventricular arrhythmia
    • An ECG with a QTc <450 ms within the past 3 mo with no new risk factors is acceptable


Any patient with no known risk factors for QTc interval prolongation
An ECG within the past year with QTc <450 ms with no new risk factors QTc interval prolongation


  • Pending baseline ECG results, methadone dose changes, and risk factors for QTc prolongation:
    • Performed 2–4 wk after initiation of methadone therapy
    • After significant dose increases in patients with risk factors for QTc interval prolongation
    • Any prior ECG demonstrating a QTc > 450 ms
    • Have a history of syncope



  • For all patients:
    • Methadone doses titrated up to 30–40 mg/d
    • Methadone doses titrated up to 100 mg/d
    • New risk factors for QTc interval prolongation
    • Signs or symptoms signifying arrhythmia


a Risk factors for QTc interval prolongation: electrolyte abnormalities (eg, hypokalemia, hypomagnesemia), impaired liver function, structural heart disease (eg, congenital heart disease, history of endocarditis, congestive heart failure), genetic predisposition, QTc-prolonging drugs.

Abbreviations: ECG, electrocardiogram; QTc, corrected QT interval.

Urine Drug Tests

UDTs have become a standard of care tool to monitor patients for treatment adherence, detecting nonprescribed drugs, and use of illicit substances. The use of IA UDT poses several advantages in providing clinicians at the point of care with objective, noninvasive, low-cost results to assess patient adherence and possible diversion.31 Notwithstanding, IA UDT comes with a high risk of false negatives and positives. However, IA UDT could be performed initially and as clinically indicated as part of the COT monitoring.14, 16, 17, 18, and 32 The typical IA UDT primarily screens for morphine, but will detect semisynthetic and synthetic opioids at high doses.33, 34, and 35 The detection time on a UDT varies based on the type of opioid, dose, frequency of use, and time of collected specimen in relation to the last dose.32Table 8 provides window of detection times. Nonphenanthrene opioids such as methadone and fentanyl will not be detected on an IA UDT screen, and therefore require a specific qualitative IA test or separate definitive test by chromatography.36 Published data indicate deficiencies in clinicians’ abilities to accurately interpret UDT results, because accurate interpretation requires an understanding of IA limitations, clinical chemistry, and opioid metabolism.31, 33, 35, and 36

Table 8 Opioid metabolism and detection times source: Data from Refs.33, 34, 35, 46, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, and 75

Opioid Metabolism PGT Impact from Phenotype for CYP450 Active Metabolites Inactive Metabolites Detection Time (h)
Buprenorphine TM CYP3A4 Y Norbuprenorphine Buprenorphine-3-glucuronide 9–76
Buprenorphine TD CYP3A4
Codeine CYP2D6 Y Morphine
Norcodeine 48
Fentanyl TD CYP3A4 Y None Norfentanyl
Heroin (diacetyl morphine) Glucuronidation via UGT2B7 Y Morphine
Normorphine 24–72
Hydrocodone CYP2D6 Y Hydromorphone Norhydrocodone 20–25
Hydromorphone Glucuronidation via UGT2B7 N Hydromorphone-3-glucuronide Minor metabolites 48–96
Levorphanol Glucironidation via UGT2B7 N Levorphanol-3-glucuronide None
Meperidine CYP3A4
Y Normeperidine Meperidinic acid 15–20
Methadone CYP3A4
Y None 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
Morphine Glucuronidation via UGT2B7 N Hydromorphone
Morphone-3-G glucuronide
Morphone-6-G glucuronide
Normorphine 48–72
Oxycodone CYP3A4
Y Noroxycodone
None 48–96
Oxymorphone Glucironidation via UGT2B7 N 6-Hydroxy-oxymorphone Oxymorphone-3-glucuronide

Abbreviations: CYP, cytochrome P450; PGT, pharmacogenetics; TD, transdermal; TM, transmucosal; UGT2B7, uridine diphosphate glucuronosyltransferase 2B7.

Prescription Drug Monitoring Program

State prescription drug monitoring programs are vital tools developed to assist with combatting prescription drug abuse, doctor shopping, and diversion. Unfortunately, prescribers have encountered several barriers with using these programs, which has prompted states to consider implementing legal mandates to access and use of these programs.37, 38, and 39 These can provide a powerful tool for clinicians and should be routinely used in practice.

High-risk patients and special populations

High-Dose Opioids and the Morphine-Equivalent Dose

According to the American Pain Society and the International Association for the Study of Pain, chronic pain is defined as “daily or near-daily use of opioids for at least 90 days, often indefinitely” and “pain that persists beyond normal tissue healing time, which is assumed to be 3 months.”18 and 40 High-dose opioid therapy is defined as more than 200 mg of oral morphine or opioid equivalent per day.17 and 18 In addition, a 120-mg dose threshold and greater was recommended by the Centers for Disease Control and Prevention to seek pain specialty consultation owing to the increased risk of opioid-related overdoses.1

Extended-Release or Long-Acting Opioids

“Improper use of any opioid can result in serious side effects including overdose and death, and this risk can be greater with ER/LA opioid analgesics.”41 The FDA recommends that extended-release/long-acting opioid analgesics should only be prescribed by clinicians who are experienced in the use of opioids for the management of pain and it is their responsibility to ensure safe and effective use of these potent drug products (see Table 5).41 Clinicians should be aware that by FDA guidelines, extended-release/long-acting opioid analgesic formulations and doses are only “indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate,” as defined in the product labeling.41


Opioids such as methadone, levorphanol, tapentadol, and tramadol may offer superiority for neuropathic pain syndromes.42 However, when using these unique opioids in conjunction with antiretroviral therapy, methadone and tramadol may be especially problematic with respect to its CYP450 drug interactions that can result in decreased efficacy and increased toxicity.42 and 43 Careful consideration for patients actively being treated for hepatitis C is in order owing to potential dangerous drug interaction risks associated with p-glycoprotein inhibitors like telaprevir or boceprevir used concomitantly with methadone or morphine.44 For this reason, levorphanol or tapentadol may be the best options because both avoid CYP450 metabolisms and neither has proven problematic with p-glycoprotein.45

Pharmacogenetics in Pain Management

Genetic variability to opioid analgesics in chronic pain management can be complex and involves various genes and phenotypes.46 Several studied genes have been identified that can alter the perception of pain, affect analgesic activity and drug metabolism, and increase risk for toxicity when polymorphisms occur. These important variations and their applicability are outlined in Table 9.

Table 9 Pharmacogenetics in pain management source: Data from Refs.46, 74, 76, and 77

Site of Activity Genes of Interest Function
Cytochrome P450 (CYP) CYP2D6 Involved in the metabolism of several opioids analgesics such as codeine to morphine, oxycodone to oxymorphone, tramadol to O-desmethyltramadol, and hydrocodone to hydromorphone
P-glycoprotein (P-gp) ABCB1/MDR1 Decreased P-gp expression and activity can affect opioid concentrations and increase patient’s risk for toxicity
Catechol-O-methyltransferase (COMT) enzyme COMT Val158Met variant May produce an increase of dopaminergic stimulation owing to dysfunctional COMT activity, upregulating expression of MORs, resulting in increased morphine efficacy
Mu opioid receptor (MOR) OPRM1 Codes for the expression of MOR higher binding affinity of β-endorphin to the opioid-μ receptor
Kappa opioid receptor (KOR) melanocortin 1 receptor (MC1R) Associated with sex-specific increased analgesic response via the KOR

Abbreviations: ABCB1, ATP-binding cassette, sub-family B, member 1; MDR1, multidrug resistance protein 1.

Discontinuation of Therapy

Whenever opioid risks outweigh benefits and functional improvement is limited, adjustments to the treatment plan must be made and may include discontinuation of opioid therapy. Patient individualized goals are established at the outset of the opioid trial, throughout therapy, and progress toward all of these goals requires close and ongoing monitoring. When patients fail to achieve the desired outcomes, opioid therapy should be discontinued. In situations where there are severe, unmanageable adverse effects, misuse or abuse of opioids, or significant nonadherence to the treatment plan, the risks of continuing opioid therapy outweigh the benefits.17

If opioids are being tapered owing to aberrant behaviors or safety concerns, a more rapid opioid taper schedule is indicated. For less urgent reasons, a taper can be completed over the course of weeks to months. Typically, the goal in designing a taper is to minimize the potential for opioid withdrawal and maximize the patient’s comfort during the taper. The Veteran’s Administration/Department of Defense (VA/DoD) Clinical Practice Guidelines for COT recommend tapering by 20% to 50% per week of the original dose for nonaddicted patients.17 Other suggestions for opioid taper include reduction by 10% each day, reduction by 20% every 3 to 5 days, or reduction by 25% each week.47 The VA/DoD practice guidelines indicate that 20% of the previous day’s dose is required to prevent withdrawal symptoms.17

Opioid Reversal: Naloxone

Risks for opioid overdose exist outside of the substance abuse population, some of which include high-daily MED, age, gender, concomitant use of benzodiazepines and/or alcohol with or without other sedative–hypnotics, chronic lung disease, chronic kidney and/or liver impairment, sleep apnea, and accidental exposure to young children in the home.48, 49, and 50 Patients on lower doses of opioids (eg, 20 MED/d)6 and even those on COT for several years remain at risk for opioid overdose as their coprescribed medications and medical status changes.

During an opioid overdose, basic life support is provided and naloxone, a mu-opioid receptor antagonist, is administered to reverse opioid-induced respiratory depression. Possible routes of administration include subcutaneous, intramuscular (traditional or by autoinjector), intravenous, or intranasally. Naloxone administration, routes of administration, advantages, and disadvantages are outlined in Table 10.

Table 10 Naloxone source: Data from Naloxone Kits and Naloxone Autoinjectors: recommendations for Issuing Naloxone Kits and Naloxone Autoinjectors for the VA Overdose Education and Naloxone Distribution (OEND) Program. Washington, DC: Veterans Affairs Pharmacy Benefits Management, Medical Advisory Panel and VISN Pharmacist Executives in collaboration with the VA OEND National Support and Development Work Group, Veterans Health Administration, Department of Veterans Affairs; 2015; and Naloxone [package insert]. Lake Forest, IL: Hospira, Inc; 2007.

Route Dose and Administration Time to “Response” Advantages Disadvantages Approved for In-home Use?
IN naloxone Spray 1 mg in 1 mL in each nostril using atomizer device (each syringe contains 2 mg in 2 mL).
May repeat dose in 3–5 min if no response.
Dose may be repeated if apnea or hypopnea recurs.
Mean 4.2 ± 2.7 min; median 3 min.
Range 2–13 min.
Decreases risk of bloodborne virus transmission.
Decreases risk of needlestick injuries.
Obviates need for needle disposal.
Easy access to nares.
May be preferred by people with an aversion to needles or injections.
May have lower bioavailability vs IM route.
Similar or slower onset vs IM route.
Similar or slightly lower responder rates vs IM naloxone.
May be more likely to require supplemental doses of naloxone.
Not manufactured in a formulation for this route (the injectable form is aerosolized).
Nasal abnormalities and prior intranasal drug use may reduce effectiveness.
Involves more steps to assemble.
Inconvenience and bulkiness of carrying the product and necessary supplies.
IM naloxone Inject 0.4 mg in 1 mL IM (using vials), through clothing if necessary.
May repeat dose in 3–5 min if no response.
Dose may be repeated if apnea or hypopnea recurs.
Mean 6–8 min. Formulation manufactured for this route.
Similar responder rates vs IV naloxone in prehospital settings.
Fewer steps to assemble.
Simpler for some people (eg, those familiar with using injections).
Risk of bloodborne virus transmission (eg, HIV, HBV, HCV).
Risk of needlestick injuries.
Risk of injury from improper injection technique.
Proper use requires training.
Requires adequate muscle mass.
Inconvenience and bulkiness of carrying the product and necessary supplies.
Autoinjector naloxone Administer 0.4 mg in 0.4 mL into the anterolateral aspect of the thigh, through clothing if necessary.
May repeat doses every 2–3 min (each carton contains 2 doses).
Mean 6–8 min (IM).
Mean 9.6 ± 4.6 min (subcutaneous or SC).
Pocket-size; convenient; portable.
Shown to be relatively easy to use even without prior training (adults took on average about 60 s [range, 30–160]) to administer simulated injections.
Retractable needle may reduce accidental needle sticks and risk of bloodborne virus transmission.
The needle is not seen before, during, or after the injection; this may be a desirable feature for persons who have an aversion to the sight of needles.
Discourages reuse of the device by injection drug users.
The autoinjector cannot be opened by hand and modified; opening it by using a tool is difficult and renders it nonfunctional.
If the voice instructions fail, persons with poor vision may have difficulty reading the label instructions because of the small font size.
Restriction to IM or SC route of administration.
Needle length in children <1 y old; the skin should be pinched to prevent the needle from contacting bone. If the needle strikes bone, the needle may be broken or damaged and delivery of drug may be obstructed.
Lack of field testing by OEND programs.
IV naloxone May be diluted for IV infusion in 0.9% sodium chloride injection or 5% dextrose injection (2 mg naloxone in 500 mL solution provides concentration of 0.004 mg/mL).
Initial dose of 0.4 mg to 2 mg and may be repeated at 2–3 min intervals.
If no response after administration of 10 mg of naloxone, diagnosis should be questioned.
Within 2 min. Rate of administration can be titrated to the patient’s response.
More rapid onset of action compared with IM or SC routes.
May be more effective in the setting of ER or LA opioid formulations.
Administered in a hospital setting.
Requires IV access.
Mixture should be used within 24 h.

Abbreviations: ER, extended release; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IM, intramuscular; IN, intranasal; LA, long acting; OEND, Overdose Education and Naloxone Distribution; SC, subcutaneous.

Note: Naloxone administration in the home using a rescue kit does not preclude the need to activate the emergency response system (calling “911”) or perform the “ABCs” (airway, breathing, circulation) of emergency response while waiting for help to arrive.

Use in Obstetrics, Gynecology, and Neonatology

The use of buprenorphine versus methadone during gestation, delivery, post partum, and in the neonate has historic and emerging new evidence suggesting that buprenorphine is the safer, more practical alternative for opioid-dependent mothers and neonatal abstinence syndrome treatment.51, 52, 53, 54, 55, and 56 This exciting therapeutic area requires more evidence-based research, requires experienced clinical teams, and is beyond the scope of this article.


COT is a viable analgesic option for the management of chronic pain in select patient populations to help improve function and overall quality of life. Clinicians should optimize nonpharmacologic and nonopioid modalities for pain management where possible before considering COT. The risks and benefits must be discussed thoroughly and documented with the patient, including a realistic understanding of expectations for functional improvement and ongoing level of pain. This is a conversation that should be revisited periodically while patients are prescribed COT and the risks versus benefits should be continuously evaluated by the treating clinician and treatment team. Universal precautions should be observed in accordance with current published clinical practice guidelines, including regular and intermittent examination with urine testing. It is crucial that clinicians stress the importance of communication, routine monitoring for efficacy and safety, appropriate and timely follow-up, and patient engagement with the treatment plan and goals while receiving COT.


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a Pain Management, Minneapolis VA Health Care System, Minneapolis, MN, USA

b Pain Management, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA

c Pain & Palliative Care, Stratton VA Medical Center, Albany, NY, USA

d Pain Management, PGY2 Pain & Palliative Care Pharmacy Residency, Stratton VA Medical Center, Albany, NY, USA

e Western New England University College of Pharmacy, Springfield, MA, USA

f Albany College of Pharmacy & Health Sciences, Albany, NY, USA

g University of Connecticut School of Pharmacy, Storrs, CT, USA

Corresponding author. PO Box 214, Delmar, NY 12054-0214.

Conflicts of Interest: This commentary is the sole opinion of the authors and does not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies mentioned or specific drugs discussed. It was not prepared as part of official government duties for authors Brooks, Kominek, Pham, or Fudin. Dr J. Fudin is an expert legal advisor and on the speakers’ bureau for Millennium Laboratories, Inc. He is on speakers’ bureaus for Kaléo Pharma and Astra Zeneca. He is a consultant to Zogenix, Astra Zeneca, Millennium Health LLC, and to Practical Pain Management in the development of the online Opioid Calculator. He is founder and owner of Remitigate LLC. Dr J. Fudin's participation does not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies listed.