Course #95140 • 15 Hours/Credits
|A)||a disproven concept that some drugs are inherently "addictive."|
|B)||diminished or lost analgesia and dose titration to regain pain relief.|
|C)||peripheral and central sensitization without detectable peripheral origin.|
|D)||an iatrogenic condition whereby patients display drug-seeking behaviors mimicking opioid use disorder but driven by intense need for pain relief.|
Pseudoaddiction: An iatrogenic condition whereby patients display drug-seeking behaviors mimicking opioid use disorder but driven by intense need for pain relief. Resolves with adequate pain control .
|A)||increased opioid prescribing.|
|B)||a change in reporting standards.|
|C)||an influx of illicit morphine from Mexico.|
|D)||increased patient misuse and diversion of opioids.|
This perception is in part the result of CDC data indicating 18,893 prescription opioid overdose deaths in 2014, up sharply from 16,300 deaths in 2013 . However, the 2014 increase was the result of a change in reporting standards. Starting in early 2014, the CDC began classifying all fentanyl overdoses as prescription opioid analgesic deaths, because laboratory tests were unable to distinguish clandestine from pharmaceutical fentanyl . Also in 2014, there was an influx of fentanyl into the illicit opioid market, largely from Mexico and often sold as heroin or oxycodone. This resulted in a significant increase in fentanyl overdose deaths.
In 2011, benzodiazepines were associated with 31% of opioid analgesic fatalities, compared with 18.4% in 2004 . However, this 2011 figure may understate the true benzodiazepine contribution. In a study of 607,156 people 15 to 64 years of age, 84.5% of those prescribed opioids for pain who died of opioid analgesic overdose were co-prescribed benzodiazepines . In another study of more than 2 million North Carolina residents receiving one or more opioid analgesics, benzodiazepines were present in 61.4% who fatally overdosed. Benzodiazepines contribute to a significant number of opioid analgesic deaths, particularly with higher-dose opioid prescribing .
|D)||headache or migraine.|
The most common anatomic locations of pain in U.S. adults are the low back (28.1%), knee (19.5%), severe headache or migraine (16.1%), neck (15.1%), shoulder (9.0%), finger (7.6%), and hip (7.1%). The lifetime prevalence of spinal pain ranges from 54% to 80% . In patients with low back pain or neck pain, 25% to 60% report pain lasting longer than one year from onset; high pain and disability levels were found in 23% of patients with low back pain and 15% of patients with neck pain. Low back pain is linked to greatest declines in function and quality of life .
|A)||Chronic pain is the leading medical cause of suicide.|
|B)||Failure to manage pain has serious physical, but not psychosocial, consequences.|
|C)||Poorly controlled moderate-to-severe chronic pain has no impact on risk of death.|
|D)||The negative impact of chronic pain on quality of life is comparable to terminal cancer.|
Pain is a distressing sensory and emotional experience for the patient, imposing potentially life-altering physiologic, psychosocial, and quality of life alterations . The negative impact of chronic pain on quality of life is more severe than heart failure, renal failure, or major depression and comparable to terminal cancer [67,68].
Failure to manage pain has serious pathophysiologic consequences, including cardiovascular (hypertension, myocardial ischemia, cardiovascular collapse) and physiologic (appetite loss, failure to thrive, immune dysfunction, endocrine failure) consequences, suppression of physical activity leading to joint and muscle deterioration, chronic sleep disturbance, dementia, and premature death [2,13,69]. Among 6,940 primary care patients followed over 10 years, those with poorly controlled moderate-to-severe chronic pain had a 68% greater risk of death than those with cardiovascular disease and 49% greater risk than all other causes combined .
Psychosocial consequences of unmanaged pain can be severe, with adverse psychologic (impaired cognitive function, pathologic anxiety/depression, suicidal ideation, despair, hopelessness) and social/interpersonal (relationship disruption, loss of employment, financial difficulties) outcomes [2,13,71,72,73]. Chronic pain is second only to bipolar disorder as a medical cause of suicide [74,75,76].
The presence of maladaptive coping styles such as catastrophizing, kinesophobia (i.e., fear of movement), and somatization (i.e., emotional distress expressed through physical symptoms) predicts development of chronic pain . Craving is strongly associated with drug misuse in patients prescribed opioids for chronic pain, and pain catastrophizing is associated with craving even after controlling for demographic, psychologic, medical, and medication regimen variables. This underscores the importance of including psychologic interventions in the overall pain care .
|C)||major depressive disorder.|
|D)||post-traumatic stress disorder.|
Major depressive disorder is the single most important and prevalent chronic pain comorbidity. It is difficult to treat and renders pain control nearly impossible; anhedonia (i.e., inability to feel pleasure) is a frequent symptom [8,66]. Primary care patients with muscle pain, headache, or stomach pain complaints are 2.5 to 10 times more likely to have diagnosable panic disorder, generalized anxiety disorder, or major depressive disorder than those without pain. Patients whose pain level results in work interference show elevated risk of panic disorder and major depressive disorder. Conversely, major depressive disorder increases the odds of muscle pain complaints, headache, stomach pain, and pain interference with daily functioning. These results reflect the complex interaction between pain and medical/psychiatric comorbidities .
At greatest risk of unrelieved pain from stigma and bias are children, the elderly, racial and ethnic minorities, active duty or military veterans, and those with cancer, HIV, or sickle cell disease. Pain undertreatment in black patients is especially widespread, from prevalent misperceptions that this group has higher pain tolerance and is more likely to abuse their opioid prescription .
|A)||mu, kappa, and delta.|
|B)||alpha, beta, and delta.|
|C)||mu, theta, and omega.|
|D)||mu, sigma, and gamma.|
Naturally occurring opioid compounds are produced in plants (e.g., opium, morphine) and in the body (the endogenous opioids) . Endogenous opioids are peptides that bind opioid receptors, function as neurotransmitters, and help regulate analgesia, hormone secretion, thermoregulation, and cardiovascular function. The three primary endogenous opioid peptide families are the endorphins, enkephalins, and dynorphins, and the three primary opioid receptor types are mu, kappa, and delta [105,106]. A quick overview of this complex pain modulation system is helpful in understanding how opioid analgesics work.
|A)||the presence of inflammation.|
|B)||plasma concentration of the drug.|
|C)||concentration of the drug on the mu receptor.|
|D)||the intrinsic properties of the opioid (e.g., lipid solubility).|
The greatest factor that contributes to opioid analgesia is concentration of the drug on the mu receptor, which can be altered by pharmacokinetic processes that influence plasma concentration of the opioid by impacting its absorption, distribution, metabolism, or excretion. Intrinsic properties of the opioid, such as lipid solubility, also contribute to opioid receptor concentration .
Raw opium contains numerous alkaloids, but only morphine, codeine, thebaine, and papaverine have an identified use in medicine. Because the synthesis of morphine is difficult, the opium poppy plant remains the primary source of morphine . Thebaine is a minor constituent of opium that chemically resembles morphine and codeine but produces a stimulant, rather than calming, effect. Thebaine is not used medicinally but is converted into oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, and buprenorphine .
OPIOID ANALGESIC CLASSIFICATION SCHEMES
Morphine (Roxanol, MS Contin, Avinza, Kadian, MorphaBond, Embeda) was first isolated from raw opium in 1803 and introduced as an analgesic in the United States in 1830. Hypodermic syringes were introduced in the mid-19th century, making morphine available for parenteral use with improved analgesic, sedative, and antitussive properties [124,125]. Morphine is the prototypical opioid and remains one of the most effective drugs for alleviating severe pain, remarkable given its clinical use spanning almost two centuries. The World Health Organization has designated morphine as a drug of choice for moderate-to-severe pain .
|A)||It has a bioavailability of more than 90%.|
|B)||It is 100 times more potent than morphine.|
|C)||It should not be administered subcutaneously.|
|D)||Its high water solubility permits very concentrated formulations.|
Hydromorphone (Dilaudid, Exalgo) is a semi-synthetic hydrogenated ketone of morphine with primary activity as a mu receptor agonist. It has roughly five to seven times the potency of morphine, with similar effects but possibly less sedation and greater euphoria . Hydromorphone can be administered by parenteral, IV, rectal, and oral routes and is considered the best opioid for SC administration. Oral hydromorphone has a bioavailability of 50% and plasma elimination half-life of 2.5 hours . Its high water solubility permits very concentrated formulations. A meta-analysis found significantly better analgesia with hydromorphone than morphine for acute pain, without significant differences in adverse effects .
|A)||has high abuse potential.|
|B)||is not associated with constipation.|
|C)||is only available for oral administration.|
|D)||is less likely to result in respiratory depression than morphine.|
Codeine can be used orally or IM for mild-to-moderate pain but has very limited use in severe pain. Codeine is also used as an antitussive and antidiarrheal. Codeine produces minimal euphoria, has low abuse liability, is less sedating, and is less likely to result in respiratory depression than morphine. Constipation is a common side effect. Because commercially available codeine is combined with acetaminophen or acetylsalicylic acid (ASA), the dosage should be monitored to ensure daily safe limits are not surpassed . Codeine has an analgesic ceiling, with no additional analgesic benefit from doses greater than 60 mg .
|A)||It produces less dysphoria.|
|B)||It is a partial, rather than a full, agonist.|
|C)||It has greater plasma than CNS concentrations.|
|D)||It is transported more slowly through the blood- brain barrier.|
Oxycodone is available in SA and ER oral formulations. Oxycodone SA has a half-life of approximately two to four hours and a bioavailability of 50% to 60%. The overall clinical effects of oxycodone reflect primary mu receptor activity, with analgesia, respiratory depression, euphoria, and abuse liability comparable to other mu agonists. Oxycodone differs from morphine by producing less dysphoria and by more rapid transport through the blood-brain barrier, resulting in greater CNS than plasma concentrations, the reverse of morphine .
|A)||for short-term analgesia of postsurgical pain.|
|B)||to block the effects of heroin and other opioid drugs.|
|C)||for the treatment of patients with opioid-induced hyperalgesia.|
|D)||to obtain pain relief in patients with chronic pain refractory to other treatments.|
High-dose methadone can block the effects of heroin and other opioid drugs by diminishing reward and reinforcement effects, and this has been the primary use of methadone in the United States over the last five decades. In the late 1990s, methadone entered clinical use as an analgesic .
|A)||2 to 4 hours|
|C)||up to 24 hours|
|D)||more than 48 hours|
Transmucosal immediate-release fentanyl formulations are approved by the FDA for use in breakthrough pain. Transdermal fentanyl was developed to circumvent unsuitability for oral use and is indicated for continuous sustained-release analgesia in the treatment of chronic pain . With initial use, the 6- to 12-hour lag time from application to onset of action requires the use of short-acting opioids for analgesic coverage and for breakthrough pain; morphine, tapentadol, or oxycodone are preferred. Steady state is usually achieved in three to six days. With patch removal, a subcutaneous reservoir remains, and up to 24 hours is usually needed for drug clearance [16,115].
Tramadol has lower abuse potential than other opioids but is associated with the significant adverse drug reactions of serotonin syndrome and seizures. Dosage should not exceed 400 mg/day due to the seizure risk, and even doses less than 400 mg/day can increase seizure potential in patients with epilepsy or risk factors for seizure . Seizure risk is elevated by concurrent use of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), cyclobenzaprine and other tricyclic compounds, other opioids, neuroleptics, and certain other drugs. Tramadol should not be used within 14 days of monoamine oxidase inhibitors (MAOIs), as this increases risk of seizures or serotonin syndrome .
Butorphanol is a mu opioid receptor antagonist and kappa opioid receptor agonist, and the opioid receptor affinity ratio of 1:25:4 for mu, kappa, and delta receptors, respectively, indicates greater delta than mu opioid receptor affinity . With parenteral administration, butorphanol has analgesic potency five to eight times greater than morphine. It has a rapid onset, with peak analgesia within 1 hour, plasma half-life of 2 to 3 hours, and elimination half-life of 4.5 to 5 hours. With oral administration, bioavailability is 17% that of a comparable IV dose. The intranasal formulation is commonly used in the treatment of migraine headache. The IV formulation is effective in moderate-to-severe pain and is typically used for postoperative pain and pain control during labor. With analgesia mediated by kappa and not mu receptor activation, butorphanol may be an effective analgesic option in patients with history of opioid use disorder . At a dose of 10 mg IM, butorphanol induces respiratory depression similar to a comparable morphine dose, but the level of depression does not increase with dose escalation due to the ceiling effect [159,160].
|C)||alcohol and opioid use disorders.|
|D)||All of the above|
In addition to opioid-induced constipation, opioid antagonists are FDA-approved for the treatment of alcohol and opioid use disorder (naltrexone 50–100 mg/day oral) and opioid overdose (naloxone 0.4–1.0 mg/dose IV or IM). In pain medicine, the dose ranges of naltrexone and naloxone are substantially lower. Of the two, naltrexone is much more widely used, and published pain medicine studies have used dose ranges of 1–5 mg (termed "low-dose") or <1 mg in microgram amounts (termed "ultra-low-dose") . For example, case studies have reported dramatic improvement in refractory pain with intrathecal administration of an opioid agonist combined with ultra-low-dose naloxone in the low nanogram range .
Most opioids, including morphine, oxycodone, hydromorphone, methadone, tramadol, tapentadol, fentanyl, sufentanil, buprenorphine, and codeine, possess high GI permeability and are completely absorbed from the GI tract following oral administration. However, fentanyl and buprenorphine, due to extensive hepatic first-pass metabolism, have very low oral bioavailability, rendering their oral use ineffective . (This differs from sublingual and buccal administration.)
|C)||St. John's wort|
Among opioid analgesics, CYP metabolism occurs by either the CYP206 or CYP3A4 pathway. The propensity for drug interactions is higher for opioids metabolized by CYP3A4, and this is the pathway by which most opioids in general use are metabolized [103,130,174]. Thus, drugs and other compounds that inhibit or induce CYP3A4 activity contribute to opioid adverse drug interactions. CYP3A4 inducers include rifampin, St. John's wort, troglitazone, and phenytoin; inhibitors include telithromycin, itraconazole, ketoconazole, miconazole, voriconazole, ritonavir, lopinavir, erythromycin, clarithromycin, and grapefruit juice. Adverse opioid-drug interactions from enzyme induction mostly involve CYP3A4 and, to a lesser extent, CYP2B6.
|A)||Shortened QTc interval|
|B)||Longer half-life than analgesia|
|C)||Lack of metabolism by CYP isoenzymes|
|D)||None of the above|
The complex pharmacology of methadone makes the drug hazardous when prescribed without extensive knowledge and experience. With a half-life (15 to 60 or more hours) longer than analgesia (4 to 8 hours), risks of accumulation and fatal overdose are increased, as when analgesia wears off and pain returns followed by re-dosing. Other factors that contribute to the risk of toxicity include :
Metabolism by numerous CYP isoenzymes, which elevates the risks of drug-drug interactions, delayed clearance, and increased serum concentrations of methadone to fatal levels
Prolongation of QTc interval, which may increase risk of life-threatening cardiac arrhythmias
P-glycoprotein (P-gp) substrate, elevating risk of drug interactions that accelerate methadone blood-brain barrier penetration
Methadone requires metabolism by at least five fully active CYP450 isoenzymes for its efficient breakdown and elimination. This makes it the opioid with greatest susceptibility to adverse drug interaction. Concurrent use of common medications such as benzodiazepines, antihistamines, antidepressants, and antiviral agents may result in inhibition of CYP450-mediated breakdown and clearance of methadone, increased plasma levels, and serious risk of oversedation and suppression of CNS respiratory centers .
|A)||establish treatment goals.|
|B)||consider how therapy will be discontinued if benefits do not outweigh risks.|
|C)||discuss patient and clinical responsibilities for managing therapy with the patient.|
|D)||All of the above|
Nonpharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain . Clinicians should consider opioid therapy only if expected benefits for pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate. Before starting opioid therapy for chronic pain, clinicians should, for all patients:
Establish treatment goals for pain and function.
Consider how therapy will be discontinued if benefits do not outweigh risks.
Continue opioid therapy only if clinically meaningful improvement in pain and function outweighs safety risks.
|A)||any opioid is prescribed at any dose.|
|B)||benzodiazepines are used concurrently with opioids.|
|C)||lower opioid dosages are prescribed (<50 mg MED/day).|
|D)||a patient has no history of opioid use (i.e., is opioid-naïve).|
Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms and incorporate into the management plan strategies to mitigate risk. Offering a naloxone kit should be considered when factors are present that increase opioid overdose risk, including:
History of overdose or substance use disorder
Higher opioid dosages (≥50 mg MED/day)
Concurrent benzodiazepine use
|A)||be presented as a time-limited trial.|
|B)||should be initiated at the highest tolerable dose.|
|C)||not be continued beyond the trial period regardless of benefits.|
|D)||begin with an extended-release/long-acting (ER/LA) formulation.|
Opioid therapy should be presented as a time-limited trial to evaluate pain, functioning and quality of life benefits, and adverse effects. Opioid-naïve patients should be started at the lowest dose, with titration to effect. In general, it is best to begin opioid therapy with an SA formulation and rotate to an ER/LA formulation, if indicated. Opioid therapy may be continued beyond the trial period after careful evaluation of benefits versus adverse effects and/or potential risks [20,182].
Although there are few class-wide contraindications for the use of mu opioid agonist analgesics, contraindications to ER/LA opioid prescribing exist by formulation and specific opioid . Contraindications to any use of opioid analgesics include :
Acute psychiatric instability
Uncontrolled suicide risk
Active, untreated alcohol or substance use disorder
True opioid allergy
Current medication use with potential for dangerous drug interactions
Prolonged QTc (≥500 ms) (with methadone)
Codeine (in pediatric patients)
|A)||prolongs the drug half-life.|
|B)||increases first-pass metabolism.|
|C)||reduces distribution of water-soluble drugs.|
|D)||results in increased opioid-related GI side effects.|
CLINICAL RELEVANCE OF AGE-RELATED PHYSIOLOGIC CHANGES
|Reduced GI function and delayed absorption||
|Reduced hepatic metabolism||
|Reduced renal excretion||Accumulation and prolonged effects of drugs and metabolites|
|Decreased receptor density, increased receptor affinity||Increased sensitivity to therapeutic and side effects|
|D)||Cytokine gene promoters|
Morphine, oxycodone, hydromorphone, and fentanyl have comparable population level efficacy but widely variable analgesic efficacy and tolerability at the individual level; the same drug/dose may be toxic in some patients and have little or no effect in others. For example, up to 30% of patients with cancer-related pain show poor morphine response from inadequate analgesia or intolerability, but most achieve pain control with alternative opioids. Genetic factors account for at least 25% of this response variation to opioids [99,192]. Genetic variations with greatest confirmation and relevance to opioid kinetics and dynamics include CYP450 enzymes, P-gp transporter ABCB1, catechol-O-methyltransferase (COMT) enzymes, and cytokine gene promoters (Table 4).
With suspected CYP450 polymorphism or in patients requiring several non-opioid medications that interact with CYP2D6, CYP3A4, CYP2C9, or CYP2C19 isoenzymes, prescribers should select an opioid with a metabolic pathway that mostly bypasses the CYP450 system. These include hydromorphone, oxymorphone, levorphanol, and tapentadol. Oxymorphone is perhaps the safest, as it lacks CYP450 metabolism and has no active or toxic metabolites.
SC, IV, rectal, transdermal, transmucosal, or intraspinal routes of administration are used when patients cannot take oral medications. IM administration is contraindicated, as it lacks any pharmacokinetic advantage and is painful. SC delivery is relatively easy, effective, and safe. IV is useful when pain is severe or pain levels have acutely increased. Transdermal fentanyl preparations are effective for patients unable to take oral medications who have stable pain control. Transmucosal fentanyl is similar to IV administration in its rapid onset and is used for acute breakthrough pain. The intraspinal route of administration is either epidural or intrathecal. This is the most invasive mode of opioid delivery and requires specialist involvement, but it confers advantages in patients with significant dose-limiting adverse effects, because systemic exposure is circumvented. Intraspinal delivery allows adjuvant medications to be directly administered to the spinal cord .
|A)||treatment of severe acute pain in an inpatient setting.|
|B)||use only in cases of failed treatment with another class of drugs.|
|C)||patients with severe chronic pain who are at high risk for opioid misuse and/or diversion.|
|D)||pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate.|
The CDC recommends initiation of opioid therapy with an SA formulation, but no further discussion or guidance is given . The FDA states that the use of ER/LA opioids is indicated for pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate . To ensure that benefits outweigh risks and to reduce risks while preserving access to opioid analgesics, the FDA has implemented risk evaluation and mitigation strategies (REMS) for ER/LA opioid analgesics. The ER/LA REMS program consists of a core prescriber education component that stresses safe product use, patient safety information, and guidance on patient counseling. This REMS-compliant education is strongly encouraged but not mandatory .
|C)||problems related to medication cost.|
|D)||All of the above|
Opioid rotation exploits these pharmacologic differences and incomplete cross-tolerance among opioids and involves switching the current opioid or route of administration to improve efficiency and safety [173,223]. Opioid rotation can be an effective strategy for overcoming analgesic failure, side effect intolerance, problematic drug interactions, opioid-induced hyperalgesia, change in clinical status, problems related to medication cost and/or availability, need for a different route of administration, and patient preference [173,223,225].
Clinicians should anticipate and monitor common opioid side effects and discuss these effects with patients before opioids are initiated. Many side effects are time-limited and lessen or resolve following stable dosing. Tolerance to opioid effects tends to develop at different rates, ranked below in descending order :
Euphoria (most rapid)
Constipation (late, if ever)
GI symptoms are among the most common side effects reported with opioid use. Providers should be alert to the character and extent of patient distress resulting from these effects and the potential for non-adherence to therapy. Opioid-induced bowel dysfunction takes various forms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation. Opioid activation of mu and kappa receptors in the neuronal plexus of the gut wall increases intestinal wall and sphincter resting tone and reduces biliary, pancreatic, and intestinal secretions. This results in dysrhythmic, non-propulsive contractions (bowel spasm), delayed passage and increased viscosity of intestinal contents, and the onset of constipation. Spasm and colic can also result from increased biliary tract tone [105,107].
Up to 91% of patients taking opioids experience constipation, the most common opioid-induced bowel dysfunction symptom. Opioid-induced constipation, often in combination with chronic nausea, can cause considerable distress, greatly diminished quality of life, and opioid discontinuation by as many as 33% of patients . Most patients require constipation management for the duration of opioid therapy because complete tolerance rarely develops .
|C)||Long-term opioid use|
|D)||Coingestion of any CNS respiratory depressant|
Therapeutic doses of morphine depress all phases of respiratory activity, including the breathing rate, minute volume, and tidal exchange. Respiratory depression results from decreased brainstem sensitivity to carbon dioxide build-up and is the primary lethal side effect of opioids . Patients are most vulnerable to respiratory depression in the first five days of opioid initiation, especially the first 24 hours. Risk factors include obesity, sleep apnea, and pre-existing respiratory disorders (e.g., acute asthma, respiratory infection). Respiratory depression is antagonized by pain, and patients with substantial pain relief following uncontrolled pain are also at risk. Coingestion of any CNS respiratory depressant, including benzodiazepines or alcohol, elevates the risk of pronounced respiratory depression and fatality [104,254].
Tramadol is the only opioid analgesic associated with serotonin syndrome. SSRIs inhibit CYP2D6, which decreases tramadol analgesic efficacy. Concurrent use of tramadol and paroxetine or venlafaxine has been reported to cause serotonin syndrome [256,257]. Genetic susceptibility to serotonin syndrome has been identified and is influenced by a patient's ability to produce different ratios of positive and negative tramadol enantiomers .