The preceding modules have established the receptor pharmacology, pharmacokinetics, drug-specific profiles, and adverse effect management of opioid analgesics. This final module translates that mechanistic foundation into clinical practice. The decision to prescribe an opioid — and equally, the decision of how to prescribe it, for how long, in what dose, and with what monitoring — requires integration of analgesic evidence with knowledge of specific clinical contexts: acute pain, cancer pain, palliative care, and the contested domain of chronic non-cancer pain. It also requires particular attention to populations with altered pharmacokinetics or heightened vulnerability to opioid harm, including the elderly, patients with renal or hepatic impairment, pregnant women, and neonates affected by intrauterine opioid exposure. This module also covers non-analgesic clinical applications of opioids, pharmacological treatment of opioid use disorder, and the framework of opioid stewardship that is now an expected component of responsible opioid prescribing in all clinical settings.
Acute pain management with opioids is most appropriate when pain is severe, time-limited, and not adequately controlled by non-opioid analgesics.1 The general principle of multimodal analgesia, combining agents with different mechanisms of action to achieve adequate pain control at lower individual doses of each agent, is now standard across acute care settings and has substantially reduced the total opioid doses required for postoperative and procedural pain management. Multimodal regimens typically combine acetaminophen, an NSAID or COX-2 inhibitor (when not contraindicated), a regional anesthetic technique when feasible (peripheral nerve block, neuraxial analgesia), and an opioid as a component rather than the primary or sole agent. Gabapentinoids (gabapentin, pregabalin) have been incorporated into multimodal regimens for their opioid-sparing effect, though their role has been moderated by accumulating evidence of harm from sedation and respiratory depression, particularly when combined with opioids in patients with obstructive sleep apnea (OSA).1
In the perioperative setting, the route and formulation of opioid delivery are chosen based on the degree of pain, the ability to take oral medications, and the duration of effect needed. Patient-controlled analgesia (PCA), which consists of IV opioid delivery systems in which the patient self-administers demand doses within programmed limits, is standard of care for moderate-to-severe postoperative pain requiring parenteral opioids. PCA systems are safer than nurse-administered bolus opioid dosing because the inherent self-limiting design (a patient who becomes too sedated to press the button cannot administer additional doses) provides a biological safety mechanism absent with externally administered dosing. Basal rate infusions on IV PCA should be used only in opioid-tolerant patients, as they eliminate the self-limiting safety mechanism and have been associated with increased respiratory depression events in opioid-naive patients.1
Epidural and intrathecal opioid delivery produce profound segmental analgesia at doses far lower than required systemically, with correspondingly reduced systemic adverse effects; their role in thoracic, abdominal, and lower extremity surgery is well-established, though the specialized monitoring requirements for delayed respiratory depression, particularly for intrathecal morphine, require institutional protocols. For acute pain in the emergency department or urgent care context, the shift toward non-opioid analgesics (IV acetaminophen, ketorolac, IV lidocaine, ketamine at sub-dissociative doses) has reduced opioid use for conditions such as renal colic, musculoskeletal pain, and migraine without compromising patient-reported pain control.1 When opioids are used in the emergency setting, short-acting formulations are preferred; prescriptions for home use following an ED visit should be limited in quantity (typically 3–7 days maximum) with specific guidance about tapering and the importance of returning unused medications.
Opioids retain a specific clinical role in several acute pain contexts that deserve individual mention.
In obstetrical labor pain management, IV opioids (fentanyl, remifentanil PCA, morphine, meperidine though now less commonly used) provide variable analgesia that is substantially inferior to epidural analgesia; all cross the placenta and can produce neonatal respiratory depression, requiring neonatal monitoring and naloxone availability at delivery.2 Remifentanil PCA has gained acceptance in patients who decline or are unable to receive neuraxial analgesia, offering rapid titration but requiring 1:1 nursing monitoring due to the risk of maternal apnea.
In renal and biliary colic, parenteral NSAIDs (ketorolac) and opioids are both effective for acute pain control; morphine, hydromorphone, or fentanyl IV are appropriate opioid choices. In acute pulmonary edema associated with severe left ventricular failure, low-dose IV morphine was historically used as an adjunct to reduce preload through venodilatation and to relieve the distress of dyspnea through central opioid receptors; however, a large registry study and subsequent analyses associated IV morphine use in acute heart failure with higher mortality, and its routine use in this setting is no longer recommended by most guidelines.1 For acute trauma pain in pre-hospital and emergency settings, parenteral opioids remain essential, with fentanyl and morphine most commonly used; intranasal fentanyl is increasingly recognized as an effective and needle-free alternative in pediatric trauma.
The World Health Organization analgesic ladder, first published in 1986 and subsequently revised, remains the conceptual framework for cancer pain management.3 The ladder organizes analgesic therapy in three steps based on pain severity: Step 1 (mild pain): non-opioid analgesics (acetaminophen, NSAIDs) with or without adjuvants; Step 2 (mild-to-moderate pain): weak opioids or low doses of strong opioids added to non-opioid therapy; Step 3 (moderate-to-severe pain): strong opioids at doses titrated to effect, combined with non-opioids and adjuvants as appropriate. The original ladder has been modified to add a fourth level, namely interventional pain management techniques (neuraxial drug delivery, nerve blocks, neuromodulation), for pain refractory to systemic pharmacotherapy. The guiding principles of the WHO ladder remain: by mouth (oral route preferred when possible), by the clock (around-the-clock dosing for persistent pain rather than as-needed dosing that allows pain to return before the next dose), by the ladder (titrate stepwise), and for the individual (doses should be determined by patient response, not by a fixed ceiling).3
Opioid titration for cancer pain follows the principle of prescribing around-the-clock (ATC) extended-release or long-acting opioid for baseline pain control, supplemented by immediate-release breakthrough doses for breakthrough pain. The conventional formula for breakthrough dosing is 10–15% of the total 24-hour opioid dose administered every 1–4 hours as needed; if a patient consistently requires more than three to four breakthrough doses per day, the total ATC dose should be increased by adding the total breakthrough dose used in 24 hours to the baseline regimen.3 There is no fixed ceiling dose for opioid analgesia in cancer pain management; the appropriate dose is the lowest dose that provides adequate pain relief with acceptable adverse effects. Dose escalation should be guided by careful reassessment of pain response, adverse effects, and functional status. The WHO ladder recommends reassessment at 24–48 hours after any dose change for patients on escalating doses.
Parenteral opioid routes become necessary when patients can no longer take oral medications due to dysphagia, intractable nausea, bowel obstruction, or decreased level of consciousness. Continuous subcutaneous infusion (CSCI) via a syringe driver is a practical and effective route in the home hospice setting that avoids repeated venipuncture; morphine, hydromorphone, oxymorphone, and fentanyl are all compatible with CSCI delivery, though fentanyl is incompatible with some diluents and requires concentration adjustment.3 Intravenous infusion is used in inpatient settings. Neuraxial opioid delivery, including intrathecal drug delivery systems (implanted pumps), is an option for patients with refractory pain or intolerable systemic adverse effects, providing profound analgesia at a fraction of the systemic dose. Specific pain syndromes in cancer patients may require adjuvant analgesics in addition to opioids: bone pain from metastases responds to NSAIDs, corticosteroids, and bisphosphonates in addition to opioids; neuropathic pain from tumor infiltration or chemotherapy-induced peripheral neuropathy responds to gabapentinoids, SNRIs (duloxetine, venlafaxine), and tricyclic antidepressants; visceral pain from bowel obstruction is managed with a combination of opioids, anticholinergics (to reduce secretions and cramping), and octreotide (to reduce GI secretion and motility).3
Pain from spinal cord compression is a palliative emergency requiring immediate high-dose corticosteroids (dexamethasone) and emergency radiation or neurosurgical consultation, with opioids used for immediate pain relief while definitive treatment is arranged.
The role of opioids in chronic non-cancer pain (CNCP), defined as pain persisting beyond the expected period of healing and not related to cancer, is substantially more contested and evidence-limited than their role in acute or cancer pain.4 The recognition of this limitation has come from accumulating evidence that opioids prescribed for CNCP often provide modest and diminishing pain relief over time due to tolerance, while carrying substantial long-term risks including opioid use disorder, overdose, endocrine dysfunction, immune suppression, and in some patients paradoxical opioid-induced hyperalgesia. The 2022 CDC Clinical Practice Guideline for Prescribing Opioids for Pain provides the most current evidence-based framework for opioid use in CNCP and supersedes the 2016 CDC guideline.4 The current evidence base for opioids in CNCP shows that opioids provide statistically significant but often clinically modest short-term pain relief in conditions such as osteoarthritis, musculoskeletal pain, and neuropathic pain; evidence for long-term (beyond 12 weeks) clinically meaningful improvement in pain and function is weak and limited by high attrition rates in trials and lack of controlled data at the doses used clinically.4
Non-opioid therapies, including NSAIDs, topical analgesics, gabapentinoids, SNRIs, tricyclic antidepressants, physical therapy, cognitive-behavioral therapy, and interventional procedures, often provide comparable or superior long-term outcomes in CNCP with more favorable risk profiles and should be the primary therapeutic approach. Opioids may be appropriate for selected patients with CNCP who have not achieved adequate pain relief and functional improvement from non-opioid therapy, when the potential benefits are expected to outweigh the risks in that individual patient.4
The 2022 CDC guideline recommendations address several key aspects of opioid prescribing in CNCP: opioids should not be considered first-line or routine therapy for CNCP; when opioids are used, the lowest effective dose should be prescribed; doses at or above 50 morphine milligram equivalents (MME) per day are associated with substantially increased overdose risk compared to lower doses; doses at or above 90 MME/day are associated with very high overdose risk and should be avoided or prescribed only with careful individualized reassessment; combination of opioids and benzodiazepines is particularly high-risk and should be avoided when possible; and patients initiated on opioids for CNCP should be evaluated within 1–4 weeks and at a minimum every 3 months thereafter for ongoing benefit, adverse effects, and signs of opioid-related harm.4
The 2022 guideline emphasizes a non-coercive approach to dose reduction for patients already on long-term high-dose opioid therapy: abrupt discontinuation or rapid tapers imposed without patient collaboration are associated with harm including undertreated pain, withdrawal, and increased risk of illicit opioid use and overdose.4 Risk stratification tools such as the Opioid Risk Tool (ORT) and the DIRE (Diagnosis, Intractability, Risk, Efficacy) score help identify patients at higher risk of opioid misuse before initiating opioid therapy, though no tool is sufficiently accurate to be used as a sole basis for prescribing or withholding opioids. Universal precautions in opioid prescribing, applied to all patients, not only those identified as high risk, include documented assessment of pain, function, and risk; written opioid treatment agreements; urine drug screening at baseline and periodically during therapy; Prescription Drug Monitoring Program (PDMP) review at initiation and at regular intervals; and reassessment of the appropriateness of opioid therapy at every encounter.4
Opioids have several well-established clinical applications beyond analgesia that exploit specific aspects of their receptor pharmacology. Antitussive therapy with subanalgesic doses of codeine or hydrocodone acts on μ and κ receptors in the brainstem cough center to raise the cough threshold; this is useful in the management of non-productive cough from viral upper respiratory infections, postinfectious cough, and malignancy-related cough in palliative care.5 Dextromethorphan, a morphinan derivative with N-methyl-D-aspartate (NMDA) receptor antagonist and sigma receptor activity but minimal analgesic opioid receptor activity at standard doses, is widely used as a non-scheduled antitussive. At high doses, dextromethorphan can produce dissociative effects and is subject to misuse, particularly among adolescents (colloquially termed "robotripping").
Antidiarrheal applications of opioids exploit μ receptor-mediated reduction in intestinal propulsive motility and increased intestinal water absorption. Diphenoxylate (combined with subtherapeutic atropine as Lomotil) and loperamide (Imodium) are phenylpiperidine derivatives with peripherally restricted activity at gut mu-opioid receptor (MOR); loperamide in particular has very low CNS penetration at recommended doses due to its P-glycoprotein-mediated efflux at the blood-brain barrier and achieves effective antidiarrheal effect without central opioid effects.5 At very high doses, far above recommended dosing, loperamide can saturate P-glycoprotein efflux and produce opioid CNS effects and dangerous cardiac QRS complex (QRS) prolongation through sodium channel blockade; high-dose loperamide misuse as a cheap opioid substitute has been reported in people with opioid use disorder and has resulted in fatalities, prompting the FDA to impose purchase quantity limits on over-the-counter loperamide.5
Opioids are used in anesthesia for their synergistic sedative and analgesic properties in balanced anesthetic techniques, for suppression of the neuroendocrine and hemodynamic stress response to surgical stimuli (particularly relevant in cardiac surgery), and in the management of post-anesthesia shivering, a specific indication for meperidine at a single low dose, that exploits its kappa receptor and NMDA receptor activity on thermoregulatory circuits, producing rapid termination of shivering at doses that do not produce meaningful analgesia.5
Three FDA-approved medications for opioid use disorder (MOUD) are available in the United States: methadone, buprenorphine (with or without naloxone), and extended-release naltrexone.6 Decades of clinical evidence from randomized trials and large real-world cohort studies consistently demonstrate that MOUD reduces mortality from overdose by 50–70%, decreases illicit opioid use, reduces criminal activity, and improves social functioning. Despite this evidence base, MOUD remains dramatically underutilized in the United States; fewer than 20% of individuals with opioid use disorder (OUD) receive any of the three approved medications. Stigma, prescriber training gaps, regulatory barriers, cost, and geographic access all contribute to this treatment gap. Methadone for OUD is dispensed daily in federally licensed opioid treatment programs (OTPs, also called methadone clinics) under Drug Enforcement Administration (DEA) Schedule II regulations.
The daily witnessed ingestion model, in which patients attend the clinic each day to receive their dose, was designed to prevent diversion of methadone into the illicit supply and to provide structure and clinical monitoring; take-home doses are progressively permitted as patients demonstrate stability.6 Methadone's long half-life (8–80 hours) suppresses opioid withdrawal symptoms for 24 hours and blocks the euphoric effect of superimposed opioids, making it effective for patients with high opioid tolerance. Initial doses in OTPs are conservatively limited (typically 30 mg or less on the first day) to avoid overdose in patients whose opioid tolerance may be lower than reported, with careful upward titration over weeks. The opioid treatment program (OTP) model is highly effective for patients who can access it but is a significant barrier to treatment for patients in rural areas, those with transportation limitations, and those with work or childcare constraints, a particular access issue for primary care-oriented, rural-serving practice settings.
Buprenorphine for OUD has been the most significant development in MOUD access in recent decades. Following the removal of the Drug Addiction Treatment Act (DATA) 2000 X-waiver prescribing requirement by the Consolidated Appropriations Act of 2023, any DEA-licensed provider can now prescribe buprenorphine for OUD in the United States, a change expected to substantially increase access in primary care, internal medicine, emergency medicine, and rural practice settings.6 Buprenorphine is used as Suboxone (buprenorphine/naloxone sublingual film or tablet); the naloxone component is inactive when taken sublingually but precipitates withdrawal if the tablet is dissolved and injected, providing a degree of abuse deterrence, or as Subutex (buprenorphine alone, used in specific situations including pregnancy).
Extended-release injectable buprenorphine (Sublocade, monthly SC injection) and buprenorphine subdermal implants (Probuphine, 6-month implants) provide continuous drug delivery that eliminates daily dosing adherence challenges and eliminates the risk of diversion. Buprenorphine induction requires that the patient be in moderate opioid withdrawal (Clinical Opiate Withdrawal Scale (COWS) score ≥8–12) before the first dose to minimize the risk of precipitated withdrawal; extended induction protocols using very low initial doses (micro-dosing or Bernese method) allow initiation without requiring prior abstinence and are increasingly used in clinical settings, particularly for patients transitioning from fentanyl (which may require longer periods to clear from receptors due to fat sequestration).6
Extended-release injectable naltrexone (Vivitrol) requires complete opioid detoxification before initiation but provides 30 days of opioid receptor blockade per injection and does not produce physical dependence. It is an effective choice for patients who prefer a non-opioid treatment approach, for patients who complete opioid detoxification in medical, correctional, or residential settings and want protection against relapse, and for motivated patients who have concerns about opioid agonist medications. Its critical limitation, namely the high overdose risk during any period of naltrexone discontinuation due to loss of opioid tolerance, requires thorough patient counseling and planning for what to do if a dose is missed.6 Current evidence suggests that buprenorphine and methadone have somewhat higher retention rates and stronger evidence for mortality reduction compared to naltrexone, though comparisons are complicated by the challenge of completing detoxification before naltrexone initiation, which creates selection bias in trials.
Elderly patients present particular opioid prescribing challenges. Age-related physiological changes alter opioid pharmacokinetics: decreased renal clearance reduces metabolite clearance (increasing M3G, M6G, and H3G accumulation); reduced hepatic blood flow slows first-pass metabolism and increases oral bioavailability of high-extraction drugs; decreased plasma albumin and α1-acid glycoprotein can alter free drug fraction; decreased body fat reduces the volume of distribution of lipophilic drugs such as fentanyl; and decreased respiratory reserve and central chemoreceptor sensitivity increase vulnerability to respiratory depression.7 Pharmacodynamically, the elderly demonstrate increased CNS sensitivity to opioids at any given plasma concentration, likely due to reduced neuronal density, changes in receptor expression, and decreased neurotransmitter reserve.
The clinical consequence is that elderly patients typically require 25–50% lower opioid doses to achieve equivalent analgesia compared to younger adults, and dose titration should proceed more slowly with more frequent reassessment. The clinical aphorism "start low, go slow" is particularly appropriate in this population. Meperidine is absolutely contraindicated in elderly patients due to normeperidine accumulation and seizure risk; codeine should be avoided due to CYP2D6 (cytochrome P450 2D6) variability and metabolite accumulation risk; propoxyphene was withdrawn from the US market in 2010 partly due to its cardiac toxicity risk in the elderly.7 Sedation, cognitive impairment, falls, and delirium are disproportionately common opioid adverse effects in elderly patients and should be specifically monitored.
The Beers Criteria (American Geriatrics Society) identify meperidine, non-COX-selective NSAIDs, and muscle relaxants as particularly high-risk medications in elderly patients and inform prescribing decisions in this population.
Patients with hepatic impairment require careful opioid selection because hepatic metabolism is the primary elimination route for virtually all opioids. The impact of hepatic impairment on opioid pharmacokinetics is complex and varies by drug and severity of impairment: decreased first-pass metabolism increases oral bioavailability of high-extraction opioids such as morphine, producing higher than expected plasma concentrations after oral dosing; reduced hepatic synthesis of albumin and α1-acid glycoprotein increases the free fraction of highly protein-bound opioids such as methadone; and reduced hepatic CYP enzyme activity prolongs the half-lives of CYP-metabolized agents including fentanyl, alfentanil, and methadone.7 Practically, patients with Child-Pugh Class B or C hepatic impairment should be started at lower opioid doses with extended dosing intervals and carefully monitored for signs of accumulation. Buprenorphine and morphine (at reduced doses) are relatively better tolerated in hepatic impairment than agents primarily dependent on CYP metabolism; methadone requires particular caution due to its CYP3A4 (cytochrome P450 3A4) dependence, prolonged variable half-life, and the unpredictability of CYP enzyme activity in cirrhosis. Tramadol is poorly tolerated in hepatic impairment due to impaired conversion to O-desmethyltramadol (M1) and reduced clearance of the parent compound.
Pregnancy and opioid prescribing require balancing maternal pain management needs with fetal and neonatal risk. All opioids cross the placenta readily due to their lipophilicity; fetal opioid exposure produces dose-dependent fetal effects including CNS depression, respiratory depression at delivery, and with prolonged exposure, neonatal opioid withdrawal syndrome (NOWS), also formerly termed neonatal abstinence syndrome.8 Short-term opioid use for acute pain in pregnancy carries a different risk profile than chronic opioid exposure; patients requiring opioids for acute severe pain (e.g., trauma, post-surgical) should receive appropriate treatment, as undertreated maternal pain also carries fetal risks through stress hormone activation.
For women with opioid use disorder who become pregnant, opioid agonist maintenance therapy with either buprenorphine or methadone is the standard of care, strongly preferred over medically supervised withdrawal (detoxification) during pregnancy because withdrawal during pregnancy substantially increases the risk of relapse to illicit opioid use, which carries far greater risks to the fetus than maintenance therapy.8 Buprenorphine is increasingly preferred over methadone for pregnant patients with opioid use disorder (OUD) because it is associated with a milder and shorter NOWS course, has a better cardiovascular safety profile, and can be prescribed in office-based settings rather than requiring daily opioid treatment program (OTP) attendance.
Neonates born to mothers receiving opioid agonist maintenance therapy should be monitored for NOWS in a setting capable of managing it, using validated scoring tools (Finnegan Neonatal Abstinence Scoring System or the Eat, Sleep, Console approach); the majority of NOWS cases can be managed with non-pharmacological measures (skin-to-skin contact, feeding support, reduced stimulation), with pharmacological treatment (oral morphine or methadone) reserved for infants with scores meeting threshold criteria.8 Maternal opioid maintenance therapy is not a contraindication to breastfeeding in the absence of other contraindications (HIV infection, illicit drug use, certain medications incompatible with breastfeeding); small amounts of buprenorphine and methadone are transferred in breast milk, and breastfeeding by mothers on stable maintenance therapy is encouraged due to its benefits for maternal-infant bonding and potential attenuation of NOWS severity.8
Opioid rotation, defined as switching from one opioid to another, is a practical skill essential for clinicians managing patients with complex pain. As reviewed in Module 2, the key principle is that incomplete cross-tolerance between opioids requires a dose reduction of 25–50% from the calculated equianalgesic dose when initiating the new opioid; this reduction prevents over-dosing because tolerance to one opioid does not fully protect against the effects of a different agent.9 Several practical principles govern safe opioid rotation in clinical settings. First, calculate the current total 24-hour opioid dose accurately, including all scheduled and as-needed (breakthrough) doses used; underestimating the current dose leads to an inadequate conversion that leaves the patient in pain, while overestimating leads to dangerous over-conversion.
Second, select the conversion ratio appropriate to the specific opioid pair and the conversion direction; equianalgesic tables differ across references, and the ratios differ depending on direction of conversion (e.g., the morphine-to-methadone ratio is strongly dose-dependent and increases at higher morphine doses). Third, apply the 25–50% incomplete cross-tolerance reduction to the calculated equianalgesic dose before prescribing; the size of the reduction should be calibrated to the clinical urgency: 25% reduction when rotating primarily due to inadequate analgesia, 50% when rotating due to toxicity or intolerance. Fourth, establish breakthrough dosing at 10–15% of the new total daily dose, available every 1–4 hours as needed. Fifth, reassess the patient within 24–48 hours of the rotation to evaluate pain control and tolerance of the new agent.9
Opioid rotation to or from methadone requires particular caution because of methadone's non-linear equianalgesic ratio with morphine, its prolonged variable half-life, and the risk of delayed toxicity as drug accumulates over 3–5 days; rotations involving methadone should ideally involve clinicians experienced with this agent.
Opioid stewardship is the coordinated application of evidence-based practices to optimize opioid prescribing, reducing unnecessary opioid use, minimizing opioid-related harm, and ensuring access to appropriate opioid therapy for patients who need it.4 It is analogous in principle to antimicrobial stewardship and encompasses prescriber education, clinical decision support, monitoring systems, and policy-level interventions. Prescription Drug Monitoring Programs (PDMPs) are state-run electronic databases that record controlled substance prescriptions dispensed by pharmacies; prescribers are required in most states to query the prescription drug monitoring program (PDMP) before prescribing opioids (thresholds and requirements vary by state). PDMP review serves to identify patients receiving opioids from multiple prescribers simultaneously (concurrent prescribing), to detect high-dose opioid prescribing, and to identify co-prescribing of dangerous drug combinations (particularly opioid-benzodiazepine combinations).4 In practice, PDMP review should be performed at opioid initiation and at clinically appropriate intervals during ongoing therapy; it is not a substitute for clinical assessment but provides an important safety check.
Urine drug screening (UDS) in opioid therapy serves two purposes: confirmation that the prescribed opioid is present (adherence), and detection of unprescribed opioids, illicit substances, and other medications that may affect safety.4 Immunoassay screening tests provide rapid results but are subject to both false positives (cross-reactivity with non-opioid substances) and false negatives (particularly for semi-synthetic opioids that are not detected by standard opioid immunoassays); confirmatory gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) is required when specific drug identification matters clinically. Prescribers should be familiar with the limitations of UDS before making prescribing decisions based solely on screening results.
The co-prescribing of naloxone to patients on opioid therapy, providing a rescue kit for use by the patient, family members, or bystanders in the event of accidental opioid overdose, is a harm reduction intervention with strong evidence for reducing opioid overdose mortality at the population level.4 The 2022 CDC guideline recommends that naloxone be considered for all patients receiving opioids for pain, particularly those receiving higher doses, those with concurrent CNS depressant prescriptions, and those with risk factors for respiratory compromise. Prescribers should provide specific instructions to patients and caregivers on how to recognize opioid overdose, how to administer naloxone, and the importance of calling emergency services. Naloxone co-prescribing in primary care and other outpatient opioid prescribing settings has been shown to increase naloxone availability in households at risk without adversely affecting patient satisfaction or opioid prescribing behavior.4
Opioid tapering, defined as the gradual reduction of opioid dose with the goal of discontinuation or dose reduction, may be appropriate for patients who no longer demonstrate ongoing benefit from opioid therapy, patients who have developed significant opioid-related adverse effects or risks, and patients who voluntarily choose to reduce their opioid use. The 2022 CDC guideline emphasizes that tapering should be patient-centered, collaborative, and undertaken at a pace that is tolerable for the individual patient.4 The previously recommended 10% per week reduction pace has been replaced by a more individualized approach; some patients with long-standing high-dose opioid therapy may require months to years of gradual tapering. Abrupt discontinuation of opioids is almost never appropriate except in the context of acute safety emergencies; it produces severe withdrawal, undertreated pain, and in some patients precipitates relapse to illicit opioid use. Adjunctive pharmacotherapy for withdrawal symptoms during tapering, including clonidine for autonomic symptoms, loperamide for diarrhea, and antiemetics, can improve tolerability.4
Patients receiving long-term opioid therapy for chronic pain present one of the most challenging perioperative analgesic management problems in clinical medicine. The degree of opioid tolerance they have developed means that standard postoperative analgesic protocols, which are designed for opioid-naive patients, will produce inadequate pain control, while the clinician unfamiliar with this population may interpret the patient's pain and opioid requests through the lens of drug-seeking rather than undertreated pain. Meticulous preoperative assessment, a clearly communicated perioperative opioid plan, and close postoperative monitoring are the foundations of safe care in this group.11 Preoperative assessment of the opioid-tolerant surgical patient must establish the patient's current total daily opioid dose in morphine milligram equivalents (MME), the specific opioids and formulations being taken, the indication for chronic opioid therapy, the presence of concurrent CNS depressants, and the patient's prior surgical and analgesic history.
In general, the patient's baseline opioid regimen should be continued through the perioperative period; abrupt opioid discontinuation in the perioperative setting produces opioid withdrawal syndrome, characterized by autonomic instability, tachycardia, hypertension, diaphoresis, and severe anxiety, that is both distressing and physiologically disruptive, complicating hemodynamic management and masking important vital sign changes.11 For patients on extended-release oral opioids who cannot take oral medications postoperatively, conversion to an equianalgesic parenteral regimen at the calculated 24-hour dose (with appropriate cross-tolerance reduction) maintains physiological stability. The basal opioid requirement established preoperatively should be delivered as scheduled background dosing; additional opioid above the baseline is then required for surgical pain superimposed on the pre-existing tolerance state.
Postoperative opioid requirements in tolerant patients are systematically higher than in opioid-naive patients, often substantially so. A patient receiving 100 MME per day for chronic pain who undergoes major abdominal surgery will require at minimum their baseline 100 MME/day continued, plus additional opioid for surgical pain, which may range from 50 to 200% above baseline in the first 48–72 hours postoperatively. IV patient-controlled analgesia (PCA) in opioid-tolerant patients requires a basal infusion rate (which is contraindicated in opioid-naive patients due to respiratory depression risk) to cover the baseline requirement, plus demand doses for breakthrough surgical pain; both the basal rate and the demand dose need to be calibrated to the patient's demonstrated tolerance level.11 Failure to provide a basal PCA infusion in tolerant patients results in inadequate analgesia and often patient frustration that is incorrectly interpreted as aberrant behavior.
Multimodal analgesic strategies, including regional nerve blocks, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), ketamine infusions, and dexmedetomidine, are particularly valuable in opioid-tolerant patients because they reduce the total postoperative opioid requirement through opioid-sparing effects at complementary analgesic targets, and they do not require dose adjustments for tolerance.11 Sub-dissociative ketamine infusions deserve specific emphasis in this context. Ketamine at low doses (0.1–0.5 mg/kg/hr IV) acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, reducing central sensitization in the spinal cord and attenuating opioid tolerance mechanisms. In opioid-tolerant surgical patients, perioperative ketamine infusions have been shown in multiple randomized controlled trials to reduce postoperative opioid consumption, decrease pain scores, and reduce opioid-induced hyperalgesia (OIH) in the early postoperative period, a particularly important benefit given that rapid opioid fluctuations in the perioperative period can trigger or worsen OIH in tolerant patients.11 Dexmedetomidine, an alpha-2 adrenergic agonist, provides sedation, anxiolysis, and opioid-sparing analgesia without respiratory depression at approved doses; it has also been used to manage sympathetic manifestations of opioid withdrawal in the perioperative period.
Patients maintained on buprenorphine for opioid use disorder (OUD) who require surgery present a specific management challenge. The historical practice of discontinuing buprenorphine 24–72 hours before surgery, intended to allow full agonists to compete for receptors postoperatively, is now generally discouraged by evidence and clinical guidelines.11 Discontinuing buprenorphine preoperatively exposes patients to relapse risk, produces withdrawal discomfort in the perioperative period, and does not reliably solve the postoperative analgesia problem because buprenorphine's very high mu-opioid receptor (MOR) affinity means residual receptor occupancy persists for 24–72 hours after the last dose anyway. The preferred approach is buprenorphine continuation throughout the perioperative period, with multimodal analgesia (regional blocks, acetaminophen, NSAIDs, ketamine) covering surgical pain; if full agonist opioids are genuinely required for breakthrough pain, doses substantially higher than standard (to overcome competitive receptor occupancy) may be needed, and this should be anticipated in the postoperative orders with anesthesia and pain team co-management.
High-dose buprenorphine itself (doses of 24–32 mg/day) provides substantial analgesia through high-level MOR partial agonism and may be the most practical analgesic for moderate perioperative pain in patients on buprenorphine maintenance.11
Several acute clinical scenarios involving opioid use carry pharmacological and clinical decision-making complexity that warrants explicit coverage beyond the general principles addressed in Section 1. Sickle Cell Vaso-Occlusive Crisis. Acute vaso-occlusive crisis (VOC) in sickle cell disease (SCD) is one of the most common reasons for emergency department (ED) visits and hospital admissions in this population, and opioid analgesia is the cornerstone of acute VOC management.12 The pain of VOC is severe, nociceptive in character, and arises from ischemia and infarction of bone marrow and other tissues due to sickling-induced microvascular occlusion. Many SCD patients receive long-term opioid therapy for chronic SCD-related pain and are therefore opioid-tolerant when presenting with acute VOC, requiring the higher dosing approach outlined in Section 9.
Current guidelines from the American Society of Hematology (ASH) recommend rapid assessment and early initiation of opioid analgesia in VOC: parenteral opioids (IV morphine or IV hydromorphone) should be administered within 30 minutes of triage, and pain should be reassessed and rescue doses given within 30 minutes of the initial dose if inadequate.12 Fixed-dose protocols or weight-based dosing using IV hydromorphone (0.3–0.5 mg IV every 15–30 minutes until pain is controlled, then transitioning to scheduled dosing) are recommended over as-needed dosing protocols that introduce delays. The opioid of choice for most SCD patients in acute VOC is hydromorphone or morphine; meperidine is contraindicated in SCD due to the seizure risk from normeperidine accumulation in a population that may receive multiple doses over prolonged admissions. Patient-controlled analgesia (PCA) with a basal infusion adjusted to the patient's prior opioid use is appropriate for hospitalized patients requiring ongoing parenteral opioid therapy. Non-opioid adjuncts including IV ketorolac and oral NSAIDs, acetaminophen, and hydration reduce opioid requirements and should be used as components of a multimodal regimen.12
A common management error in VOC is undertreating acute pain due to unfounded concerns about addiction in SCD patients; the physical dependence that accompanies chronic opioid therapy in SCD is a pharmacological inevitability, not evidence of opioid use disorder (OUD), and should not be conflated with addiction when making dosing decisions.
Opioid Analgesics in Acute Myocardial Infarction. IV morphine has been used for decades in acute myocardial infarction (MI) for both analgesia and as an adjunct to reduce preload through venodilation, with the assumption that pain relief would reduce the adrenergic stress response and its adverse hemodynamic consequences. Evidence from the CRUSADE registry and subsequent analyses challenged this practice, showing an association between IV morphine use in non-ST-elevation MI (NSTEMI) and higher in-hospital mortality, even after adjustment for confounders. This finding is mechanistically plausible: morphine delays gastric emptying and reduces oral drug absorption, including that of orally administered P2Y12 inhibitors (clopidogrel, ticagrelor), impairing antiplatelet loading at a time-critical moment. Morphine also reduces platelet inhibition by P2Y12 inhibitors in pharmacokinetic and pharmacodynamic studies. Current guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) reflect this evidence by downgrading IV morphine from a recommended to a cautiously used intervention in acute MI, reserving it for patients with refractory pain or acute pulmonary edema complicating MI in whom the analgesia benefit outweighs the risk.
In ST-elevation MI (STEMI), where the same concerns apply, alternatives to IV morphine for pain management include IV fentanyl (which has less gastric emptying delay and shorter duration of action) and reassessment of pain after reperfusion therapy, which often substantially reduces ischemic pain.
Rib Fracture Pain Management. Multiple rib fractures, typically defined as three or more contiguous fractures, produce a pain syndrome that creates a dangerous physiological vicious cycle: severe pain inhibits deep breathing and coughing, leading to retained secretions, atelectasis, pneumonia, and respiratory failure.13 Opioid analgesia for rib fractures must be balanced against opioids' own respiratory depressant effects; aggressive opioid dosing sufficient to permit normal breathing may also impair respiratory drive, particularly in elderly patients and those with baseline pulmonary disease. Multimodal analgesia with regional techniques is the standard of care for significant rib fractures: thoracic epidural analgesia or erector spinae plane (ESP) block or serratus anterior plane (SAP) block provides superior pain control compared to systemic opioids alone, allows lower systemic opioid doses, and preserves respiratory function more effectively.13
When regional analgesia is used, systemic opioids serve as a complement rather than a primary analgesic, and doses can be substantially reduced from what would be required for systemic therapy alone. IV ketamine infusion as an opioid-sparing adjunct is particularly valuable in rib fracture patients because it maintains respiratory drive while reducing opioid requirements. In patients who cannot receive regional analgesia, IV opioid PCA with acetaminophen and NSAIDs (when not contraindicated) represents the practical alternative; the clinical target is analgesia sufficient to permit incentive spirometry to at least 50% of predicted inspiratory volume. Pulmonary complications from inadequately treated rib fracture pain, including pneumonia, empyema, and acute respiratory distress syndrome (ARDS), substantially worsen outcomes and mortality, making aggressive early multimodal analgesia a patient-safety imperative rather than simply a comfort measure.13
Abuse-deterrent formulations (ADFs) of opioid analgesics represent a pharmacological and regulatory strategy to reduce opioid misuse without eliminating therapeutic access to opioids for patients with legitimate pain.11 The US Food and Drug Administration (FDA) has established a framework for evaluating and labeling ADFs based on evidence that the formulation makes common abuse routes more difficult, less attractive, or less rewarding. ADFs do not prevent opioid abuse; they create physical, chemical, or pharmacological barriers to the routes of abuse most commonly associated with misuse, primarily crushing and intranasal insufflation or dissolving and IV injection, while preserving the intended oral bioavailability of the therapeutic product.
Physical and chemical barrier technologies are the most widely deployed ADF mechanism. These formulations use polymer matrices that resist crushing, breaking, or dissolution, producing a gel-like consistency when attempts are made to manipulate the tablet.
OxyContin OP (extended-release oxycodone) was reformulated in 2010 using a polyethylene oxide matrix that gels when wetted, substantially reducing the ability to crush the tablet for insufflation or dissolve it for injection.11 Epidemiological data following the 2010 OxyContin reformulation showed a reduction in intranasal and IV oxycodone abuse, though a compensatory increase in heroin use was observed in some populations, illustrating the concept of drug substitution, a phenomenon in which ADF adoption shifts abuse patterns toward other opioids rather than reducing total opioid abuse burden.
Other agents with approved physical barrier ADFs include extended-release hydrocodone (Hysingla ER, Zohydro ER with BeadTek technology), extended-release oxymorphone (Opana ER, reformulated in 2012), extended-release morphine (MorphaBond ER), and extended-release hydromorphone (Exalgo, which uses an osmotic release oral system (OROS) delivery mechanism that produces a hollow shell when tampered with).
Agonist-antagonist combination products represent a second ADF category. Suboxone (buprenorphine/naloxone) is the canonical example: naloxone is inactive when taken sublingually as intended, because sublingual naloxone undergoes extensive first-pass metabolism and produces negligible systemic antagonism. However, if the tablet or film is dissolved and injected, the naloxone is delivered intravenously at full bioavailability and precipitates acute withdrawal in opioid-dependent individuals, deterring parenteral abuse.11 The reformulated Talwin NX (pentazocine/naloxone) uses the same principle. Embeda (extended-release morphine with sequestered naltrexone) places naltrexone pellets in the core of morphine beads; when taken intact, the naltrexone is not released and has no systemic effect, but when the beads are crushed, naltrexone is released and blunts opioid effect. Aversion technologies incorporate substances that produce unpleasant effects when the formulation is abused by non-oral routes; niacin (producing flushing when injected), irritants, or bittering agents have been incorporated into some formulations, though FDA labeling as ADFs requires specific category evidence standards.
The clinical prescribing implications of ADFs are important for practicing clinicians to understand.11 FDA labeling as an ADF provides limited but meaningful reassurance that the formulation has demonstrated abuse-deterrent properties in laboratory and human abuse-liability studies, but it does not confer immunity from oral abuse; patients who simply take more tablets than prescribed circumvent all physical and chemical barrier technologies. ADFs carry a higher acquisition cost than non-ADF equivalents, which affects formulary decisions and patient access. The 2022 CDC guideline does not specifically recommend ADFs over non-ADF formulations, noting that the evidence that ADFs reduce population-level opioid-related harm remains limited, though individual patient-specific risk factors for abuse may justify preferential prescribing of an ADF product in selected patients. Clinicians should be aware that the FDA has required post-market epidemiological studies from ADF manufacturers to evaluate real-world impact on abuse patterns, and that this evidence base continues to evolve.
The clinical management of opioid withdrawal requires a structured approach built on accurate severity assessment, mechanism-based pharmacotherapy, and a clear understanding of whether the goal is symptomatic management of withdrawal (in a patient undergoing opioid tapering or detoxification) or induction onto opioid agonist maintenance therapy.10 The Clinical Opiate Withdrawal Scale (COWS) is the validated standard instrument for quantifying opioid withdrawal severity in clinical settings. It assesses eleven objective and subjective withdrawal signs and symptoms, including resting pulse rate, diaphoresis, restlessness, pupil size, bone/joint aches, runny nose or tearing, gastrointestinal (GI) upset, tremor, yawning, anxiety or irritability, and piloerection, each rated on an ordinal scale, with total scores classifying withdrawal as mild (5–12), moderate (13–24), moderate-severe (25–36), or severe (above 36).10 COWS scores are used both to monitor withdrawal progression and to determine readiness for buprenorphine induction; the standard threshold for initiating buprenorphine is a COWS score of 8–12 or greater, corresponding to at least moderate withdrawal. Using COWS to guide clinical decision-making reduces the risk of empirically treating patients who do not require pharmacological intervention and provides an objective basis for dose titration.
Pharmacological management of opioid withdrawal without opioid agonist therapy, termed symptomatic management, is appropriate for patients who have completed detoxification and are transitioning to extended-release naltrexone, or for patients undergoing voluntary opioid tapering who decline agonist maintenance. The cornerstone agent is clonidine, an alpha-2 adrenergic agonist that suppresses the noradrenergic hyperactivity arising from the locus coeruleus during opioid withdrawal.10 The locus coeruleus, the principal noradrenergic nucleus in the brain, is normally tonically inhibited by mu-opioid receptor (MOR) activation; opioid withdrawal removes this inhibition, producing the autonomic storm of withdrawal, characterized by tachycardia, hypertension, diaphoresis, piloerection, diarrhea, and anxiety, which is mediated by excess norepinephrine release centrally and peripherally. Clonidine at doses of 0.1–0.3 mg orally every 6–8 hours (maximum 1.2 mg/day, adjusted for blood pressure response) substantially reduces autonomic withdrawal symptoms within 1–2 hours of administration. It does not address insomnia, myalgia, or the subjective craving component of withdrawal, and its use is limited by hypotension and sedation. Blood pressure should be checked before each dose; clonidine should be held if systolic blood pressure falls below 90 mmHg.10
Lofexidine (Lucemyra), a selective alpha-2A adrenergic agonist approved by the FDA in 2018 specifically for management of opioid withdrawal symptoms in adults, is pharmacologically similar to clonidine but produces less hypotension due to greater alpha-2A selectivity and lower affinity for peripheral alpha-2B receptors that mediate the hypotensive effect. Lofexidine is administered at 0.54 mg (three 0.18 mg tablets) four times daily for up to 14 days with gradual dose tapering at discontinuation.10 It is the only FDA-approved non-opioid pharmacotherapy specifically indicated for opioid withdrawal. Adjunctive symptomatic pharmacotherapy includes loperamide for diarrhea and GI cramping (peripheral MOR agonist with no central opioid effect at standard doses), hydroxyzine or trazodone for insomnia, ibuprofen or acetaminophen for myalgia, and ondansetron for nausea and vomiting. This combination approach, using clonidine or lofexidine as the core agent with targeted adjuncts, can manage mild-to-moderate withdrawal symptoms sufficiently to permit detoxification completion in motivated patients in supported clinical settings.10
Opioid agonist-based withdrawal management uses buprenorphine or methadone to suppress withdrawal symptoms while simultaneously beginning the transition to maintenance therapy or facilitating a structured taper. Buprenorphine-based withdrawal management is preferred over methadone in most settings outside of opioid treatment programs (OTPs), because buprenorphine can be prescribed in office-based settings, has a more favorable safety profile, and provides a natural transition to long-term buprenorphine maintenance therapy if the patient chooses that option. As described in Section 5, buprenorphine induction requires a COWS score of at least 8–12 to minimize the risk of precipitated withdrawal. In the fentanyl era, standard induction protocols have required modification: because illicitly manufactured fentanyl (IMF) has extensive lipophilic tissue sequestration, patients using IMF may have lower COWS scores than their actual withdrawal state would predict, and premature buprenorphine administration risks precipitating a severe withdrawal reaction.
Low-dose buprenorphine induction (the Bernese method or micro-induction protocol) begins with very small sublingual doses (0.5–1 mg) that partially fill receptor sites without displacing sufficient fentanyl to precipitate withdrawal, with progressive dose escalation over 3–7 days until therapeutic doses are achieved.10 This approach allows induction without requiring a withdrawal period and is increasingly standard for patients transitioning from fentanyl. Management of withdrawal in hospitalized patients who were not knowingly opioid-dependent, including patients whose prescribed opioids were abruptly discontinued during hospitalization, patients in whom opioid-producing medications were stopped during an acute illness, and patients with unrecognized opioid use disorder (OUD) admitted for another indication, follows the same COWS-guided, mechanism-based approach, with the additional imperative to address the circumstances that led to withdrawal and to engage addiction medicine or substance use disorder consultation when OUD is identified.10
Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists. J Pain. 2016;17(2):131–157
doi:10.1016/j.jpain.2015.12.008Likis FE, Andrews JC, Collins MR, et al. Nitrous oxide for the management of labor pain: a systematic review. Anesth Analg. 2014;118(1):153–167
doi:10.1213/ANE.0b013e3182a7f73cWorld Health Organization. WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents. Geneva: WHO; 2018. ISBN 978-92-4-155039-0.
Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice guideline for prescribing opioids for pain — United States, 2022. MMWR Recomm Rep. 2022;71(3):1–95
doi:10.15585/mmwr.rr7103a1Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):S133–S153. PMID:18443637
Substance Abuse and Mental Health Services Administration. Medications for Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63. Rockville, MD: SAMHSA; 2021. Publication No. PEP21-02-01-002.
American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052–2081
doi:10.1111/jgs.18372Substance Abuse and Mental Health Services Administration. Clinical guidance for treating pregnant and parenting women with opioid use disorder and their infants. HHS Publication No. (SMA) 18-5054. Rockville, MD: SAMHSA; 2018.
Brant JM. Opioid equianalgesic conversion: the right dose. Clin J Oncol Nurs. 2001;5(4):163–165
doi:10.1188/01.CJON.163-165Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003;35(2):253–259doi:10.1080/02791072.2003.10400007
Coluzzi F, Bifulco F, Cuomo A, et al. The challenge of perioperative pain management in opioid-tolerant patients. Ther Clin Risk Manag. 2017;13:1163–1173
doi:10.2147/TCRM.S141332Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656–2701
doi:10.1182/bloodadvances.2020001851Galvagno SM Jr, Smith CE, Varon AJ, et al. Pain management for blunt thoracic trauma: a joint practice management guideline from the Eastern Association for the Surgery of Trauma and Trauma Anesthesiology Society. J Trauma Acute Care Surg. 2016;81(5):936–951
doi:10.1097/TA.0000000000001209